03838nas a2200829 4500008004100000022001400041245013700055210006900192260001300261300001100274490000600285520145100291653001001742653000901752653002201761653002801783653001901811653004001830653001101870653001501881653001701896653003401913653001101947653000901958653001601967653001301983653003601996653001602032100001902048700001602067700002002083700001702103700001902120700002402139700002002163700002002183700001802203700002202221700002202243700001802265700002002283700002202303700002302325700002202348700001902370700002102389700001902410700002302429700002602452700001802478700002002496700002302516700002202539700001802561700002402579700002102603700002302624700002802647700002402675700002202699700002002721700002102741700002102762700002102783700003002804700002802834700002302862700002302885700002102908710004302929856003602972 2009 eng d a1942-326800aAssociation of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.0 aAssociation of novel genetic Loci with circulating fibrinogen le c2009 Apr a125-330 v23 a
BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.
METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).
CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPedigree10aPolymorphism, Single Nucleotide10aYoung Adult1 aDehghan, Abbas1 aYang, Qiong1 aPeters, Annette1 aBasu, Saonli1 aBis, Joshua, C1 aRudnicka, Alicja, R1 aKavousi, Maryam1 aChen, Ming-Huei1 aBaumert, Jens1 aLowe, Gordon, D O1 aMcKnight, Barbara1 aTang, Weihong1 ade Maat, Moniek1 aLarson, Martin, G1 aEyhermendy, Susana1 aMcArdle, Wendy, L1 aLumley, Thomas1 aPankow, James, S1 aHofman, Albert1 aMassaro, Joseph, M1 aRivadeneira, Fernando1 aKolz, Melanie1 aTaylor, Kent, D1 aDuijn, Cornelia, M1 aKathiresan, Sekar1 aIllig, Thomas1 aAulchenko, Yurii, S1 aVolcik, Kelly, A1 aJohnson, Andrew, D1 aUitterlinden, André, G1 aTofler, Geoffrey, H1 aGieger, Christian1 aPsaty, Bruce, M1 aCouper, David, J1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aO'Donnell, Christopher, J1 aWitteman, Jacqueline, C1 aStrachan, David, P1 aSmith, Nicholas, L1 aFolsom, Aaron, R1 aWellcome Trust Case Control Consortium uhttps://chs-nhlbi.org/node/115303253nas a2200457 4500008004100000022001400041245017300055210006900228260001300297300001000310490000600320520189200326653001002218653000902228653001002237653001902247653001102266653003802277653003402315653001302349653001902362653001102381653000902392653002702401653001602428653001402444653002002458653001702478100002002495700003002515700002402545700002402569700002102593700002202614700002802636700002202664700003002686700002102716710002202737856003602759 2009 eng d a1942-326800aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts.0 aCohorts for Heart and Aging Research in Genomic Epidemiology CHA c2009 Feb a73-800 v23 aBACKGROUND: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.
CONCLUSIONS: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.
10aAdult10aAged10aAging10aCohort Studies10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHeart Diseases10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPhenotype10aResearch Design10aRisk Factors1 aPsaty, Bruce, M1 aO'Donnell, Christopher, J1 aGudnason, Vilmundur1 aLunetta, Kathryn, L1 aFolsom, Aaron, R1 aRotter, Jerome, I1 aUitterlinden, André, G1 aHarris, Tamara, B1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aCHARGE Consortium uhttps://chs-nhlbi.org/node/115205728nas a2201213 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520227000293653001002563653000902573653002202582653001002604653002802614653002102642653004002663653001102703653003402714653001302748653001602761653002102777653001102798653000902809653001602818653001502834653001402849653003602863653001702899653003402916653003102950100002702981700002203008700002103030700001903051700002103070700002203091700002303113700002203136700002303158700001903181700002303200700002003223700002203243700002203265700002203287700001903309700002403328700002003352700001803372700001803390700002303408700002103431700001903452700002603471700002203497700002403519700001803543700002003561700001503581700002703596700002703623700001703650700002303667700002103690700001803711700002103729700001703750700002003767700002003787700002303807700003003830700002303860700002303883700002103906700002503927700002603952700001703978700002203995700001804017700002104035700001904056700002404075700002804099700002204127700002004149700002004169700002004189700002004209700002304229700002204252700002204274700002104296700002404317700002204341700002804363700002404391700002004415700001904435700002404454856003604478 2009 eng d a1538-359800aGenetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.0 aGenetic variants associated with cardiac structure and function c2009 Jul 08 a168-780 v3023 aCONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.
OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.
DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.
MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.
RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).
CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aAorta10aCardiovascular Diseases10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHeart Ventricles10aHumans10aMale10aMiddle Aged10aOrgan Size10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aVentricular Dysfunction, Left10aVentricular Function, Left1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aFelix, Janine, F1 aLieb, Wolfgang1 aWild, Philipp, S1 aFelix, Stephan, B1 aWatzinger, Norbert1 aLarson, Martin, G1 aSmith, Nicholas, L1 aDehghan, Abbas1 aGrosshennig, Anika1 aSchillert, Arne1 aTeumer, Alexander1 aSchmidt, Reinhold1 aKathiresan, Sekar1 aLumley, Thomas1 aAulchenko, Yurii, S1 aKönig, Inke, R1 aZeller, Tanja1 aHomuth, Georg1 aStruchalin, Maksim1 aAragam, Jayashri1 aBis, Joshua, C1 aRivadeneira, Fernando1 aErdmann, Jeanette1 aSchnabel, Renate, B1 aDörr, Marcus1 aZweiker, Robert1 aLind, Lars1 aRodeheffer, Richard, J1 aGreiser, Karin, Halina1 aLevy, Daniel1 aHaritunians, Talin1 aDeckers, Jaap, W1 aStritzke, Jan1 aLackner, Karl, J1 aVölker, Uwe1 aIngelsson, Erik1 aKullo, Iftikhar1 aHaerting, Johannes1 aO'Donnell, Christopher, J1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aZiegler, Andreas1 aReffelmann, Thorsten1 aRedfield, Margaret, M1 aWerdan, Karl1 aMitchell, Gary, F1 aRice, Kenneth1 aArnett, Donna, K1 aHofman, Albert1 aGottdiener, John, S1 aUitterlinden, André, G1 aMeitinger, Thomas1 aBlettner, Maria1 aFriedrich, Nele1 aWang, Thomas, J1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aMunzel, Thomas, F1 aKroemer, Heyo, K1 aBenjamin, Emelia, J1 aRotter, Jerome, I1 aWitteman, Jacqueline, C1 aSchunkert, Heribert1 aSchmidt, Helena1 aVölzke, Henry1 aBlankenberg, Stefan uhttps://chs-nhlbi.org/node/110801824nas a2200241 4500008004100000022001400041245010400055210006900159260001300228300001100241490001400252520108000266653002801346653003801374653003401412653001101446653002801457653001701485100001301502700001601515700001501531856003601546 2009 eng d a1538-783600aGenome-wide association studies of cardiovascular risk factors: design, conduct and interpretation.0 aGenomewide association studies of cardiovascular risk factors de c2009 Jul a308-110 v7 Suppl 13 aRelying on known biology, candidate-gene studies have been only modestly successful in identifying genetic variants associated with cardiovascular risk factors. Genome-wide association (GWA) studies, in contrast, allow broad scans across millions of loci in search of unsuspected genetic associations with phenotypes. The large numbers of statistical tests in GWA studies and the large sample sizes required to detect modest-sized associations have served as a powerful incentive for the development of large collaborative efforts such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. This article uses published data on three phenotypes, fibrinogen, uric acid, and electrocardiographic QT interval duration, from the CHARGE Consortium to describe several methodologic issues in the design, conduct, and interpretation of GWA studies, including the use of imputation and the need for additional genotyping. Even with large studies, novel genetic loci explain only a small proportion of the variance of cardiovascular phenotypes.
10aCardiovascular Diseases10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aQuantitative Trait Loci10aRisk Factors1 aBis, J C1 aGlazer, N L1 aPsaty, B M uhttps://chs-nhlbi.org/node/111704313nas a2200889 4500008004100000022001400041245004600055210004500101260001600146300001200162490000800174520183800182653003902020653000902059653003202068653001902100653004002119653001102159653002002170653003802190653003402228653001302262653001102275653000902286653001602295653003602311653003202347653001702379653001102396100002002407700002002427700001902447700002002466700002402486700002402510700002302534700001902557700002102576700002802597700002002625700001802645700001802663700002202681700001702703700002302720700001702743700002202760700002302782700002602805700002602831700002002857700001802877700001902895700002102914700002302935700002402958700001602982700002302998700002003021700001803041700002303059700001703082700002303099700002003122700002303142700001903165700002803184700002203212700002103234700002003255700002203275700002303297700002703320700002003347700002003367856003603387 2009 eng d a1533-440600aGenomewide association studies of stroke.0 aGenomewide association studies of stroke c2009 Apr 23 a1718-280 v3603 aBACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.
METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.
RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.
CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
10aAfrican Continental Ancestry Group10aAged10aChromosomes, Human, Pair 1210aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aRisk Factors10aStroke1 aIkram, Arfan, M1 aSeshadri, Sudha1 aBis, Joshua, C1 aFornage, Myriam1 aDeStefano, Anita, L1 aAulchenko, Yurii, S1 aDebette, Stephanie1 aLumley, Thomas1 aFolsom, Aaron, R1 avan den Herik, Evita, G1 aBos, Michiel, J1 aBeiser, Alexa1 aCushman, Mary1 aLauner, Lenore, J1 aShahar, Eyal1 aStruchalin, Maksim1 aDu, Yangchun1 aGlazer, Nicole, L1 aRosamond, Wayne, D1 aRivadeneira, Fernando1 aKelly-Hayes, Margaret1 aLopez, Oscar, L1 aCoresh, Josef1 aHofman, Albert1 aDeCarli, Charles1 aHeckbert, Susan, R1 aKoudstaal, Peter, J1 aYang, Qiong1 aSmith, Nicholas, L1 aKase, Carlos, S1 aRice, Kenneth1 aHaritunians, Talin1 aRoks, Gerwin1 ade Kort, Paul, L M1 aTaylor, Kent, D1 ade Lau, Lonneke, M1 aOostra, Ben, A1 aUitterlinden, André, G1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aMosley, Thomas, H1 aDuijn, Cornelia, M1 aBreteler, Monique, M B1 aLongstreth, W T1 aWolf, Philip, A uhttps://chs-nhlbi.org/node/109203588nas a2200877 4500008004100000022001400041245007000055210006800125260001300193300001100206490000700217520113400224653001901358653001401377653002301391653002301414653001301437653003101450653003201481653003401513653001101547653001701558653001001575653001601585653002701601653001501628653001401643653001501657653002001672653001201692100001701704700002001721700001801741700002601759700002201785700001901807700002201826700002401848700002301872700001901895700002101914700001901935700001901954700002701973700002602000700002402026700001702050700001902067700002202086700003302108700002102141700001702162700002302179700002002202700002502222700001602247700002202263700002202285700003002307700001902337700002202356700001802378700002402396700002802420700001902448700002102467700003002488700002102518700002002539700002402559700002202583700002602605700002002631700002302651856003602674 2009 eng d a1546-171800aGenome-wide association study of blood pressure and hypertension.0 aGenomewide association study of blood pressure and hypertension c2009 Jun a677-870 v413 aBlood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
10aBlood Pressure10aCell Line10aChromosome Mapping10aChromosomes, Human10aDiastole10aGene Expression Regulation10aGenetic Association Studies10aGenome-Wide Association Study10aHumans10aHypertension10aLiver10aLymphocytes10aMeta-Analysis as Topic10aOdds Ratio10aPhenotype10aPrevalence10aRisk Assessment10aSystole1 aLevy, Daniel1 aEhret, Georg, B1 aRice, Kenneth1 aVerwoert, Germaine, C1 aLauner, Lenore, J1 aDehghan, Abbas1 aGlazer, Nicole, L1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aAspelund, Thor1 aAulchenko, Yurii1 aLumley, Thomas1 aKöttgen, Anna1 aVasan, Ramachandran, S1 aRivadeneira, Fernando1 aEiriksdottir, Gudny1 aGuo, Xiuqing1 aArking, Dan, E1 aMitchell, Gary, F1 aMattace-Raso, Francesco, U S1 aSmith, Albert, V1 aTaylor, Kent1 aScharpf, Robert, B1 aHwang, Shih-Jen1 aSijbrands, Eric, J G1 aBis, Joshua1 aHarris, Tamara, B1 aGanesh, Santhi, K1 aO'Donnell, Christopher, J1 aHofman, Albert1 aRotter, Jerome, I1 aCoresh, Josef1 aBenjamin, Emelia, J1 aUitterlinden, André, G1 aHeiss, Gerardo1 aFox, Caroline, S1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aWang, Thomas, J1 aGudnason, Vilmundur1 aLarson, Martin, G1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aDuijn, Cornelia, M uhttps://chs-nhlbi.org/node/109803239nas a2200481 4500008004100000022001400041245010600055210006900161260000900230300001000239490000600249520187600255653004102131653001502172653001002187653002202197653000902219653002702228653002402255653001802279653004002297653001102337653003402348653001902382653001502401653002302416653001102439653001802450653002702468653000902495653001602504653003602520653001602556653001602572100001902588700001602607700001502623700002002638700001602658700002102674700002602695856003602721 2009 eng d a1932-620300aMultiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.0 aMultiple independent genetic factors at NOS1AP modulate the QT i c2009 ae43330 v43 aExtremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.
10aAdaptor Proteins, Signal Transducing10aAdolescent10aAdult10aAfrican Americans10aAged10aDeath, Sudden, Cardiac10aElectrocardiography10aEthnic Groups10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHeart Diseases10aHeart Rate10aHispanic Americans10aHumans10aLinear Models10aLinkage Disequilibrium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSex Factors10aYoung Adult1 aArking, Dan, E1 aKhera, Amit1 aXing, Chao1 aKao, Linda, W H1 aPost, Wendy1 aBoerwinkle, Eric1 aChakravarti, Aravinda uhttps://chs-nhlbi.org/node/107403209nas a2200769 4500008004100000022001400041245008800055210006900143260001300212300001000225490000700235520104200242653002301284653001901307653002201326653003401348653003101382653001101413653001101424653002801435653002701463653001701490653001601507653003601523653001501559653001501574100001901589700002201608700001901630700002001649700001601669700001201685700001601697700002401713700002201737700002201759700002101781700001901802700001901821700002101840700002001861700002001881700002301901700002201924700002001946700002301966700001901989700001702008700002102025700002402046700001702070700002102087700002402108700001902132700002602151700002802177700002302205700002302228700002102251700002002272700002002292700002802312700001802340700002402358700002102382856003602403 2009 eng d a1546-171800aMultiple loci associated with indices of renal function and chronic kidney disease.0 aMultiple loci associated with indices of renal function and chro c2009 Jun a712-70 v413 aChronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.
10aChromosome Mapping10aCohort Studies10aGenetic Variation10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aMeta-Analysis as Topic10aMucoproteins10aNetherlands10aPolymorphism, Single Nucleotide10aPrevalence10aUromodulin1 aKöttgen, Anna1 aGlazer, Nicole, L1 aDehghan, Abbas1 aHwang, Shih-Jen1 aKatz, Ronit1 aLi, Man1 aYang, Qiong1 aGudnason, Vilmundur1 aLauner, Lenore, J1 aHarris, Tamara, B1 aSmith, Albert, V1 aArking, Dan, E1 aAstor, Brad, C1 aBoerwinkle, Eric1 aEhret, Georg, B1 aRuczinski, Ingo1 aScharpf, Robert, B1 aChen, Yii-Der Ida1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSarnak, Mark1 aSiscovick, David1 aBenjamin, Emelia, J1 aLevy, Daniel1 aUpadhyay, Ashish1 aAulchenko, Yurii, S1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aChasman, Daniel, I1 aParé, Guillaume1 aRidker, Paul, M1 aKao, Linda, W H1 aWitteman, Jacqueline, C1 aCoresh, Josef1 aShlipak, Michael, G1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/109904054nas a2201033 4500008004100000022001400041245007700055210006900132260001300201300001100214490000700225520114900232653001901381653001401400653001901414653002201433653001701455653002001472653001801492653003401510653001101544653001701555653001401572653003601586653002801622100002201650700001901672700002601691700002001717700002101737700002201758700002001780700001901800700002201819700001901841700002101860700001901881700001601900700002001916700001801936700002101954700002601975700002202001700002102023700002202044700002002066700001802086700002102104700002002125700002402145700001702169700002202186700002102208700002202229700001902251700002602270700002302296700001602319700002502335700002502360700001802385700001902403700002802422700002302450700002202473700002502495700001902520700002302539700002402562700002002586700002302606700002002629700002002649700002002669700002202689700002402711700002302735700002002758700002002778700002602798700002402824700003002848700003002878700001702908700001802925700002202943700001902965856003602984 2009 eng d a1546-171800aMultiple loci influence erythrocyte phenotypes in the CHARGE Consortium.0 aMultiple loci influence erythrocyte phenotypes in the CHARGE Con c2009 Nov a1191-80 v413 aMeasurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
10aBlood Pressure10aCell Line10aCohort Studies10aEndothelial Cells10aErythrocytes10aGene Expression10aGenome, Human10aGenome-Wide Association Study10aHumans10aHypertension10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aGanesh, Santhi, K1 aZakai, Neil, A1 avan Rooij, Frank, J A1 aSoranzo, Nicole1 aSmith, Albert, V1 aNalls, Michael, A1 aChen, Ming-Huei1 aKöttgen, Anna1 aGlazer, Nicole, L1 aDehghan, Abbas1 aKuhnel, Brigitte1 aAspelund, Thor1 aYang, Qiong1 aTanaka, Toshiko1 aJaffe, Andrew1 aBis, Joshua, C M1 aVerwoert, Germaine, C1 aTeumer, Alexander1 aFox, Caroline, S1 aGuralnik, Jack, M1 aEhret, Georg, B1 aRice, Kenneth1 aFelix, Janine, F1 aRendon, Augusto1 aEiriksdottir, Gudny1 aLevy, Daniel1 aPatel, Kushang, V1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aHofman, Albert1 aSambrook, Jennifer, G1 aHernandez, Dena, G1 aZheng, Gang1 aBandinelli, Stefania1 aSingleton, Andrew, B1 aCoresh, Josef1 aLumley, Thomas1 aUitterlinden, André, G1 aVangils, Janine, M1 aLauner, Lenore, J1 aCupples, Adrienne, L1 aOostra, Ben, A1 aZwaginga, Jaap-Jan1 aOuwehand, Willem, H1 aThein, Swee-Lay1 aMeisinger, Christa1 aDeloukas, Panos1 aNauck, Matthias1 aSpector, Tim, D1 aGieger, Christian1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aFerrucci, Luigi1 aChakravarti, Aravinda1 aGreinacher, Andreas1 aO'Donnell, Christopher, J1 aWitteman, Jacqueline, C M1 aFurth, Susan1 aCushman, Mary1 aHarris, Tamara, B1 aLin, Jing-Ping uhttps://chs-nhlbi.org/node/114104323nas a2201033 4500008004100000022001400041245011200055210006900167260001300236300001300249490000600262520134000268653000901608653002001617653001901637653004001656653001101696653003801707653003401745653001101779653000901790653001601799653002601815653001201841653003601853653002401889100002601913700002501939700001901964700001901983700002202002700001202024700002302036700002102059700001902080700002402099700002002123700002202143700002102165700002502186700002402211700002302235700002602258700002102284700001902305700002302324700002102347700002102368700002202389700002202411700002202433700002002455700002202475700001602497700002002513700002002533700002202553700002602575700001602601700002302617700002202640700001602662700001602678700002502694700001902719700002102738700001902759700002402778700002402802700003002826700002702856700002202883700002402905700001902929700001902948700002602967700002802993700003003021700001903051700002203070700002403092700002603116700002303142700002303165700002503188700002103213700001903234856003603253 2009 eng d a1553-740400aNRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.0 aNRXN3 is a novel locus for waist circumference a genomewide asso c2009 Jun ae10005390 v53 aCentral abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
10aAged10aBody Mass Index10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aObesity10aPolymorphism, Single Nucleotide10aWaist Circumference1 aHeard-Costa, Nancy, L1 aZillikens, Carola, M1 aMonda, Keri, L1 aJohansson, Asa1 aHarris, Tamara, B1 aFu, Mao1 aHaritunians, Talin1 aFeitosa, Mary, F1 aAspelund, Thor1 aEiriksdottir, Gudny1 aGarcia, Melissa1 aLauner, Lenore, J1 aSmith, Albert, V1 aMitchell, Braxton, D1 aMcArdle, Patrick, F1 aShuldiner, Alan, R1 aBielinski, Suzette, J1 aBoerwinkle, Eric1 aBrancati, Fred1 aDemerath, Ellen, W1 aPankow, James, S1 aArnold, Alice, M1 aChen, Yii-Der Ida1 aGlazer, Nicole, L1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aAmin, Najaf1 aCampbell, Harry1 aGyllensten, Ulf1 aPattaro, Cristian1 aPramstaller, Peter, P1 aRudan, Igor1 aStruchalin, Maksim1 aVitart, Veronique1 aGao, Xiaoyi1 aKraja, Aldi1 aProvince, Michael, A1 aZhang, Qunyuan1 aAtwood, Larry, D1 aDupuis, Josée1 aHirschhorn, Joel, N1 aJaquish, Cashell, E1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWhite, Charles, C1 aAulchenko, Yurii, S1 aEstrada, Karol1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aOostra, Ben, A1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aCupples, Adrienne, L1 aFox, Caroline, S1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/110703278nas a2200937 4500008004100000022001400041245009900055210006900154260001300223300001100236490000700247520051100254653002400765653003200789653004000821653003800861653003400899653002500933653001100958653002700969653001300996653003601009653003101045100002401076700002101100700001901121700001801140700002501158700002101183700002401204700001901228700002101247700002201268700001901290700002201309700002501331700001901356700002001375700001801395700001901413700002901432700002201461700002601483700002401509700002601533700002001559700002401579700001701603700002001620700001201640700002701652700001901679700002701698700002201725700002201747700002001769700002201789700002601811700001301837700002201850700002301872700002601895700002801921700002001949700002201969700001901991700002302010700002202033700002102055700002002076700002302096700002202119700002402141700002302165700002402188700001902212700001902231700002402250700003002274856003602304 2009 eng d a1546-171800aVariants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.0 aVariants in ZFHX3 are associated with atrial fibrillation in ind c2009 Aug a879-810 v413 aWe conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).
10aAtrial Fibrillation10aChromosomes, Human, Pair 1610aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeodomain Proteins10aHumans10aMeta-Analysis as Topic10aMutation10aPolymorphism, Single Nucleotide10aReproducibility of Results1 aBenjamin, Emelia, J1 aRice, Kenneth, M1 aArking, Dan, E1 aPfeufer, Arne1 avan Noord, Charlotte1 aSmith, Albert, V1 aSchnabel, Renate, B1 aBis, Joshua, C1 aBoerwinkle, Eric1 aSinner, Moritz, F1 aDehghan, Abbas1 aLubitz, Steven, A1 aD'Agostino, Ralph, B1 aLumley, Thomas1 aEhret, Georg, B1 aHeeringa, Jan1 aAspelund, Thor1 aNewton-Cheh, Christopher1 aLarson, Martin, G1 aMarciante, Kristin, D1 aSoliman, Elsayed, Z1 aRivadeneira, Fernando1 aWang, Thomas, J1 aEiriksdottir, Gudny1 aLevy, Daniel1 aPsaty, Bruce, M1 aLi, Man1 aChamberlain, Alanna, M1 aHofman, Albert1 aVasan, Ramachandran, S1 aHarris, Tamara, B1 aRotter, Jerome, I1 aKao, Linda, W H1 aAgarwal, Sunil, K1 aStricker, Bruno, H Ch1 aWang, Ke1 aLauner, Lenore, J1 aSmith, Nicholas, L1 aChakravarti, Aravinda1 aUitterlinden, André, G1 aWolf, Philip, A1 aSotoodehnia, Nona1 aKöttgen, Anna1 aDuijn, Cornelia, M1 aMeitinger, Thomas1 aMueller, Martina1 aPerz, Siegfried1 aSteinbeck, Gerhard1 aWichmann, H-Erich1 aLunetta, Kathryn, L1 aHeckbert, Susan, R1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aKääb, Stefan1 aEllinor, Patrick, T1 aWitteman, Jacqueline, C M uhttps://chs-nhlbi.org/node/111414196nas a2204789 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2010 eng d a1546-171800aAssociation analyses of 249,796 individuals reveal 18 new loci associated with body mass index.0 aAssociation analyses of 249796 individuals reveal 18 new loci as c2010 Nov a937-480 v423 aObesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
10aBody Height10aBody Mass Index10aBody Size10aBody Weight10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aObesity10aPolymorphism, Single Nucleotide1 aSpeliotes, Elizabeth, K1 aWiller, Cristen, J1 aBerndt, Sonja, I1 aMonda, Keri, L1 aThorleifsson, Gudmar1 aJackson, Anne, U1 aAllen, Hana, Lango1 aLindgren, Cecilia, M1 aLuan, Jian'an1 aMägi, Reedik1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWinkler, Thomas, W1 aQi, Lu1 aWorkalemahu, Tsegaselassie1 aHeid, Iris, M1 aSteinthorsdottir, Valgerdur1 aStringham, Heather, M1 aWeedon, Michael, N1 aWheeler, Eleanor1 aWood, Andrew, R1 aFerreira, Teresa1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aEstrada, Karol1 aLiang, Liming1 aNemesh, James1 aPark, Ju-Hyun1 aGustafsson, Stefan1 aKilpeläinen, Tuomas, O1 aYang, Jian1 aBouatia-Naji, Nabila1 aEsko, Tõnu1 aFeitosa, Mary, F1 aKutalik, Zoltán1 aMangino, Massimo1 aRaychaudhuri, Soumya1 aScherag, Andre1 aSmith, Albert, Vernon1 aWelch, Ryan1 aZhao, Jing Hua1 aAben, Katja, K1 aAbsher, Devin, M1 aAmin, Najaf1 aDixon, Anna, L1 aFisher, Eva1 aGlazer, Nicole, L1 aGoddard, Michael, E1 aHeard-Costa, Nancy, L1 aHoesel, Volker1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJohnson, Toby1 aKetkar, Shamika1 aLamina, Claudia1 aLi, Shengxu1 aMoffatt, Miriam, F1 aMyers, Richard, H1 aNarisu, Narisu1 aPerry, John, R B1 aPeters, Marjolein, J1 aPreuss, Michael1 aRipatti, Samuli1 aRivadeneira, Fernando1 aSandholt, Camilla1 aScott, Laura, J1 aTimpson, Nicholas, J1 aTyrer, Jonathan, P1 avan Wingerden, Sophie1 aWatanabe, Richard, M1 aWhite, Charles, C1 aWiklund, Fredrik1 aBarlassina, Christina1 aChasman, Daniel, I1 aCooper, Matthew, N1 aJansson, John-Olov1 aLawrence, Robert, W1 aPellikka, Niina1 aProkopenko, Inga1 aShi, Jianxin1 aThiering, Elisabeth1 aAlavere, Helene1 aAlibrandi, Maria, T S1 aAlmgren, Peter1 aArnold, Alice, M1 aAspelund, Thor1 aAtwood, Larry, D1 aBalkau, Beverley1 aBalmforth, Anthony, J1 aBennett, Amanda, J1 aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBergmann, Sven1 aBiebermann, Heike1 aBlakemore, Alexandra, I F1 aBoes, Tanja1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBrown, Morris, J1 aBuchanan, Thomas, A1 aBusonero, Fabio1 aCampbell, Harry1 aCappuccio, Francesco, P1 aCavalcanti-Proença, Christine1 aChen, Yii-Der Ida1 aChen, Chih-Mei1 aChines, Peter, S1 aClarke, Robert1 aCoin, Lachlan1 aConnell, John1 aDay, Ian, N M1 aHeijer, Martin, den1 aDuan, Jubao1 aEbrahim, Shah1 aElliott, Paul1 aElosua, Roberto1 aEiriksdottir, Gudny1 aErdos, Michael, R1 aEriksson, Johan, G1 aFacheris, Maurizio, F1 aFelix, Stephan, B1 aFischer-Posovszky, Pamela1 aFolsom, Aaron, R1 aFriedrich, Nele1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGejman, Pablo, V1 aGeus, Eco, J C1 aGieger, Christian1 aGjesing, Anette, P1 aGoel, Anuj1 aGoyette, Philippe1 aGrallert, Harald1 aGrässler, Jürgen1 aGreenawalt, Danielle, M1 aGroves, Christopher, J1 aGudnason, Vilmundur1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHall, Alistair, S1 aHavulinna, Aki, S1 aHayward, Caroline1 aHeath, Andrew, C1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHinney, Anke1 aHofman, Albert1 aHomuth, Georg1 aHui, Jennie1 aIgl, Wilmar1 aIribarren, Carlos1 aIsomaa, Bo1 aJacobs, Kevin, B1 aJarick, Ivonne1 aJewell, Elizabeth1 aJohn, Ulrich1 aJørgensen, Torben1 aJousilahti, Pekka1 aJula, Antti1 aKaakinen, Marika1 aKajantie, Eero1 aKaplan, Lee, M1 aKathiresan, Sekar1 aKettunen, Johannes1 aKinnunen, Leena1 aKnowles, Joshua, W1 aKolcic, Ivana1 aKönig, Inke, R1 aKoskinen, Seppo1 aKovacs, Peter1 aKuusisto, Johanna1 aKraft, Peter1 aKvaløy, Kirsti1 aLaitinen, Jaana1 aLantieri, Olivier1 aLanzani, Chiara1 aLauner, Lenore, J1 aLecoeur, Cécile1 aLehtimäki, Terho1 aLettre, Guillaume1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aLuben, Robert, N1 aLudwig, Barbara1 aManunta, Paolo1 aMarek, Diana1 aMarre, Michel1 aMartin, Nicholas, G1 aMcArdle, Wendy, L1 aMcCarthy, Anne1 aMcKnight, Barbara1 aMeitinger, Thomas1 aMelander, Olle1 aMeyre, David1 aMidthjell, Kristian1 aMontgomery, Grant, W1 aMorken, Mario, A1 aMorris, Andrew, P1 aMulic, Rosanda1 aNgwa, Julius, S1 aNelis, Mari1 aNeville, Matt, J1 aNyholt, Dale, R1 aO'Donnell, Christopher, J1 aO'Rahilly, Stephen1 aOng, Ken, K1 aOostra, Ben1 aParé, Guillaume1 aParker, Alex, N1 aPerola, Markus1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPlatou, Carl, G P1 aPolasek, Ozren1 aPouta, Anneli1 aRafelt, Suzanne1 aRaitakari, Olli1 aRayner, Nigel, W1 aRidderstråle, Martin1 aRief, Winfried1 aRuokonen, Aimo1 aRobertson, Neil, R1 aRzehak, Peter1 aSalomaa, Veikko1 aSanders, Alan, R1 aSandhu, Manjinder, S1 aSanna, Serena1 aSaramies, Jouko1 aSavolainen, Markku, J1 aScherag, Susann1 aSchipf, Sabine1 aSchreiber, Stefan1 aSchunkert, Heribert1 aSilander, Kaisa1 aSinisalo, Juha1 aSiscovick, David, S1 aSmit, Jan, H1 aSoranzo, Nicole1 aSovio, Ulla1 aStephens, Jonathan1 aSurakka, Ida1 aSwift, Amy, J1 aTammesoo, Mari-Liis1 aTardif, Jean-Claude1 aTeder-Laving, Maris1 aTeslovich, Tanya, M1 aThompson, John, R1 aThomson, Brian1 aTönjes, Anke1 aTuomi, Tiinamaija1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aViikari, Jorma1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogel, Carla, I G1 aVoight, Benjamin, F1 aWaite, Lindsay, L1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWiegand, Susanna1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aWitteman, Jacqueline, C1 aXu, Jianfeng1 aZhang, Qunyuan1 aZgaga, Lina1 aZiegler, Andreas1 aZitting, Paavo1 aBeilby, John, P1 aFarooqi, Sadaf1 aHebebrand, Johannes1 aHuikuri, Heikki, V1 aJames, Alan, L1 aKähönen, Mika1 aLevinson, Douglas, F1 aMacciardi, Fabio1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRidker, Paul, M1 aStumvoll, Michael1 aBeckmann, Jacques, S1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCollins, Francis, S1 aCupples, Adrienne, L1 aSmith, George Davey1 aErdmann, Jeanette1 aFroguel, Philippe1 aGrönberg, Henrik1 aGyllensten, Ulf1 aHall, Per1 aHansen, Torben1 aHarris, Tamara, B1 aHattersley, Andrew, T1 aHayes, Richard, B1 aHeinrich, Joachim1 aHu, Frank, B1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aKaprio, Jaakko1 aKarpe, Fredrik1 aKhaw, Kay-Tee1 aKiemeney, Lambertus, A1 aKrude, Heiko1 aLaakso, Markku1 aLawlor, Debbie, A1 aMetspalu, Andres1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPedersen, Oluf1 aPenninx, Brenda, W1 aPeters, Annette1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aReinehr, Thomas1 aRissanen, Aila1 aRudan, Igor1 aSamani, Nilesh, J1 aSchwarz, Peter, E H1 aShuldiner, Alan, R1 aSpector, Timothy, D1 aTuomilehto, Jaakko1 aUda, Manuela1 aUitterlinden, Andre1 aValle, Timo, T1 aWabitsch, Martin1 aWaeber, Gérard1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWilson, James, F1 aWright, Alan, F1 aZillikens, Carola, M1 aChatterjee, Nilanjan1 aMcCarroll, Steven, A1 aPurcell, Shaun1 aSchadt, Eric, E1 aVisscher, Peter, M1 aAssimes, Themistocles, L1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aFrayling, Timothy, M1 aThorsteinsdottir, Unnur1 aAbecasis, Goncalo, R1 aBarroso, Inês1 aBoehnke, Michael1 aStefansson, Kari1 aNorth, Kari, E1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aIngelsson, Erik1 aLoos, Ruth, J F1 aMAGIC1 aProcardis Consortium uhttps://chs-nhlbi.org/node/123704239nas a2200781 4500008004100000022001400041245024400055210006900299260001300368300001100381490000600392520185900398653002202257653000902279653002202288653001902310653001902329653004002348653001102388653003402399653001802433653001102451653001402462653000902476653001602485653003602501653000902537653003302546100002302579700002102602700002402623700002302647700002202670700002002692700002502712700001902737700001902756700002302775700001902798700002602817700001902843700002102862700002102883700002402904700002302928700001802951700002102969700001802990700002303008700002403031700002303055700002003078700002103098700001903119700002303138700001803161700003003179700002803209700002203237700002403259700001703283700002303300700002003323700003003343700002103373700002703394856003603421 2010 eng d a1942-326800aAssociation of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.0 aAssociation of genomewide variation with the risk of incident he c2010 Jun a256-660 v33 aBACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.
CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.
10aAfrican Americans10aAged10aAged, 80 and over10aCohort Studies10aEndopeptidases10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHeart Failure10aHumans10aIncidence10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk10aUbiquitin-Specific Proteases1 aSmith, Nicholas, L1 aFelix, Janine, F1 aMorrison, Alanna, C1 aDemissie, Serkalem1 aGlazer, Nicole, L1 aLoehr, Laura, R1 aCupples, Adrienne, L1 aDehghan, Abbas1 aLumley, Thomas1 aRosamond, Wayne, D1 aLieb, Wolfgang1 aRivadeneira, Fernando1 aBis, Joshua, C1 aFolsom, Aaron, R1 aBenjamin, Emelia1 aAulchenko, Yurii, S1 aHaritunians, Talin1 aCouper, David1 aMurabito, Joanne1 aWang, Ying, A1 aStricker, Bruno, H1 aGottdiener, John, S1 aChang, Patricia, P1 aWang, Thomas, J1 aRice, Kenneth, M1 aHofman, Albert1 aHeckbert, Susan, R1 aFox, Ervin, R1 aO'Donnell, Christopher, J1 aUitterlinden, André, G1 aRotter, Jerome, I1 aWillerson, James, T1 aLevy, Daniel1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/119709616nas a2202929 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520140900238653002201647653001201669653003701681653002101718653002101739653002801760653001101788653004001799653001101839653001701850653003401867653001301901653001101914653002101925653001101946653001001957653000901967653000901976653003901985653001402024653003602038653002602074653003102100653001802131100002402149700002002173700002102193700002502214700002602239700002102265700002602286700002002312700002302332700002302355700002902378700002402407700001802431700002002449700001902469700002302488700001902511700002402530700002502554700002102579700001902600700002502619700001902644700001802663700001602681700001702697700001602714700002002730700001702750700002002767700002002787700001802807700001602825700001702841700002402858700003002882700002102912700002102933700001802954700002002972700001402992700001803006700002003024700002103044700001803065700002103083700002003104700003003124700002103154700002303175700002203198700002303220700002403243700002503267700002003292700002403312700002403336700002203360700002803382700001703410700002303427700002203450700002003472700001703492700002603509700002003535700002003555700002203575700001903597700002003616700002503636700002003661700001703681700002403698700001803722700002003740700002003760700002003780700001903800700001603819700001903835700002003854700001703874700002003891700002603911700001903937700001903956700002703975700002304002700002204025700002004047700002104067700001904088700003004107700002404137700002604161700002504187700002204212700002004234700002204254700001904276700001804295700002404313700001904337700002104356700002704377700001704404700001804421700002004439700002304459700002204482700002404504700002204528700002304550700002104573700002204594700002404616700002004640700001804660700001904678700001904697700001904716700002704735700002604762700002004788700001604808700001804824700002404842700001904866700002104885700002804906700001804934700002204952700002204974700002404996700002205020700002305042700002205065700002005087700002205107700001905129700002005148700002205168700002305190700002005213700002205233700001805255700002205273700002005295700002405315700002305339700002505362700001905387700001805406700002205424700002405446700002105470700002305491700002005514700001905534700002505553700002305578700002405601700002405625700001905649700002505668700002805693700002905721700002405750700002105774700002005795700001805815700001805833700002105851700002705872700002005899700002205919700002305941700002305964700002105987700001606008700002806024700002406052700002206076700002106098700002106119700002406140700002206164700001806186700002206204700002506226700002006251700002206271700002106293700002306314700002006337700002106357700002406378700002206402700002406424700002506448700002506473700002006498700002106518700002306539700002006562700002506582700002106607700002206628856003606650 2010 eng d a1476-468700aBiological, clinical and population relevance of 95 loci for blood lipids.0 aBiological clinical and population relevance of 95 loci for bloo c2010 Aug 05 a707-130 v4663 aPlasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
10aAfrican Americans10aAnimals10aAsian Continental Ancestry Group10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aLipid Metabolism10aLipids10aLiver10aMale10aMice10aN-Acetylgalactosaminyltransferases10aPhenotype10aPolymorphism, Single Nucleotide10aProtein Phosphatase 110aReproducibility of Results10aTriglycerides1 aTeslovich, Tanya, M1 aMusunuru, Kiran1 aSmith, Albert, V1 aEdmondson, Andrew, C1 aStylianou, Ioannis, M1 aKoseki, Masahiro1 aPirruccello, James, P1 aRipatti, Samuli1 aChasman, Daniel, I1 aWiller, Cristen, J1 aJohansen, Christopher, T1 aFouchier, Sigrid, W1 aIsaacs, Aaron1 aPeloso, Gina, M1 aBarbalic, Maja1 aRicketts, Sally, L1 aBis, Joshua, C1 aAulchenko, Yurii, S1 aThorleifsson, Gudmar1 aFeitosa, Mary, F1 aChambers, John1 aOrho-Melander, Marju1 aMelander, Olle1 aJohnson, Toby1 aLi, Xiaohui1 aGuo, Xiuqing1 aLi, Mingyao1 aCho, Yoon, Shin1 aGo, Min, Jin1 aKim, Young, Jin1 aLee, Jong-Young1 aPark, Taesung1 aKim, Kyunga1 aSim, Xueling1 aOng, Rick, Twee-Hee1 aCroteau-Chonka, Damien, C1 aLange, Leslie, A1 aSmith, Joshua, D1 aSong, Kijoung1 aZhao, Jing, Hua1 aYuan, Xin1 aLuan, Jian'an1 aLamina, Claudia1 aZiegler, Andreas1 aZhang, Weihua1 aZee, Robert, Y L1 aWright, Alan, F1 aWitteman, Jacqueline, C M1 aWilson, James, F1 aWillemsen, Gonneke1 aWichmann, H-Erich1 aWhitfield, John, B1 aWaterworth, Dawn, M1 aWareham, Nicholas, J1 aWaeber, Gérard1 aVollenweider, Peter1 aVoight, Benjamin, F1 aVitart, Veronique1 aUitterlinden, André, G1 aUda, Manuela1 aTuomilehto, Jaakko1 aThompson, John, R1 aTanaka, Toshiko1 aSurakka, Ida1 aStringham, Heather, M1 aSpector, Tim, D1 aSoranzo, Nicole1 aSmit, Johannes, H1 aSinisalo, Juha1 aSilander, Kaisa1 aSijbrands, Eric, J G1 aScuteri, Angelo1 aScott, James1 aSchlessinger, David1 aSanna, Serena1 aSalomaa, Veikko1 aSaharinen, Juha1 aSabatti, Chiara1 aRuokonen, Aimo1 aRudan, Igor1 aRose, Lynda, M1 aRoberts, Robert1 aRieder, Mark1 aPsaty, Bruce, M1 aPramstaller, Peter, P1 aPichler, Irene1 aPerola, Markus1 aPenninx, Brenda, W J H1 aPedersen, Nancy, L1 aPattaro, Cristian1 aParker, Alex, N1 aParé, Guillaume1 aOostra, Ben, A1 aO'Donnell, Christopher, J1 aNieminen, Markku, S1 aNickerson, Deborah, A1 aMontgomery, Grant, W1 aMeitinger, Thomas1 aMcPherson, Ruth1 aMcCarthy, Mark, I1 aMcArdle, Wendy1 aMasson, David1 aMartin, Nicholas, G1 aMarroni, Fabio1 aMangino, Massimo1 aMagnusson, Patrik, K E1 aLucas, Gavin1 aLuben, Robert1 aLoos, Ruth, J F1 aLokki, Marja-Liisa1 aLettre, Guillaume1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLakatta, Edward, G1 aLaaksonen, Reijo1 aKyvik, Kirsten, O1 aKronenberg, Florian1 aKönig, Inke, R1 aKhaw, Kay-Tee1 aKaprio, Jaakko1 aKaplan, Lee, M1 aJohansson, Asa1 aJarvelin, Marjo-Riitta1 aJanssens, Cecile, J W1 aIngelsson, Erik1 aIgl, Wilmar1 aHovingh, Kees1 aHottenga, Jouke-Jan1 aHofman, Albert1 aHicks, Andrew, A1 aHengstenberg, Christian1 aHeid, Iris, M1 aHayward, Caroline1 aHavulinna, Aki, S1 aHastie, Nicholas, D1 aHarris, Tamara, B1 aHaritunians, Talin1 aHall, Alistair, S1 aGyllensten, Ulf1 aGuiducci, Candace1 aGroop, Leif, C1 aGonzalez, Elena1 aGieger, Christian1 aFreimer, Nelson, B1 aFerrucci, Luigi1 aErdmann, Jeanette1 aElliott, Paul1 aEjebe, Kenechi, G1 aDöring, Angela1 aDominiczak, Anna, F1 aDemissie, Serkalem1 aDeloukas, Panagiotis1 aGeus, Eco, J C1 ade Faire, Ulf1 aCrawford, Gabriel1 aCollins, Francis, S1 aChen, Yii-der, I1 aCaulfield, Mark, J1 aCampbell, Harry1 aBurtt, Noel, P1 aBonnycastle, Lori, L1 aBoomsma, Dorret, I1 aBoekholdt, Matthijs1 aBergman, Richard, N1 aBarroso, Inês1 aBandinelli, Stefania1 aBallantyne, Christie, M1 aAssimes, Themistocles, L1 aQuertermous, Thomas1 aAltshuler, David1 aSeielstad, Mark1 aWong, Tien, Y1 aTai, E-Shyong1 aFeranil, Alan, B1 aKuzawa, Christopher, W1 aAdair, Linda, S1 aTaylor, Herman, A1 aBorecki, Ingrid, B1 aGabriel, Stacey, B1 aWilson, James, G1 aHolm, Hilma1 aThorsteinsdottir, Unnur1 aGudnason, Vilmundur1 aKrauss, Ronald, M1 aMohlke, Karen, L1 aOrdovas, Jose, M1 aMunroe, Patricia, B1 aKooner, Jaspal, S1 aTall, Alan, R1 aHegele, Robert, A1 aKastelein, John, J P1 aSchadt, Eric, E1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aStrachan, David, P1 aMooser, Vincent1 aStefansson, Kari1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aDuijn, Cornelia, M1 aPeltonen, Leena1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/122105927nas a2201285 4500008004100000022001400041245009300055210006900148260001600217300001000233490000800243520230500251653001102556653003202567653003102599653001902630653002402649653001102673653004002684653003802724653003402762653001702796653001502813653001102828653001602839653003002855653002702885653003602912653001202948653001802960653001402978653002502992100002003017700001603037700002003053700002203073700002403095700001703119700002103136700002703157700001903184700002203203700002003225700002103245700002203266700002303288700002203311700002403333700001903357700001503376700002603391700002203417700001803439700002003457700002103477700001703498700002203515700002003537700002103557700001903578700001903597700002303616700001603639700001803655700002003673700002103693700002203714700002503736700002203761700001803783700002003801700001803821700001803839700002303857700002803880700001803908700002403926700002103950700002003971700001903991700001604010700002104026700001704047700001704064700002204081700002004103700002704123700002004150700001904170700002004189700002304209700002004232700002204252700001904274700002304293700002004316700002804336700001904364700002704383700001904410700002404429700002204453700002804475700002004503700001804523700001904541700002104560700002404581856003604605 2010 eng d a1474-547X00aCommon genetic determinants of vitamin D insufficiency: a genome-wide association study.0 aCommon genetic determinants of vitamin D insufficiency a genomew c2010 Jul 17 a180-80 v3763 aBACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.
METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.
FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.
INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.
FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
10aCanada10aChromosomes, Human, Pair 1110aChromosomes, Human, Pair 410aCohort Studies10aDietary Supplements10aEurope10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeterozygote10aHomozygote10aHumans10aImmunoassay10aInternational Cooperation10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide10aSeasons10aUnited States10aVitamin D10aVitamin D Deficiency1 aWang, Thomas, J1 aZhang, Feng1 aRichards, Brent1 aKestenbaum, Bryan1 avan Meurs, Joyce, B1 aBerry, Diane1 aKiel, Douglas, P1 aStreeten, Elizabeth, A1 aOhlsson, Claes1 aKoller, Daniel, L1 aPeltonen, Leena1 aCooper, Jason, D1 aO'Reilly, Paul, F1 aHouston, Denise, K1 aGlazer, Nicole, L1 aVandenput, Liesbeth1 aPeacock, Munro1 aShi, Julia1 aRivadeneira, Fernando1 aMcCarthy, Mark, I1 aAnneli, Pouta1 ade Boer, Ian, H1 aMangino, Massimo1 aKato, Bernet1 aSmyth, Deborah, J1 aBooth, Sarah, L1 aJacques, Paul, F1 aBurke, Greg, L1 aGoodarzi, Mark1 aCheung, Ching-Lung1 aWolf, Myles1 aRice, Kenneth1 aGoltzman, David1 aHidiroglou, Nick1 aLadouceur, Martin1 aWareham, Nicholas, J1 aHocking, Lynne, J1 aHart, Deborah1 aArden, Nigel, K1 aCooper, Cyrus1 aMalik, Suneil1 aFraser, William, D1 aHartikainen, Anna-Liisa1 aZhai, Guangju1 aMacdonald, Helen, M1 aForouhi, Nita, G1 aLoos, Ruth, J F1 aReid, David, M1 aHakim, Alan1 aDennison, Elaine1 aLiu, Yongmei1 aPower, Chris1 aStevens, Helen, E1 aJaana, Laitinen1 aVasan, Ramachandran, S1 aSoranzo, Nicole1 aBojunga, Jörg1 aPsaty, Bruce, M1 aLorentzon, Mattias1 aForoud, Tatiana1 aHarris, Tamara, B1 aHofman, Albert1 aJansson, John-Olov1 aCauley, Jane, A1 aUitterlinden, André, G1 aGibson, Quince1 aJarvelin, Marjo-Riitta1 aKarasik, David1 aSiscovick, David, S1 aEcons, Michael, J1 aKritchevsky, Stephen, B1 aFlorez, Jose, C1 aTodd, John, A1 aDupuis, Josée1 aHyppönen, Elina1 aSpector, Timothy, D uhttps://chs-nhlbi.org/node/120404123nas a2200817 4500008004100000022001400041245007500055210006900130260001300199300001200212490000700224520182200231653001002053653000902063653004002072653001102112653003002123653001902153653001702172653002202189653003402211653001102245653001102256653000902267653001602276653001502292653003602307653003102343653001602374653005402390100002202444700002202466700001902488700002102507700002002528700001702548700001702565700002802582700002402610700002602634700002202660700002002682700002202702700001802724700002302742700002002765700002202785700001602807700002002823700002002843700002102863700002202884700001202906700001902918700002102937700001802958700001602976700001702992700002603009700001903035700002603054700002803080700001903108700002303127700002403150700002003174700003003194700002403224700002103248856003603269 2010 eng d a1533-345000aCommon genetic variants associate with serum phosphorus concentration.0 aCommon genetic variants associate with serum phosphorus concentr c2010 Jul a1223-320 v213 aPhosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.
10aAdult10aAged10aEuropean Continental Ancestry Group10aFemale10aFibroblast Growth Factors10aGene Frequency10aGenetic Loci10aGenetic Variation10aGenome-Wide Association Study10aHumans10aKidney10aMale10aMiddle Aged10aPhosphorus10aPolymorphism, Single Nucleotide10aReceptors, Calcium-Sensing10aSex Factors10aSodium-Phosphate Cotransporter Proteins, Type IIa1 aKestenbaum, Bryan1 aGlazer, Nicole, L1 aKöttgen, Anna1 aFelix, Janine, F1 aHwang, Shih-Jen1 aLiu, Yongmei1 aLohman, Kurt1 aKritchevsky, Stephen, B1 aHausman, Dorothy, B1 aPetersen, Ann-Kristin1 aGieger, Christian1 aRied, Janina, S1 aMeitinger, Thomas1 aStrom, Tim, M1 aWichmann, Erich, H1 aCampbell, Harry1 aHayward, Caroline1 aRudan, Igor1 ade Boer, Ian, H1 aPsaty, Bruce, M1 aRice, Kenneth, M1 aChen, Yii-Der Ida1 aLi, Man1 aArking, Dan, E1 aBoerwinkle, Eric1 aCoresh, Josef1 aYang, Qiong1 aLevy, Daniel1 avan Rooij, Frank, J A1 aDehghan, Abbas1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aDuijn, Cornelia, M1 aShlipak, Michael, G1 aKao, Linda, W H1 aWitteman, Jacqueline, C M1 aSiscovick, David, S1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/120605521nas a2201561 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520109100256653001201347653002101359653002301380653002601403653002401429653001701453653003401470653002801504653001101532653000901543653002101552653001901573653002201592653004001614653003601654653002001690100002201710700001801732700002501750700001801775700002901793700001901822700001501841700002101856700002201877700001901899700002101918700002501939700002201964700002601986700001902012700002302031700001702054700002202071700002602093700001802119700002002137700002202157700001202179700001902191700002602210700001902236700001902255700001802274700001802292700001902310700001802329700001802347700002702365700001902392700002402411700001902435700001702454700002002471700002702491700001702518700002602535700002202561700001702583700002302600700002202623700002402645700002402669700002002693700001902713700002502732700002002757700002302777700002802800700001902828700002402847700001702871700002102888700002402909700002202933700002002955700001702975700002202992700001903014700003003033700002103063700002003084700002303104700002203127700001903149700002003168700002103188700002803209700002903237700003003266700002603296700002303322700002103345700001903366700001603385700001703401700002603418700002403444700002203468700002203490700002903512700002003541700002003561700001803581700001603599700002003615700002103635700002603656700002403682700002003706700002403726700002303750700002203773700002203795700002003817700002603837700002203863700001903885700001903904856003603923 2010 eng d a1546-171800aCommon variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.0 aCommon variants in 22 loci are associated with QRS duration and c2010 Dec a1068-760 v423 aThe QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
10aAnimals10aAnimals, Newborn10aChromosomes, Human10aComputational Biology10aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMice10aMice, Transgenic10aModels, Animal10aMyocytes, Cardiac10aNAV1.8 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSodium Channels1 aSotoodehnia, Nona1 aIsaacs, Aaron1 ade Bakker, Paul, I W1 aDörr, Marcus1 aNewton-Cheh, Christopher1 aNolte, Ilja, M1 aHarst, Pim1 aMüller, Martina1 aEijgelsheim, Mark1 aAlonso, Alvaro1 aHicks, Andrew, A1 aPadmanabhan, Sandosh1 aHayward, Caroline1 aSmith, Albert, Vernon1 aPolasek, Ozren1 aGiovannone, Steven1 aFu, Jingyuan1 aMagnani, Jared, W1 aMarciante, Kristin, D1 aPfeufer, Arne1 aGharib, Sina, A1 aTeumer, Alexander1 aLi, Man1 aBis, Joshua, C1 aRivadeneira, Fernando1 aAspelund, Thor1 aKöttgen, Anna1 aJohnson, Toby1 aRice, Kenneth1 aSie, Mark, P S1 aWang, Ying, A1 aKlopp, Norman1 aFuchsberger, Christian1 aWild, Sarah, H1 aLeach, Irene, Mateo1 aEstrada, Karol1 aVölker, Uwe1 aWright, Alan, F1 aAsselbergs, Folkert, W1 aQu, Jiaxiang1 aChakravarti, Aravinda1 aSinner, Moritz, F1 aKors, Jan, A1 aPetersmann, Astrid1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aOostra, Ben, A1 aCupples, Adrienne, L1 aPerz, Siegfried1 ade Boer, Rudolf, A1 aUitterlinden, André, G1 aVölzke, Henry1 aSpector, Timothy, D1 aLiu, Fang-Yu1 aBoerwinkle, Eric1 aDominiczak, Anna, F1 aRotter, Jerome, I1 avan Herpen, Gé1 aLevy, Daniel1 aWichmann, H-Erich1 aGilst, Wiek, H1 aWitteman, Jacqueline, C M1 aKroemer, Heyo, K1 aKao, Linda, W H1 aHeckbert, Susan, R1 aMeitinger, Thomas1 aHofman, Albert1 aCampbell, Harry1 aFolsom, Aaron, R1 avan Veldhuisen, Dirk, J1 aSchwienbacher, Christine1 aO'Donnell, Christopher, J1 aVolpato, Claudia, Beu1 aCaulfield, Mark, J1 aConnell, John, M1 aLauner, Lenore1 aLu, Xiaowen1 aFranke, Lude1 aFehrmann, Rudolf, S N1 aMeerman, Gerard, te1 aGroen, Harry, J M1 aWeersma, Rinse, K1 avan den Berg, Leonard, H1 aWijmenga, Cisca1 aOphoff, Roel, A1 aNavis, Gerjan1 aRudan, Igor1 aSnieder, Harold1 aWilson, James, F1 aPramstaller, Peter, P1 aSiscovick, David, S1 aWang, Thomas, J1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aFelix, Stephan, B1 aFishman, Glenn, I1 aJamshidi, Yalda1 aStricker, Bruno, H Ch1 aSamani, Nilesh, J1 aKääb, Stefan1 aArking, Dan, E uhttps://chs-nhlbi.org/node/124404063nas a2201069 4500008004100000022001400041245007500055210006900130260001300199300001000212490000700222520107100229653001501300653001001315653000901325653002401334653002501358653001901383653001101402653003401413653001101447653001201458653000901470653002701479653001601506653003601522653005901558653001601617100002401633700002401657700002201681700001801703700001901721700001901740700002201759700002501781700002101806700002201827700001501849700001901864700002301883700002301906700002401929700002401953700002101977700002601998700002202024700002502046700001302071700002002084700002202104700002202126700002302148700002102171700002202192700002202214700001802236700001602254700002002270700002002290700001602310700001902326700002002345700002902365700001202394700002402406700002002430700002002450700002702470700002302497700002102520700002602541700001902567700002802586700001702614700002102631700002102652700001902673700002602692700002402718700002002742700001802762700002202780700002202802700003002824700001802854700001902872700002402891700002302915700001902938856003602957 2010 eng d a1546-171800aCommon variants in KCNN3 are associated with lone atrial fibrillation.0 aCommon variants in KCNN3 are associated with lone atrial fibrill c2010 Mar a240-40 v423 aAtrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
10aAdolescent10aAdult10aAged10aAtrial Fibrillation10aCase-Control Studies10aCohort Studies10aFemale10aGenome-Wide Association Study10aHumans10aIntrons10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aSmall-Conductance Calcium-Activated Potassium Channels10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aGlazer, Nicole, L1 aPfeufer, Arne1 aAlonso, Alvaro1 aChung, Mina, K1 aSinner, Moritz, F1 ade Bakker, Paul, I W1 aMueller, Martina1 aLubitz, Steven, A1 aFox, Ervin1 aDarbar, Dawood1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aSchnabel, Renate, B1 aSoliman, Elsayed, Z1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aBeckmann, Britt-M1 avan Noord, Charlotte1 aWang, Ke1 aEhret, Georg, B1 aRotter, Jerome, I1 aHazen, Stanley, L1 aSteinbeck, Gerhard1 aSmith, Albert, V1 aLauner, Lenore, J1 aHarris, Tamara, B1 aMakino, Seiko1 aNelis, Mari1 aMilan, David, J1 aPerz, Siegfried1 aEsko, Tõnu1 aKöttgen, Anna1 aMoebus, Susanne1 aNewton-Cheh, Christopher1 aLi, Man1 aMöhlenkamp, Stefan1 aWang, Thomas, J1 aKao, Linda, W H1 aVasan, Ramachandran, S1 aNöthen, Markus, M1 aMacRae, Calum, A1 aStricker, Bruno, H Ch1 aHofman, Albert1 aUitterlinden, André, G1 aLevy, Daniel1 aBoerwinkle, Eric1 aMetspalu, Andres1 aTopol, Eric, J1 aChakravarti, Aravinda1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aRoden, Dan, M1 aMeitinger, Thomas1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aBarnard, John1 aArking, Dan, E1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aKääb, Stefan uhttps://chs-nhlbi.org/node/117003170nas a2200481 4500008004100000022001400041245008500055210006900140260001600209300001200225490000800237520177400245653002202019653000902041653002402050653004002074653001102114653003402125653001102159653000902170653001602179653001702195100002302212700001902235700002302254700002202277700002202299700002202321700001802343700002402361700001702385700002202402700001502424700002202439700002302461700002402484700002002508700002402528700002402552700002302576710005302599856003602652 2010 eng d a1524-453900aEuropean ancestry as a risk factor for atrial fibrillation in African Americans.0 aEuropean ancestry as a risk factor for atrial fibrillation in Af c2010 Nov 16 a2009-150 v1223 aBACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF.
METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results.
CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.
10aAfrican Americans10aAged10aAtrial Fibrillation10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aRisk Factors1 aMarcus, Gregory, M1 aAlonso, Alvaro1 aPeralta, Carmen, A1 aLettre, Guillaume1 aVittinghoff, Eric1 aLubitz, Steven, A1 aFox, Ervin, R1 aLevitzky, Yamini, S1 aMehra, Reena1 aKerr, Kathleen, F1 aDeo, Rajat1 aSotoodehnia, Nona1 aAkylbekova, Meggie1 aEllinor, Patrick, T1 aPaltoo, Dina, N1 aSoliman, Elsayed, Z1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aCandidate-Gene Association Resource (CARe) Study uhttps://chs-nhlbi.org/node/124805209nas a2201129 4500008004100000022001400041245009100055210006900146260001600215300001300231490000600244520200900250653001502259653001002274653000902284653002202293653002802315653001002343653002102353653003202374653003202406653003102438653003102469653001902500653004002519653001102559653001702570653003402587653001102621653000902632653002702641653002102668653001602689653003602705653002002741653001602761100001802777700001702795700001702812700002302829700002502852700002002877700002002897700001902917700001802936700002402954700002702978700001703005700001703022700001903039700002803058700002603086700001903112700002703131700002303158700001503181700002003196700002603216700002203242700001903264700002203283700002003305700002303325700002403348700001903372700002203391700002203413700002003435700001603455700002203471700001803493700002603511700002103537700002203558700002403580700002003604700001703624700002203641700002303663700002803686700001703714700001903731700001603750700002703766700002103793700002303814700002203837700002203859700002103881700001903902700002403921700002403945700002803969700001803997710002804015856003604043 2010 eng d a1553-740400aFour novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.0 aFour novel Loci 19q13 6q24 12q24 and 5q14 influence the microcir c2010 Oct 28 ae10011840 v63 aThere is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aChild10aChild, Preschool10aChromosomes, Human, Pair 1210aChromosomes, Human, Pair 1910aChromosomes, Human, Pair 510aChromosomes, Human, Pair 610aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMicrocirculation10aMiddle Aged10aPolymorphism, Single Nucleotide10aRetinal Vessels10aYoung Adult1 aIkram, Kamran1 aSim, Xueling1 aXueling, Sim1 aJensen, Richard, A1 aCotch, Mary, Frances1 aHewitt, Alex, W1 aIkram, Arfan, M1 aWang, Jie, Jin1 aKlein, Ronald1 aKlein, Barbara, E K1 aBreteler, Monique, M B1 aCheung, Ning1 aLiew, Gerald1 aMitchell, Paul1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aHofman, Albert1 ade Jong, Paulus, T V M1 aDuijn, Cornelia, M1 aKao, Linda1 aCheng, Ching-Yu1 aSmith, Albert, Vernon1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aJonasson, Fridbert1 aEiriksdottir, Gudny1 aAspelund, Thor1 aHarris, Tamara, B1 aLauner, Lenore, J1 aTaylor, Kent, D1 aLi, Xiaohui1 aIyengar, Sudha, K1 aXi, Quansheng1 aSivakumaran, Theru, A1 aMackey, David, A1 aMacgregor, Stuart1 aMartin, Nicholas, G1 aYoung, Terri, L1 aBis, Josh, C1 aWiggins, Kerri, L1 aHeckbert, Susan, R1 aHammond, Christopher, J1 aAndrew, Toby1 aFahy, Samantha1 aAttia, John1 aHolliday, Elizabeth, G1 aScott, Rodney, J1 aIslam, F, M Amirul1 aRotter, Jerome, I1 aMcAuley, Annie, K1 aBoerwinkle, Eric1 aTai, Shyong, E1 aGudnason, Vilmundur1 aSiscovick, David, S1 aVingerling, Johannes, R1 aWong, Tien, Y1 aGlobal BPgen Consortium uhttps://chs-nhlbi.org/node/124303239nas a2200577 4500008004100000022001400041245008800055210006900143260001600212300001200228490000700240520165400247653001501901653001001916653000901926653001001935653002101945653001901966653001801985653001102003653002402014653003402038653001102072653000902083653001602092653003602108653001602144100002602160700002302186700002002209700002302229700001702252700002002269700001902289700002302308700001602331700002202347700001802369700001902387700001902406700001602425700002102441700001502462700002102477700002302498700001702521700002302538700002202561710004202583856003602625 2010 eng d a1460-208300aFucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.0 aFucosyltransferase 2 FUT2 nonsecretor status is associated with c2010 Sep 01 a3468-760 v193 aGenetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
10aAdolescent10aAdult10aAged10aChild10aChild, Preschool10aCohort Studies10aCrohn Disease10aFemale10aFucosyltransferases10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aYoung Adult1 aMcGovern, Dermot, P B1 aJones, Michelle, R1 aTaylor, Kent, D1 aMarciante, Kristin1 aYan, Xiaofei1 aDubinsky, Marla1 aIppoliti, Andy1 aVasiliauskas, Eric1 aBerel, Dror1 aDerkowski, Carrie1 aDutridge, Deb1 aFleshner, Phil1 aShih, David, Q1 aMelmed, Gil1 aMengesha, Emebet1 aKing, Lily1 aPressman, Sheila1 aHaritunians, Talin1 aGuo, Xiuqing1 aTargan, Stephan, R1 aRotter, Jerome, I1 aInternational IBD Genetics Consortium uhttps://chs-nhlbi.org/node/120903246nas a2200529 4500008004100000022001400041245006700055210006600122260001300188300001200201490000700213520174900220653001801969653001501987653001002002653001902012653001402031653002402045653001102069653001702080653003402097653001102131653003702142653000902179653003602188653001702224653003002241653005502271653001602326100002302342700002002365700002302385700002002408700002102428700001702449700001702466700001902483700001602502700002102518700002002539700002202559700002602581700002202607700002502629700002602654856003602680 2010 eng d a1536-484400aGenetic predictors of medically refractory ulcerative colitis.0 aGenetic predictors of medically refractory ulcerative colitis c2010 Nov a1830-400 v163 aBACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC.
METHODS: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls.
RESULTS: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)).
CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.
10aAcute Disease10aAdolescent10aAdult10aCohort Studies10aColectomy10aColitis, Ulcerative10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMajor Histocompatibility Complex10aMale10aPolymorphism, Single Nucleotide10aRisk Factors10aSeverity of Illness Index10aTumor Necrosis Factor Ligand Superfamily Member 1510aYoung Adult1 aHaritunians, Talin1 aTaylor, Kent, D1 aTargan, Stephan, R1 aDubinsky, Marla1 aIppoliti, Andrew1 aKwon, Soonil1 aGuo, Xiuqing1 aMelmed, Gil, Y1 aBerel, Dror1 aMengesha, Emebet1 aPsaty, Bruce, M1 aGlazer, Nicole, L1 aVasiliauskas, Eric, A1 aRotter, Jerome, I1 aFleshner, Phillip, R1 aMcGovern, Dermot, P B uhttps://chs-nhlbi.org/node/122905807nas a2201045 4500008004100000022001400041245007600055210006900131260001600200300001200216490000800228520280100236653001703037653000903054653002203063653002503085653001703110653003803127653003403165653001103199653001503210653003603225100002003261700002803281700002003309700002403329700002403353700001703377700001903394700002103413700002903434700002703463700001903490700003103509700002603540700002303566700002003589700002603609700002003635700003103655700002303686700001903709700002203728700001803750700002103768700002403789700002303813700002403836700002103860700002003881700001703901700002203918700002403940700002203964700002403986700001904010700002104029700002504050700002604075700002104101700002604122700002204148700002804170700002304198700002204221700001804243700001904261700002204280700002004302700001804322700002204340700001404362700002004376700002804396700002304424700001904447700001804466700002004484700002204504700002204526700002004548700002204568700002004590700002304610700002704633710002204660710002204682710002104704856003604725 2010 eng d a1538-359800aGenome-wide analysis of genetic loci associated with Alzheimer disease.0 aGenomewide analysis of genetic loci associated with Alzheimer di c2010 May 12 a1832-400 v3033 aCONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).
OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).
DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.
MAIN OUTCOME MEASURE: Presence of Alzheimer disease.
RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).
CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
10aAge of Onset10aAged10aAlzheimer Disease10aCase-Control Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aOdds Ratio10aPolymorphism, Single Nucleotide1 aSeshadri, Sudha1 aFitzpatrick, Annette, L1 aIkram, Arfan, M1 aDeStefano, Anita, L1 aGudnason, Vilmundur1 aBoada, Merce1 aBis, Joshua, C1 aSmith, Albert, V1 aCarassquillo, Minerva, M1 aLambert, Jean, Charles1 aHarold, Denise1 aSchrijvers, Elisabeth, M C1 aRamirez-Lorca, Reposo1 aDebette, Stephanie1 aLongstreth, W T1 aJanssens, Cecile, J W1 aPankratz, Shane1 aDartigues, Jean, François1 aHollingworth, Paul1 aAspelund, Thor1 aHernandez, Isabel1 aBeiser, Alexa1 aKuller, Lewis, H1 aKoudstaal, Peter, J1 aDickson, Dennis, W1 aTzourio, Christophe1 aAbraham, Richard1 aAntunez, Carmen1 aDu, Yangchun1 aRotter, Jerome, I1 aAulchenko, Yurii, S1 aHarris, Tamara, B1 aPetersen, Ronald, C1 aBerr, Claudine1 aOwen, Michael, J1 aLopez-Arrieta, Jesus1 aVaradarajan, Badri, N1 aBecker, James, T1 aRivadeneira, Fernando1 aNalls, Michael, A1 aGraff-Radford, Neill, R1 aCampion, Dominique1 aAuerbach, Sanford1 aRice, Kenneth1 aHofman, Albert1 aJonsson, Palmi, V1 aSchmidt, Helena1 aLathrop, Mark1 aMosley, Thomas, H1 aAu, Rhoda1 aPsaty, Bruce, M1 aUitterlinden, André, G1 aFarrer, Lindsay, A1 aLumley, Thomas1 aRuiz, Agustin1 aWilliams, Julie1 aAmouyel, Philippe1 aYounkin, Steve, G1 aWolf, Philip, A1 aLauner, Lenore, J1 aLopez, Oscar, L1 aDuijn, Cornelia, M1 aBreteler, Monique, M B1 aCHARGE Consortium1 aGERAD1 Consortium1 aEADI1 Consortium uhttps://chs-nhlbi.org/node/119905113nas a2201189 4500008004100000022001400041245009300055210006900148260001600217300001200233490000700245520181400252653001002066653000902076653001702085653001902102653001102121653001702132653001802149653003402167653001502201653001102216653000902227653001602236653003602252653000902288100002202297700002902319700002202348700002502370700002102395700002402416700002102440700001802461700001802479700001802497700001702515700002702532700001902559700001902578700001902597700002002616700001902636700002402655700001902679700002202698700002402720700002602744700002502770700002102795700002002816700001902836700002002855700001702875700002402892700002302916700001802939700001902957700001902976700002202995700002303017700002303040700001903063700002203082700002103104700001903125700002103144700002003165700002003185700001803205700001903223700002103242700001803263700001903281700002003300700002203320700001703342700003003359700002003389700002203409700002203431700001903453700002403472700002003496700002803516700002103544700002203565700002103587700002303608700002003631700002603651700002303677700002303700700002203723700002403745700001803769700002303787700002603810700002103836700003003857856003603887 2010 eng d a1460-208300aGenome-wide association analysis identifies multiple loci related to resting heart rate.0 aGenomewide association analysis identifies multiple loci related c2010 Oct 01 a3885-940 v193 aHigher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
10aAdult10aAged10aBase Pairing10aCohort Studies10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHeart Rate10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRest1 aEijgelsheim, Mark1 aNewton-Cheh, Christopher1 aSotoodehnia, Nona1 ade Bakker, Paul, I W1 aMüller, Martina1 aMorrison, Alanna, C1 aSmith, Albert, V1 aIsaacs, Aaron1 aSanna, Serena1 aDörr, Marcus1 aNavarro, Pau1 aFuchsberger, Christian1 aNolte, Ilja, M1 aGeus, Eco, J C1 aEstrada, Karol1 aHwang, Shih-Jen1 aBis, Joshua, C1 aRückert, Ina-Maria1 aAlonso, Alvaro1 aLauner, Lenore, J1 aHottenga, Jouke Jan1 aRivadeneira, Fernando1 aNoseworthy, Peter, A1 aRice, Kenneth, M1 aPerz, Siegfried1 aArking, Dan, E1 aSpector, Tim, D1 aKors, Jan, A1 aAulchenko, Yurii, S1 aTarasov, Kirill, V1 aHomuth, Georg1 aWild, Sarah, H1 aMarroni, Fabio1 aGieger, Christian1 aLicht, Carmilla, M1 aPrineas, Ronald, J1 aHofman, Albert1 aRotter, Jerome, I1 aHicks, Andrew, A1 aErnst, Florian1 aNajjar, Samer, S1 aWright, Alan, F1 aPeters, Annette1 aFox, Ervin, R1 aOostra, Ben, A1 aKroemer, Heyo, K1 aCouper, David1 aVölzke, Henry1 aCampbell, Harry1 aMeitinger, Thomas1 aUda, Manuela1 aWitteman, Jacqueline, C M1 aPsaty, Bruce, M1 aWichmann, H-Erich1 aHarris, Tamara, B1 aKääb, Stefan1 aSiscovick, David, S1 aJamshidi, Yalda1 aUitterlinden, André, G1 aFolsom, Aaron, R1 aLarson, Martin, G1 aWilson, James, F1 aPenninx, Brenda, W1 aSnieder, Harold1 aPramstaller, Peter, P1 aDuijn, Cornelia, M1 aLakatta, Edward, G1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aPfeufer, Arne1 aHeckbert, Susan, R1 aStricker, Bruno, H Ch1 aBoerwinkle, Eric1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/121703839nas a2200889 4500008004100000022001400041245008800055210006900143260001300212300001000225490000700235520129300242653002401535653003801559653003401597653001101631653002201642653002701664653003601691653001901727100002601746700001901772700002001791700002201811700001801833700002001851700002301871700001901894700002201913700001301935700001601948700002601964700002401990700002502014700001902039700001902058700002202077700002302099700002002122700002102142700002202163700002402185700001802209700002102227700002502248700002402273700002002297700002102317700002402338700002202362700002002384700002402404700001702428700001302445700002002458700002102478700002002499700002202519700002302541700002202564700002302586700001902609700001902628700002402647700002602671700002302697700001702720700002002737700002102757700002202778700002202800700001802822700001902840700002002859710003402879856003602913 2010 eng d a1546-171800aGenome-wide association identifies multiple ulcerative colitis susceptibility loci.0 aGenomewide association identifies multiple ulcerative colitis su c2010 Apr a332-70 v423 aUlcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
10aColitis, Ulcerative10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMembrane Proteins10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aReceptors, IgG1 aMcGovern, Dermot, P B1 aGardet, Agnès1 aTörkvist, Leif1 aGoyette, Philippe1 aEssers, Jonah1 aTaylor, Kent, D1 aNeale, Benjamin, M1 aOng, Rick, T H1 aLagacé, Caroline1 aLi, Chun1 aGreen, Todd1 aStevens, Christine, R1 aBeauchamp, Claudine1 aFleshner, Phillip, R1 aCarlson, Marie1 aD'Amato, Mauro1 aHalfvarson, Jonas1 aHibberd, Martin, L1 aLördal, Mikael1 aPadyukov, Leonid1 aAndriulli, Angelo1 aColombo, Elisabetta1 aLatiano, Anna1 aPalmieri, Orazio1 aBernard, Edmond-Jean1 aDeslandres, Colette1 aHommes, Daan, W1 ade Jong, Dirk, J1 aStokkers, Pieter, C1 aWeersma, Rinse, K1 aSharma, Yashoda1 aSilverberg, Mark, S1 aCho, Judy, H1 aWu, Jing1 aRoeder, Kathryn1 aBrant, Steven, R1 aSchumm, Phillip1 aDuerr, Richard, H1 aDubinsky, Marla, C1 aGlazer, Nicole, L1 aHaritunians, Talin1 aIppoliti, Andy1 aMelmed, Gil, Y1 aSiscovick, David, S1 aVasiliauskas, Eric, A1 aTargan, Stephan, R1 aAnnese, Vito1 aWijmenga, Cisca1 aPettersson, Sven1 aRotter, Jerome, I1 aXavier, Ramnik, J1 aDaly, Mark, J1 aRioux, John, D1 aSeielstad, Mark1 aNIDDK IBD Genetics Consortium uhttps://chs-nhlbi.org/node/117403424nas a2200589 4500008004100000022001400041245010200055210006900157260001600226300001100242490000800253520173500261653001901996653003402015653001302049653001102062653001502073653003602088653002102124653001302145653003002158100001702188700002402205700002002229700002102249700002002270700001402290700001902304700002802323700001602351700002302367700002402390700002802414700002102442700002202463700001602485700002002501700002402521700002102545700002702566700002502593700002202618700001602640700001802656700002102674700002102695700002002716700002002736700002402756700001802780856003602798 2010 eng d a1091-649000aGenome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.0 aGenomewide association identifies OBFC1 as a locus involved in h c2010 May 18 a9293-80 v1073 aTelomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.
10aCohort Studies10aGenome-Wide Association Study10aGenotype10aHumans10aLeukocytes10aPolymorphism, Single Nucleotide10aReceptors, CXCR410aTelomere10aTelomere-Binding Proteins1 aLevy, Daniel1 aNeuhausen, Susan, L1 aHunt, Steven, C1 aKimura, Masayuki1 aHwang, Shih-Jen1 aChen, Wei1 aBis, Joshua, C1 aFitzpatrick, Annette, L1 aSmith, Erin1 aJohnson, Andrew, D1 aGardner, Jeffrey, P1 aSrinivasan, Sathanur, R1 aSchork, Nicholas1 aRotter, Jerome, I1 aHerbig, Utz1 aPsaty, Bruce, M1 aSastrasinh, Malinee1 aMurray, Sarah, S1 aVasan, Ramachandran, S1 aProvince, Michael, A1 aGlazer, Nicole, L1 aLu, Xiaobin1 aCao, Xiaojian1 aKronmal, Richard1 aMangino, Massimo1 aSoranzo, Nicole1 aSpector, Tim, D1 aBerenson, Gerald, S1 aAviv, Abraham uhttps://chs-nhlbi.org/node/119204951nas a2201009 4500008004100000022001400041245010900055210006900164260001300233300001000246490000700256520207300263653002202336653000902358653001002367653002102377653001902398653002802417653001102445653001902456653002002475653003802495653002002533653002202553653003402575653001102609653002702620653003102647653000902678653001602687653003602703653002402739100002302763700001902786700002002805700002002825700002002845700002502865700001902890700002302909700002102932700002202953700002102975700001902996700002203015700002403037700002403061700002403085700002403109700002003133700002003153700002403173700001903197700001903216700002403235700001803259700002203277700002403299700002103323700002103344700002203365700002603387700002103413700001803434700002603452700002403478700002803502700002603530700001803556700001703574700002103591700002403612700001903636700002003655700001703675700002303692700001403715700002303729700002003752700002203772700002003794700002703814700002203841700002203863700002003885856003603905 2010 eng d a1524-462800aGenome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.0 aGenomewide association studies of MRIdefined brain infarcts meta c2010 Feb a210-70 v413 aBACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).
RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.
CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
10aAfrican Americans10aAged10aBrain10aBrain Infarction10aCohort Studies10aDNA Mutational Analysis10aFemale10aGene Frequency10aGenetic Markers10aGenetic Predisposition to Disease10aGenetic Testing10aGenetic Variation10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies1 aDebette, Stephanie1 aBis, Joshua, C1 aFornage, Myriam1 aSchmidt, Helena1 aIkram, Arfan, M1 aSigurdsson, Sigurdur1 aHeiss, Gerardo1 aStruchalin, Maksim1 aSmith, Albert, V1 avan der Lugt, Aad1 aDeCarli, Charles1 aLumley, Thomas1 aKnopman, David, S1 aEnzinger, Christian1 aEiriksdottir, Gudny1 aKoudstaal, Peter, J1 aDeStefano, Anita, L1 aPsaty, Bruce, M1 aDufouil, Carole1 aCatellier, Diane, J1 aFazekas, Franz1 aAspelund, Thor1 aAulchenko, Yurii, S1 aBeiser, Alexa1 aRotter, Jerome, I1 aTzourio, Christophe1 aShibata, Dean, K1 aTscherner, Maria1 aHarris, Tamara, B1 aRivadeneira, Fernando1 aAtwood, Larry, D1 aRice, Kenneth1 aGottesman, Rebecca, F1 avan Buchem, Mark, A1 aUitterlinden, André, G1 aKelly-Hayes, Margaret1 aCushman, Mary1 aZhu, Yicheng1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aHofman, Albert1 aRomero, Jose, R1 aLopez, Oscar1 aDuijn, Cornelia, M1 aAu, Rhoda1 aHeckbert, Susan, R1 aWolf, Philip, A1 aMosley, Thomas, H1 aSeshadri, Sudha1 aBreteler, Monique, M B1 aSchmidt, Reinhold1 aLauner, Lenore, J1 aLongstreth, W T uhttps://chs-nhlbi.org/node/115604031nas a2200733 4500008004100000022001400041245014700055210006900202260001600271490000600287520185700293653001002150653000902160653004002169653001102209653003402220653001102254653001402265653000902279653001602288653003602304653001402340653001102354100002002365700002602385700002002411700002202431700002102453700002602474700002002500700002102520700002102541700002202562700002202584700001602606700001902622700001902641700001602660700001802676700001902694700001902713700002002732700002202752700001802774700001802792700002202810700001802832700001902850700002002869700002202889700002802911700002602939700002002965700002302985700002003008700003003028700002403058700002403082700002103106700001903127710004803146710006703194856003603261 2010 eng d a1553-740400aGenome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels.0 aGenomewide association studies of serum magnesium potassium and c2010 Aug 050 v63 aMagnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.
10aAdult10aAged10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMagnesium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aPotassium10aSodium1 aMeyer, Tamra, E1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aGlazer, Nicole, L1 aSmith, Albert, V1 avan Rooij, Frank, J A1 aEhret, Georg, B1 aBoerwinkle, Eric1 aFelix, Janine, F1 aLeak, Tennille, S1 aHarris, Tamara, B1 aYang, Qiong1 aDehghan, Abbas1 aAspelund, Thor1 aKatz, Ronit1 aHomuth, Georg1 aKocher, Thomas1 aRettig, Rainer1 aRied, Janina, S1 aGieger, Christian1 aPrucha, Hanna1 aPfeufer, Arne1 aMeitinger, Thomas1 aCoresh, Josef1 aHofman, Albert1 aSarnak, Mark, J1 aChen, Yii-Der Ida1 aUitterlinden, André, G1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aKao, Linda, W H1 aWitteman, Jacqueline, C M1 aGudnason, Vilmundur1 aSiscovick, David, S1 aFox, Caroline, S1 aKöttgen, Anna1 aGenetic Factors for Osteoporosis Consortium1 aMeta Analysis of Glucose and Insulin Related Traits Consortium uhttps://chs-nhlbi.org/node/122303497nas a2200565 4500008004100000022001400041245011700055210006900172260001600241300001000257490000600267520187300273653000902146653001202155653002502167653001902192653002702211653001802238653001102256653003802267653003402305653001402339653001902353653001102372653000902383653001602392653002002408653004402428653001102472653003602483100001902519700002202538700001602560700001802576700001702594700002102611700002302632700002102655700002002676700002502696700001602721700002202737700002402759700002202783700002102805700002202826700002602848700002102874856003602895 2010 eng d a1932-620300aGenome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.0 aGenomewide association study identifies GPC5 as a novel genetic c2010 Mar 25 ae98790 v53 aBACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.
METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).
CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.
10aAged10aAlleles10aCase-Control Studies10aCohort Studies10aDeath, Sudden, Cardiac10aEthnic Groups10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlypicans10aHeart Diseases10aHumans10aMale10aMiddle Aged10aModels, Genetic10aOligonucleotide Array Sequence Analysis10aOregon10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aReinier, Kyndaron1 aPost, Wendy1 aJui, Jonathan1 aHilton, Gina1 aO'Connor, Ashley1 aPrineas, Ronald, J1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aTomaselli, Gordon, F1 aRea, Thomas1 aSotoodehnia, Nona1 aSiscovick, David, S1 aBurke, Gregory, L1 aMarbán, Eduardo1 aSpooner, Peter, M1 aChakravarti, Aravinda1 aChugh, Sumeet, S uhttps://chs-nhlbi.org/node/118204048nas a2201057 4500008004100000022001400041245005000055210004800105260001300153300001000166490000700176520109100183653000901274653002401283653001901307653002401326653001101350653001701361653003801378653003401416653002801450653001101478653000901489653002701498100001801525700002501543700002601568700001901594700002201613700002601635700002301661700002101684700002201705700002201727700002601749700001201775700002001787700001901807700001801826700001901844700002001863700001801883700002201901700002601923700001901949700001701968700002501985700002802010700002302038700002302061700001902084700002202103700002202125700002902147700002002176700002202196700002402218700001902242700001802261700002302279700002602302700002702328700001902355700002402374700002202398700002202420700002102442700002002463700002402483700001702507700002502524700002802549700002002577700002102597700002602618700002402644700002402668700002002692700002202712700002202734700001702756700002402773700002402797700001802821700001902839700003002858700001902888700002402907700002302931856003602954 2010 eng d a1546-171800aGenome-wide association study of PR interval.0 aGenomewide association study of PR interval c2010 Feb a153-90 v423 aThe electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.
10aAged10aAtrial Fibrillation10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMale10aMeta-Analysis as Topic1 aPfeufer, Arne1 avan Noord, Charlotte1 aMarciante, Kristin, D1 aArking, Dan, E1 aLarson, Martin, G1 aSmith, Albert, Vernon1 aTarasov, Kirill, V1 aMüller, Martina1 aSotoodehnia, Nona1 aSinner, Moritz, F1 aVerwoert, Germaine, C1 aLi, Man1 aKao, Linda, W H1 aKöttgen, Anna1 aCoresh, Josef1 aBis, Joshua, C1 aPsaty, Bruce, M1 aRice, Kenneth1 aRotter, Jerome, I1 aRivadeneira, Fernando1 aHofman, Albert1 aKors, Jan, A1 aStricker, Bruno, H C1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aBeckmann, Britt, M1 aSauter, Wiebke1 aGieger, Christian1 aLubitz, Steven, A1 aNewton-Cheh, Christopher1 aWang, Thomas, J1 aMagnani, Jared, W1 aSchnabel, Renate, B1 aChung, Mina, K1 aBarnard, John1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aVasan, Ramachandran, S1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLauner, Lenore, J1 aNajjar, Samer, S1 aLakatta, Edward1 aSchlessinger, David1 aUda, Manuela1 aAbecasis, Goncalo, R1 aMüller-Myhsok, Bertram1 aEhret, Georg, B1 aBoerwinkle, Eric1 aChakravarti, Aravinda1 aSoliman, Elsayed, Z1 aLunetta, Kathryn, L1 aPerz, Siegfried1 aWichmann, H-Erich1 aMeitinger, Thomas1 aLevy, Daniel1 aGudnason, Vilmundur1 aEllinor, Patrick, T1 aSanna, Serena1 aKääb, Stefan1 aWitteman, Jacqueline, C M1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/115902260nas a2200325 4500008004100000022001400041245008700055210006900142260001300211300001000224490000700234520135200241653001601593653001201609653002301621653001101644653001101655653003401666653001301700653001101713653000901724653002701733653001501760653001401775653003601789653002501825653001201850110003601862856003601898 2010 eng d a1546-171800aGenome-wide meta-analyses identify multiple loci associated with smoking behavior.0 aGenomewide metaanalyses identify multiple loci associated with s c2010 May a441-70 v423 aConsistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
10aAge Factors10aAlleles10aChromosome Mapping10aFemale10aGenome10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMolecular Epidemiology10aOdds Ratio10aPhenotype10aPolymorphism, Single Nucleotide10aReceptors, Nicotinic10aSmoking1 aTobacco and Genetics Consortium uhttps://chs-nhlbi.org/node/119104709nas a2201405 4500008004100000022001400041245010700055210006900162260001300231300001200244490000700256520077800263653002601041653001801067653002001085653001701105653003801122653002201160653001801182653003401200653001101234653003101245100001801276700002601294700002401320700001401344700002901358700001701387700002101404700002101425700001501446700002101461700002201482700001901504700002301523700002201546700002401568700002001592700001601612700002301628700001801651700001801669700002701687700002501714700002501739700002501764700002201789700001901811700002001830700001901850700002001869700002001889700002001909700002601929700002001955700002501975700001902000700002102019700001802040700002902058700001902087700002002106700001602126700002002142700001902162700002002181700002102201700001602222700002302238700002002261700001802281700002202299700002402321700002202345700002302367700002302390700001702413700001902430700001802449700001702467700001702484700002202501700001902523700001702542700002002559700002002579700001902599700002402618700002102642700002102663700002002684700002202704700001702726700001902743700002302762700002602785700002002811700002402831700001802855700002002873700002302893700002102916700001902937700001902956700002202975700002202997700002303019700002303042700002303065700002203088700002403110700001903134700002203153700001703175700001703192700002203209700001803231700001803249856003603267 2010 eng d a1546-171800aGenome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.0 aGenomewide metaanalysis increases to 71 the number of confirmed c2010 Dec a1118-250 v423 aWe undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
10aComputational Biology10aCrohn Disease10aGenetic Linkage10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aReproducibility of Results1 aFranke, Andre1 aMcGovern, Dermot, P B1 aBarrett, Jeffrey, C1 aWang, Kai1 aRadford-Smith, Graham, L1 aAhmad, Tariq1 aLees, Charlie, W1 aBalschun, Tobias1 aLee, James1 aRoberts, Rebecca1 aAnderson, Carl, A1 aBis, Joshua, C1 aBumpstead, Suzanne1 aEllinghaus, David1 aFesten, Eleonora, M1 aGeorges, Michel1 aGreen, Todd1 aHaritunians, Talin1 aJostins, Luke1 aLatiano, Anna1 aMathew, Christopher, G1 aMontgomery, Grant, W1 aPrescott, Natalie, J1 aRaychaudhuri, Soumya1 aRotter, Jerome, I1 aSchumm, Philip1 aSharma, Yashoda1 aSimms, Lisa, A1 aTaylor, Kent, D1 aWhiteman, David1 aWijmenga, Cisca1 aBaldassano, Robert, N1 aBarclay, Murray1 aBayless, Theodore, M1 aBrand, Stephan1 aBüning, Carsten1 aCohen, Albert1 aColombel, Jean-Frederick1 aCottone, Mario1 aStronati, Laura1 aDenson, Ted1 aDe Vos, Martine1 aD'Inca, Renata1 aDubinsky, Marla1 aEdwards, Cathryn1 aFlorin, Tim1 aFranchimont, Denis1 aGearry, Richard1 aGlas, Jürgen1 aVan Gossum, Andre1 aGuthery, Stephen, L1 aHalfvarson, Jonas1 aVerspaget, Hein, W1 aHugot, Jean-Pierre1 aKarban, Amir1 aLaukens, Debby1 aLawrance, Ian1 aLemann, Marc1 aLevine, Arie1 aLibioulle, Cecile1 aLouis, Edouard1 aMowat, Craig1 aNewman, William1 aPanés, Julián1 aPhillips, Anne1 aProctor, Deborah, D1 aRegueiro, Miguel1 aRussell, Richard1 aRutgeerts, Paul1 aSanderson, Jeremy1 aSans, Miquel1 aSeibold, Frank1 aSteinhart, Hillary1 aStokkers, Pieter, C F1 aTörkvist, Leif1 aKullak-Ublick, Gerd1 aWilson, David1 aWalters, Thomas1 aTargan, Stephan, R1 aBrant, Steven, R1 aRioux, John, D1 aD'Amato, Mauro1 aWeersma, Rinse, K1 aKugathasan, Subra1 aGriffiths, Anne, M1 aMansfield, John, C1 aVermeire, Severine1 aDuerr, Richard, H1 aSilverberg, Mark, S1 aSatsangi, Jack1 aSchreiber, Stefan1 aCho, Judy, H1 aAnnese, Vito1 aHakonarson, Hakon1 aDaly, Mark, J1 aParkes, Miles uhttps://chs-nhlbi.org/node/124904080nas a2200757 4500008004100000022001400041245019100055210006900246260001300315300001100328490000600339520181900345653002202164653000902186653002202195653001502217653001902232653004002251653001102291653003402302653001302336653001802349653001102367653001202378653000902390653003802399653002202437653001602459653003602475653001702511100002402528700002102552700002502573700002202598700002002620700001902640700002302659700001902682700002302701700002402724700001802748700002302766700002102789700002602810700002402836700001902860700001802879700002302897700003002920700002102950700002302971700001902994700001703013700002203030700001803052700002803070700002003098700002003118700002403138700002303162700002103185700003003206700002703236700002303263856003603286 2010 eng d a1942-326800aGenomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium.0 aGenomic variation associated with mortality among adults of Euro c2010 Jun a248-550 v33 aBACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.
METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.
CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.
10aAfrican Americans10aAged10aAged, 80 and over10aChemokines10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Failure10aHumans10aIntrons10aMale10aMARVEL Domain-Containing Proteins10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aMorrison, Alanna, C1 aFelix, Janine, F1 aCupples, Adrienne, L1 aGlazer, Nicole, L1 aLoehr, Laura, R1 aDehghan, Abbas1 aDemissie, Serkalem1 aBis, Joshua, C1 aRosamond, Wayne, D1 aAulchenko, Yurii, S1 aWang, Ying, A1 aHaritunians, Talin1 aFolsom, Aaron, R1 aRivadeneira, Fernando1 aBenjamin, Emelia, J1 aLumley, Thomas1 aCouper, David1 aStricker, Bruno, H1 aO'Donnell, Christopher, J1 aRice, Kenneth, M1 aChang, Patricia, P1 aHofman, Albert1 aLevy, Daniel1 aRotter, Jerome, I1 aFox, Ervin, R1 aUitterlinden, André, G1 aWang, Thomas, J1 aPsaty, Bruce, M1 aWillerson, James, T1 aDuijn, Cornelia, M1 aBoerwinkle, Eric1 aWitteman, Jacqueline, C M1 aVasan, Ramachandran, S1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/118712698nas a2203781 4500008004100000022001400041245009600055210006900151260001600220300001000236490000800246520210000254653001602354653003102370653001702401653003802418653001802456653003402474653001102508653003602519653003102555653001402586653003602600100002302636700001902659700002202678700002102700700002302721700002602744700002302770700002102793700002202814700002502836700002102861700002002882700002202902700002302924700002802947700002102975700002002996700001803016700001503034700002503049700002603074700002303100700001103123700002603134700001803160700001903178700001803197700001803215700001803233700002503251700002303276700002403299700001703323700002003340700003103360700002403391700001903415700002503434700002103459700001603480700001803496700002003514700001703534700002103551700002103572700001803593700001803611700001903629700002203648700002203670700002403692700002103716700002303737700002103760700001903781700001903800700002003819700002103839700002303860700003203883700002303915700002403938700002103962700001703983700001904000700002004019700002004039700001904059700002104078700001704099700002404116700002704140700001604167700001904183700002104202700002304223700002304246700002004269700001804289700002304307700001904330700001904349700002004368700001204388700002104400700001904421700002304440700002004463700001504483700002404498700002504522700002304547700002204570700002204592700002104614700002204635700001904657700002004676700001904696700001704715700001804732700001704750700001604767700002204783700002404805700002404829700002604853700002204879700002204901700002104923700001904944700002604963700002004989700002105009700002605030700002105056700001605077700001805093700002005111700002305131700002305154700001905177700002105196700001805217700002805235700002205263700002105285700001605306700001605322700001805338700001605356700001905372700002805391700002105419700001805440700002005458700001805478700002005496700001705516700002305533700001705556700002005573700002205593700002105615700002105636700002005657700001905677700002305696700001905719700002705738700001805765700002605783700002205809700002605831700002105857700002905878700001905907700001705926700002605943700001905969700002105988700001906009700002306028700001806051700001606069700001906085700002006104700002006124700002206144700001606166700002506182700002006207700002606227700001906253700002306272700002506295700002006320700002406340700001906364700002406383700001806407700002406425700002406449700002106473700002206494700002006516700002306536700002206559700002006581700001906601700002206620700002406642700001906666700002206685700002206707700001906729700001906748700002006767700002406787700003006811700001906841700001606860700002006876700002006896700002006916700001906936700001906955700001906974700002406993700002307017700002407040700002207064700001807086700002307104700002407127700001907151700002107170700002407191700002507215700002507240700002007265700002107285700002107306700002107327700002407348700002007372700002207392700002207414700001407436700002607450700002807476700002207504700002107526700002007547700002207567700001707589700002107606700002007627700002907647700001907676700001907695700002107714700002307735700002307758700002507781700002207806700002107828700002407849700002007873700002207893700002207915700002707937700002007964700002407984700002408008700002308032700002608055700002408081700001608105700002208121700002408143700001908167700001808186700002108204700001908225700002308244700001708267700002208284700002108306700001908327700002408346700002508370700002108395700002608416700002308442700002208465700002308487700002308510700002008533700002808553700002008581700002808601700002308629700002508652700002008677700002108697700002208718700002008740700002508760700002508785700002108810700002508831700002408856856003608880 2010 eng d a1476-468700aHundreds of variants clustered in genomic loci and biological pathways affect human height.0 aHundreds of variants clustered in genomic loci and biological pa c2010 Oct 14 a832-80 v4673 aMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
10aBody Height10aChromosomes, Human, Pair 310aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMetabolic Networks and Pathways10aMultifactorial Inheritance10aPhenotype10aPolymorphism, Single Nucleotide1 aAllen, Hana, Lango1 aEstrada, Karol1 aLettre, Guillaume1 aBerndt, Sonja, I1 aWeedon, Michael, N1 aRivadeneira, Fernando1 aWiller, Cristen, J1 aJackson, Anne, U1 aVedantam, Sailaja1 aRaychaudhuri, Soumya1 aFerreira, Teresa1 aWood, Andrew, R1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aSpeliotes, Elizabeth, K1 aWheeler, Eleanor1 aSoranzo, Nicole1 aPark, Ju-Hyun1 aYang, Jian1 aGudbjartsson, Daniel1 aHeard-Costa, Nancy, L1 aRandall, Joshua, C1 aQi, Lu1 aSmith, Albert, Vernon1 aMägi, Reedik1 aPastinen, Tomi1 aLiang, Liming1 aHeid, Iris, M1 aLuan, Jian'an1 aThorleifsson, Gudmar1 aWinkler, Thomas, W1 aGoddard, Michael, E1 aLo, Ken, Sin1 aPalmer, Cameron1 aWorkalemahu, Tsegaselassie1 aAulchenko, Yurii, S1 aJohansson, Asa1 aZillikens, Carola, M1 aFeitosa, Mary, F1 aEsko, Tõnu1 aJohnson, Toby1 aKetkar, Shamika1 aKraft, Peter1 aMangino, Massimo1 aProkopenko, Inga1 aAbsher, Devin1 aAlbrecht, Eva1 aErnst, Florian1 aGlazer, Nicole, L1 aHayward, Caroline1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aKnowles, Joshua, W1 aKutalik, Zoltán1 aMonda, Keri, L1 aPolasek, Ozren1 aPreuss, Michael1 aRayner, Nigel, W1 aRobertson, Neil, R1 aSteinthorsdottir, Valgerdur1 aTyrer, Jonathan, P1 aVoight, Benjamin, F1 aWiklund, Fredrik1 aXu, Jianfeng1 aZhao, Jing Hua1 aNyholt, Dale, R1 aPellikka, Niina1 aPerola, Markus1 aPerry, John, R B1 aSurakka, Ida1 aTammesoo, Mari-Liis1 aAltmaier, Elizabeth, L1 aAmin, Najaf1 aAspelund, Thor1 aBhangale, Tushar1 aBoucher, Gabrielle1 aChasman, Daniel, I1 aChen, Constance1 aCoin, Lachlan1 aCooper, Matthew, N1 aDixon, Anna, L1 aGibson, Quince1 aGrundberg, Elin1 aHao, Ke1 aJunttila, Juhani1 aKaplan, Lee, M1 aKettunen, Johannes1 aKönig, Inke, R1 aKwan, Tony1 aLawrence, Robert, W1 aLevinson, Douglas, F1 aLorentzon, Mattias1 aMcKnight, Barbara1 aMorris, Andrew, P1 aMüller, Martina1 aNgwa, Julius, Suh1 aPurcell, Shaun1 aRafelt, Suzanne1 aSalem, Rany, M1 aSalvi, Erika1 aSanna, Serena1 aShi, Jianxin1 aSovio, Ulla1 aThompson, John, R1 aTurchin, Michael, C1 aVandenput, Liesbeth1 aVerlaan, Dominique, J1 aVitart, Veronique1 aWhite, Charles, C1 aZiegler, Andreas1 aAlmgren, Peter1 aBalmforth, Anthony, J1 aCampbell, Harry1 aCitterio, Lorena1 aDe Grandi, Alessandro1 aDominiczak, Anna1 aDuan, Jubao1 aElliott, Paul1 aElosua, Roberto1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aGeus, Eco, J C1 aGlorioso, Nicola1 aHaiqing, Shen1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aIllig, Thomas1 aJula, Antti1 aKajantie, Eero1 aKilpeläinen, Tuomas, O1 aKoiranen, Markku1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aLaitinen, Jaana1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aMarusic, Ana1 aMaschio, Andrea1 aMeitinger, Thomas1 aMulas, Antonella1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPetersmann, Astrid1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPouta, Anneli1 aRidderstråle, Martin1 aRotter, Jerome, I1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSchmidt, Carsten, Oliver1 aSinisalo, Juha1 aSmit, Jan, H1 aStringham, Heather, M1 aWalters, Bragi1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aZagato, Laura1 aZgaga, Lina1 aZitting, Paavo1 aAlavere, Helene1 aFarrall, Martin1 aMcArdle, Wendy, L1 aNelis, Mari1 aPeters, Marjolein, J1 aRipatti, Samuli1 avan Meurs, Joyce, B J1 aAben, Katja, K1 aArdlie, Kristin, G1 aBeckmann, Jacques, S1 aBeilby, John, P1 aBergman, Richard, N1 aBergmann, Sven1 aCollins, Francis, S1 aCusi, Daniele1 aHeijer, Martin, den1 aEiriksdottir, Gudny1 aGejman, Pablo, V1 aHall, Alistair, S1 aHamsten, Anders1 aHuikuri, Heikki, V1 aIribarren, Carlos1 aKähönen, Mika1 aKaprio, Jaakko1 aKathiresan, Sekar1 aKiemeney, Lambertus1 aKocher, Thomas1 aLauner, Lenore, J1 aLehtimäki, Terho1 aMelander, Olle1 aMosley, Tom, H1 aMusk, Arthur, W1 aNieminen, Markku, S1 aO'Donnell, Christopher, J1 aOhlsson, Claes1 aOostra, Ben1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aRioux, John, D1 aRissanen, Aila1 aRivolta, Carlo1 aSchunkert, Heribert1 aShuldiner, Alan, R1 aSiscovick, David, S1 aStumvoll, Michael1 aTönjes, Anke1 aTuomilehto, Jaakko1 avan Ommen, Gert-Jan1 aViikari, Jorma1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aProvince, Michael, A1 aKayser, Manfred1 aArnold, Alice, M1 aAtwood, Larry, D1 aBoerwinkle, Eric1 aChanock, Stephen, J1 aDeloukas, Panos1 aGieger, Christian1 aGrönberg, Henrik1 aHall, Per1 aHattersley, Andrew, T1 aHengstenberg, Christian1 aHoffman, Wolfgang1 aLathrop, Mark, G1 aSalomaa, Veikko1 aSchreiber, Stefan1 aUda, Manuela1 aWaterworth, Dawn1 aWright, Alan, F1 aAssimes, Themistocles, L1 aBarroso, Inês1 aHofman, Albert1 aMohlke, Karen, L1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCupples, Adrienne, L1 aErdmann, Jeanette1 aFox, Caroline, S1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHarris, Tamara, B1 aHayes, Richard, B1 aJarvelin, Marjo-Riitta1 aMooser, Vincent1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aRudan, Igor1 aSamani, Nilesh, J1 aSpector, Timothy, D1 aVölzke, Henry1 aWatkins, Hugh1 aWilson, James, F1 aGroop, Leif, C1 aHaritunians, Talin1 aHu, Frank, B1 aKaplan, Robert, C1 aMetspalu, Andres1 aNorth, Kari, E1 aSchlessinger, David1 aWareham, Nicholas, J1 aHunter, David, J1 aO'Connell, Jeffrey, R1 aStrachan, David, P1 aWichmann, H-Erich1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aSchadt, Eric, E1 aThorsteinsdottir, Unnur1 aPeltonen, Leena1 aUitterlinden, André, G1 aVisscher, Peter, M1 aChatterjee, Nilanjan1 aLoos, Ruth, J F1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aIngelsson, Erik1 aLindgren, Cecilia, M1 aAbecasis, Goncalo, R1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N uhttps://chs-nhlbi.org/node/123405042nas a2201093 4500008004100000022001400041245017600055210006900231260001300300300001200313490000700325520188300332653001002215653000902225653001802234653001702252653004002269653001202309653001102321653001702332653003402349653001302383653001102396653001202407653000902419653001602428653003602444100002702480700002302507700002202530700002402552700002502576700001702601700002602618700002102644700002402665700001402689700001702703700002002720700002602740700002002766700001802786700002102804700002902825700002502854700002502879700002502904700002302929700002302952700002102975700002002996700002103016700002703037700002103064700001903085700001903104700002303123700001703146700002403163700002803187700002403215700001903239700001703258700001803275700001903293700002503312700002003337700001803357700001703375700002103392700002203413700002003435700002503455700001703480700001803497700003103515700002803546700002503574700002103599700002103620700002303641700002003664700003003684700001903714700002503733700002103758700002003779700002503799700002403824700002003848700002003868710002403888856003603912 2010 eng d a1935-554800aInteractions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.0 aInteractions of dietary wholegrain intake with fasting glucose a c2010 Dec a2684-910 v333 aOBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.
RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.
RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.
CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
10aAdult10aAged10aBlood Glucose10aEdible Grain10aEuropean Continental Ancestry Group10aFasting10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aNettleton, Jennifer, A1 aMcKeown, Nicola, M1 aKanoni, Stavroula1 aLemaitre, Rozenn, N1 aHivert, Marie-France1 aNgwa, Julius1 avan Rooij, Frank, J A1 aSonestedt, Emily1 aWojczynski, Mary, K1 aYe, Zheng1 aTanaka, Tosh1 aGarcia, Melissa1 aAnderson, Jennifer, S1 aFollis, Jack, L1 aDjoussé, Luc1 aMukamal, Kenneth1 aPapoutsakis, Constantina1 aMozaffarian, Dariush1 aZillikens, Carola, M1 aBandinelli, Stefania1 aBennett, Amanda, J1 aBorecki, Ingrid, B1 aFeitosa, Mary, F1 aFerrucci, Luigi1 aForouhi, Nita, G1 aGroves, Christopher, J1 aHallmans, Göran1 aHarris, Tamara1 aHofman, Albert1 aHouston, Denise, K1 aHu, Frank, B1 aJohansson, Ingegerd1 aKritchevsky, Stephen, B1 aLangenberg, Claudia1 aLauner, Lenore1 aLiu, Yongmei1 aLoos, Ruth, J1 aNalls, Michael1 aOrho-Melander, Marju1 aRenstrom, Frida1 aRice, Kenneth1 aRiserus, Ulf1 aRolandsson, Olov1 aRotter, Jerome, I1 aSaylor, Georgia1 aSijbrands, Eric, J G1 aSjogren, Per1 aSmith, Albert1 aSteingrímsdóttir, Laufey1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aProkopenko, Inga1 aPankow, James, S1 aDuijn, Cornelia, M1 aFlorez, Jose, C1 aWitteman, Jacqueline, C M1 aDupuis, Josée1 aDedoussis, George, V1 aOrdovas, Jose, M1 aIngelsson, Erik1 aCupples, Adrienne, L1 aSiscovick, David, S1 aFranks, Paul, W1 aMeigs, James, B1 aMAGIC investigators uhttps://chs-nhlbi.org/node/122203243nas a2200625 4500008004100000022001400041245009400055210006900149260001600218300001200234490000700246520141500253653002701668653002001695653003801715653004001753653001701793653003401810653001101844653003801855653001501893100001901908700001901927700001901946700001901965700002201984700002402006700001702030700002102047700002302068700002002091700001302111700002202124700001802146700001702164700002002181700001802201700002202219700002702241700002202268700002202290700002802312700002302340700001702363700002302380700002002403700002102423700001902444700002102463700002002484700002802504700002502532700002402557856003602581 2010 eng d a1460-208300aLarge-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels.0 aLargescale genomic studies reveal central role of ABO in sPselec c2010 May 01 a1863-720 v193 aP-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.
10aABO Blood-Group System10aBlood Platelets10aEnzyme-Linked Immunosorbent Assay10aEuropean Continental Ancestry Group10aFluorescence10aGenome-Wide Association Study10aHumans10aIntercellular Adhesion Molecule-110aP-Selectin1 aBarbalic, Maja1 aDupuis, Josée1 aDehghan, Abbas1 aBis, Joshua, C1 aHoogeveen, Ron, C1 aSchnabel, Renate, B1 aNambi, Vijay1 aBretler, Monique1 aSmith, Nicholas, L1 aPeters, Annette1 aLu, Chen1 aTracy, Russell, P1 aAleksic, Nena1 aHeeriga, Jan1 aKeaney, John, F1 aRice, Kenneth1 aLip, Gregory, Y H1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aLarson, Martin, G1 aUitterlinden, André, G1 aYamamoto, Jennifer1 aDurda, Peter1 aHaritunians, Talin1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aHofman, Albert1 aKoenig, Wolfgang1 aJenny, Nancy, S1 aWitteman, Jacqueline, C1 aBallantyne, Christie1 aBenjamin, Emelia, J uhttps://chs-nhlbi.org/node/116902822nas a2200637 4500008004100000022001400041245011200055210006900167260001300236300001000249490000700259520095900266653002301225653001101248653002901259653003801288653001801326653003401344653001101378653000901389653001801398653000901416653002701425653003601452653001501488653001901503100002101522700002201543700001901565700002001584700002001604700002601624700002301650700003001673700001901703700001701722700002501739700002101764700002201785700002001807700002301827700002201850700002801872700001901900700002301919700002601942700002401968700002101992700001902013700002302032700001902055700002502074700002402099700002502123856003602148 2010 eng d a1546-171800aMeta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.0 aMetaanalyses of genomewide association studies identify multiple c2010 Jan a45-520 v423 aSpirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.
10aDatabases, Genetic10aFemale10aForced Expiratory Volume10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLung10aLung Diseases10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aSpirometry10aVital Capacity1 aHancock, Dana, B1 aEijgelsheim, Mark1 aWilk, Jemma, B1 aGharib, Sina, A1 aLoehr, Laura, R1 aMarciante, Kristin, D1 aFranceschini, Nora1 avan Durme, Yannick, M T A1 aChen, Ting-Hsu1 aBarr, Graham1 aSchabath, Matthew, B1 aCouper, David, J1 aBrusselle, Guy, G1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aRotter, Jerome, I1 aUitterlinden, André, G1 aHofman, Albert1 aPunjabi, Naresh, M1 aRivadeneira, Fernando1 aMorrison, Alanna, C1 aEnright, Paul, L1 aNorth, Kari, E1 aHeckbert, Susan, R1 aLumley, Thomas1 aStricker, Bruno, H C1 aO'Connor, George, T1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/115011930nas a2203889 4500008004100000022001400041245014500055210006900200260001300269300001100282490000700293520104400300653001901344653001601363653002301379653001101402653001801413653003401431653001101465653000901476653002701485653003601512653002401548653002001572100001801592700002101610700002301631700002301654700001101677700003201688700002501720700002501745700002801770700001801798700003101816700002201847700002501869700002201894700002101916700002001937700002301957700002301980700001802003700002202021700001602043700002802059700002102087700001602108700001902124700001902143700002702162700001902189700001802208700001902226700002302245700001902268700002202287700002002309700002402329700002102353700002102374700002302395700002202418700002102440700002002461700001902481700002402500700002202524700002102546700002002567700001902587700002602606700002302632700001502655700002502670700001802695700002402713700001802737700001602755700001902771700001802790700002202808700002202830700002602852700002402878700001902902700001802921700002102939700001702960700002002977700002302997700001703020700001903037700002003056700002603076700002203102700002203124700001603146700002103162700002503183700001903208700002103227700002103248700002003269700002603289700002303315700001803338700001603356700001703372700002203389700002603411700002203437700001903459700003503478700002103513700001603534700002403550700002103574700001903595700002203614700002003636700002003656700001703676700002403693700002403717700002803741700002503769700001603794700002303810700002303833700002303856700002303879700002403902700002003926700001903946700002403965700002003989700001904009700002104028700002304049700001904072700002504091700002504116700002404141700002004165700001804185700001704203700001804220700001804238700002204256700002304278700002304301700001204324700001804336700001904354700002304373700002104396700002304417700002704440700002204467700002804489700002204517700002204539700002304561700002104584700001604605700001604621700002204637700001604659700001904675700002004694700001804714700002004732700001804752700002104770700002204791700002204813700001904835700002004854700002204874700002104896700002304917700002104940700002004961700002204981700001905003700002105022700001605043700002105059700002105080700002005101700001905121700001905140700002705159700002205186700001805208700002605226700002205252700002005274700001905294700001705313700002505330700002605355700001805381700002405399700001905423700002005442700002605462700002405488700001905512700002405531700002505555700002205580700002105602700001905623700002305642700002105665700001605686700001905702700002005721700001905741700002005760700002205780700002405802700001905826700002005845700002005865700002005885700002205905700001805927700001905945700002105964700002105985700002406006700001906030700002406049700001806073700002206091700001906113700002806132700002006160700001506180700002306195700001906218700001806237700001906255700002206274700001806296700002206314700002106336700002406357700001906381700002006400700002406420700002206444700002306466700001906489700002506508700002106533700002506554700001906579700002106598700002306619700002306642700002406665700002406689700002406713700002006737700002006757700002606777700001906803700001706822700001806839700002206857700002706879700002006906700001906926700002206945700002406967700001606991700002307007700002607030700002007056700002407076700001907100700001607119700002307135700002007158700002407178700002807202700001707230700002407247700001907271700002407290700002107314700002807335700002007363700002507383700002107408700002307429700002007452700002507472700001907497700002307516700002107539700002207560700001907582700002607601700002007627700002407647700002307671700002407694700002907718700002207747700002807769700002307797700002107820700002507841700002007866700001907886700002207905700002107927700002107948700002507969710001007994856003608004 2010 eng d a1546-171800aMeta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.0 aMetaanalysis identifies 13 new loci associated with waisthip rat c2010 Nov a949-600 v423 aWaist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
10aAdipose Tissue10aAge Factors10aChromosome Mapping10aFemale10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist-Hip Ratio1 aHeid, Iris, M1 aJackson, Anne, U1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aQi, Lu1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aZillikens, Carola, M1 aSpeliotes, Elizabeth, K1 aMägi, Reedik1 aWorkalemahu, Tsegaselassie1 aWhite, Charles, C1 aBouatia-Naji, Nabila1 aHarris, Tamara, B1 aBerndt, Sonja, I1 aIngelsson, Erik1 aWiller, Cristen, J1 aWeedon, Michael, N1 aLuan, Jian'an1 aVedantam, Sailaja1 aEsko, Tõnu1 aKilpeläinen, Tuomas, O1 aKutalik, Zoltán1 aLi, Shengxu1 aMonda, Keri, L1 aDixon, Anna, L1 aHolmes, Christopher, C1 aKaplan, Lee, M1 aLiang, Liming1 aMin, Josine, L1 aMoffatt, Miriam, F1 aMolony, Cliona1 aNicholson, George1 aSchadt, Eric, E1 aZondervan, Krina, T1 aFeitosa, Mary, F1 aFerreira, Teresa1 aAllen, Hana, Lango1 aWeyant, Robert, J1 aWheeler, Eleanor1 aWood, Andrew, R1 aEstrada, Karol1 aGoddard, Michael, E1 aLettre, Guillaume1 aMangino, Massimo1 aNyholt, Dale, R1 aPurcell, Shaun1 aSmith, Albert, Vernon1 aVisscher, Peter, M1 aYang, Jian1 aMcCarroll, Steven, A1 aNemesh, James1 aVoight, Benjamin, F1 aAbsher, Devin1 aAmin, Najaf1 aAspelund, Thor1 aCoin, Lachlan1 aGlazer, Nicole, L1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKapur, Karen1 aKetkar, Shamika1 aKnowles, Joshua, W1 aKraft, Peter1 aKraja, Aldi, T1 aLamina, Claudia1 aLeitzmann, Michael, F1 aMcKnight, Barbara1 aMorris, Andrew, P1 aOng, Ken, K1 aPerry, John, R B1 aPeters, Marjolein, J1 aPolasek, Ozren1 aProkopenko, Inga1 aRayner, Nigel, W1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRobertson, Neil, R1 aSanna, Serena1 aSovio, Ulla1 aSurakka, Ida1 aTeumer, Alexander1 avan Wingerden, Sophie1 aVitart, Veronique1 aZhao, Jing Hua1 aCavalcanti-Proença, Christine1 aChines, Peter, S1 aFisher, Eva1 aKulzer, Jennifer, R1 aLecoeur, Cécile1 aNarisu, Narisu1 aSandholt, Camilla1 aScott, Laura, J1 aSilander, Kaisa1 aStark, Klaus1 aTammesoo, Mari-Liis1 aTeslovich, Tanya, M1 aTimpson, Nicholas, John1 aWatanabe, Richard, M1 aWelch, Ryan1 aChasman, Daniel, I1 aCooper, Matthew, N1 aJansson, John-Olov1 aKettunen, Johannes1 aLawrence, Robert, W1 aPellikka, Niina1 aPerola, Markus1 aVandenput, Liesbeth1 aAlavere, Helene1 aAlmgren, Peter1 aAtwood, Larry, D1 aBennett, Amanda, J1 aBiffar, Reiner1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBuchanan, Thomas, A1 aCampbell, Harry1 aDay, Ian, N M1 aDei, Mariano1 aDörr, Marcus1 aElliott, Paul1 aErdos, Michael, R1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGeus, Eco, J C1 aGjesing, Anette, P1 aGrallert, Harald1 aGrässler, Jürgen1 aGroves, Christopher, J1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHavulinna, Aki, S1 aHerzig, Karl-Heinz1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aJousilahti, Pekka1 aJula, Antti1 aKajantie, Eero1 aKinnunen, Leena1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aKroemer, Heyo, K1 aKrzelj, Vjekoslav1 aKuusisto, Johanna1 aKvaloy, Kirsti1 aLaitinen, Jaana1 aLantieri, Olivier1 aLathrop, Mark, G1 aLokki, Marja-Liisa1 aLuben, Robert, N1 aLudwig, Barbara1 aMcArdle, Wendy, L1 aMcCarthy, Anne1 aMorken, Mario, A1 aNelis, Mari1 aNeville, Matt, J1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPlatou, Carl, G P1 aPouta, Anneli1 aRidderstråle, Martin1 aSamani, Nilesh, J1 aSaramies, Jouko1 aSinisalo, Juha1 aSmit, Jan, H1 aStrawbridge, Rona, J1 aStringham, Heather, M1 aSwift, Amy, J1 aTeder-Laving, Maris1 aThomson, Brian1 aUsala, Gianluca1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aVolpato, Claudia, B1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aZgaga, Lina1 aZitting, Paavo1 aBeilby, John, P1 aJames, Alan, L1 aKähönen, Mika1 aLehtimäki, Terho1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aStumvoll, Michael1 aTönjes, Anke1 aViikari, Jorma1 aBalkau, Beverley1 aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBoeing, Heiner1 aSmith, George Davey1 aEbrahim, Shah1 aFroguel, Philippe1 aHansen, Torben1 aHengstenberg, Christian1 aHveem, Kristian1 aIsomaa, Bo1 aJørgensen, Torben1 aKarpe, Fredrik1 aKhaw, Kay-Tee1 aLaakso, Markku1 aLawlor, Debbie, A1 aMarre, Michel1 aMeitinger, Thomas1 aMetspalu, Andres1 aMidthjell, Kristian1 aPedersen, Oluf1 aSalomaa, Veikko1 aSchwarz, Peter, E H1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aValle, Timo, T1 aWareham, Nicholas, J1 aArnold, Alice, M1 aBeckmann, Jacques, S1 aBergmann, Sven1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCollins, Francis, S1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHattersley, Andrew, T1 aHofman, Albert1 aHu, Frank, B1 aIllig, Thomas1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aKao, Linda, W H1 aKaprio, Jaakko1 aLauner, Lenore, J1 aMunroe, Patricia, B1 aOostra, Ben1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRissanen, Aila1 aRudan, Igor1 aShuldiner, Alan, R1 aSoranzo, Nicole1 aSpector, Timothy, D1 aSyvänen, Ann-Christine1 aUda, Manuela1 aUitterlinden, Andre1 aVölzke, Henry1 aVollenweider, Peter1 aWilson, James, F1 aWitteman, Jacqueline, C1 aWright, Alan, F1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFrayling, Timothy, M1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aHirschhorn, Joel, N1 aAssimes, Themistocles, L1 aWichmann, H-Erich1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aStefansson, Kari1 aCupples, Adrienne, L1 aLoos, Ruth, J F1 aBarroso, Inês1 aMcCarthy, Mark, I1 aFox, Caroline, S1 aMohlke, Karen, L1 aLindgren, Cecilia, M1 aMAGIC uhttps://chs-nhlbi.org/node/123604122nas a2200841 4500008004100000022001400041245017500055210006900230260001300299300001100312490000700323520169700330653001002027653001602037653000902053653002202062653001202084653001902096653002502115653001102140653003402151653001302185653001102198653001402209653000902223653001602232653001502248653003602263100002002299700001902319700002402338700002302362700002002385700002302405700002102428700001902449700002402468700002402492700002302516700002502539700002802564700002302592700002202615700002402637700001902661700001902680700001902699700002602718700002102744700002202765700002602787700002302813700001902836700002202855700002002877700002002897700002602917700001902943700002002962700002102982700002003003700002203023700001603045700002803061700002103089700002003110700002603130700002203156700001903178700002303197700002403220856003603244 2010 eng d a1758-535X00aA meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.0 ametaanalysis of four genomewide association studies of survival c2010 May a478-870 v653 aBACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.
METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.
RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.
CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.
10aAdult10aAge Factors10aAged10aAged, 80 and over10aAlleles10aCohort Studies10aConfidence Intervals10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aLongevity10aMale10aMiddle Aged10aOdds Ratio10aPolymorphism, Single Nucleotide1 aNewman, Anne, B1 aWalter, Stefan1 aLunetta, Kathryn, L1 aGarcia, Melissa, E1 aSlagboom, Eline1 aChristensen, Kaare1 aArnold, Alice, M1 aAspelund, Thor1 aAulchenko, Yurii, S1 aBenjamin, Emelia, J1 aChristiansen, Lene1 aD'Agostino, Ralph, B1 aFitzpatrick, Annette, L1 aFranceschini, Nora1 aGlazer, Nicole, L1 aGudnason, Vilmundur1 aHofman, Albert1 aKaplan, Robert1 aKarasik, David1 aKelly-Hayes, Margaret1 aKiel, Douglas, P1 aLauner, Lenore, J1 aMarciante, Kristin, D1 aMassaro, Joseph, M1 aMiljkovic, Iva1 aNalls, Michael, A1 aHernandez, Dena1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome1 aSeshadri, Sudha1 aSmith, Albert, V1 aTaylor, Kent, D1 aTiemeier, Henning1 aUh, Hae-Won1 aUitterlinden, André, G1 aVaupel, James, W1 aWalston, Jeremy1 aWestendorp, Rudi, G J1 aHarris, Tamara, B1 aLumley, Thomas1 aDuijn, Cornelia, M1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/117903867nas a2200745 4500008004100000022001400041245012900055210006900184260001300253300001100266490000600277520177500283653002802058653002102086653001102107653001702118653003402135653000902169653001102178653000902189653001702198653001402215100001602229700001902245700001902264700002102283700002202304700002002326700002302346700001902369700002402388700002202412700001902434700001902453700002002472700001902492700002102511700002002532700001202552700002002564700002102584700002302605700001202628700001902640700002002659700002102679700002002700700002202720700003002742700002102772700002302793700001902816700002602835700002002861700002802881700002102909700002002930700002002950700002402970700002402994700002803018700002103046700001803067856003603085 2010 eng d a1942-326800aMultiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.0 aMultiple genetic loci influence serum urate levels and their rel c2010 Dec a523-300 v33 aBACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).
METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.
CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
10aCardiovascular Diseases10aCoronary Disease10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGout10aHumans10aMale10aRisk Factors10aUric Acid1 aYang, Qiong1 aKöttgen, Anna1 aDehghan, Abbas1 aSmith, Albert, V1 aGlazer, Nicole, L1 aChen, Ming-Huei1 aChasman, Daniel, I1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLauner, Lenore1 aNalls, Michael1 aHernandez, Dena1 aArking, Dan, E1 aBoerwinkle, Eric1 aGrove, Megan, L1 aLi, Man1 aKao, W, H Linda1 aChonchol, Michel1 aHaritunians, Talin1 aLi, Guo1 aLumley, Thomas1 aPsaty, Bruce, M1 aShlipak, Michael1 aHwang, Shih-Jen1 aLarson, Martin, G1 aO'Donnell, Christopher, J1 aUpadhyay, Ashish1 aDuijn, Cornelia, M1 aHofman, Albert1 aRivadeneira, Fernando1 aStricker, Bruno1 aUitterlinden, André, G1 aParé, Guillaume1 aParker, Alex, N1 aRidker, Paul, M1 aSiscovick, David, S1 aGudnason, Vilmundur1 aWitteman, Jacqueline, C1 aFox, Caroline, S1 aCoresh, Josef uhttps://chs-nhlbi.org/node/123512636nas a2204069 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2010 eng d a1546-171800aNew genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.0 aNew genetic loci implicated in fasting glucose homeostasis and t c2010 Feb a105-160 v423 aLevels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
10aAdolescent10aAdult10aAlleles10aBlood Glucose10aChild10aDatabases, Genetic10aDiabetes Mellitus, Type 210aDNA Copy Number Variations10aFasting10aGene Expression Regulation10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeostasis10aHumans10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aReproducibility of Results1 aDupuis, Josée1 aLangenberg, Claudia1 aProkopenko, Inga1 aSaxena, Richa1 aSoranzo, Nicole1 aJackson, Anne, U1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aGloyn, Anna, L1 aLindgren, Cecilia, M1 aMägi, Reedik1 aMorris, Andrew, P1 aRandall, Joshua1 aJohnson, Toby1 aElliott, Paul1 aRybin, Denis1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aHenneman, Peter1 aGrallert, Harald1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aFranklin, Christopher, S1 aNavarro, Pau1 aSong, Kijoung1 aGoel, Anuj1 aPerry, John, R B1 aEgan, Josephine, M1 aLajunen, Taina1 aGrarup, Niels1 aSparsø, Thomas1 aDoney, Alex1 aVoight, Benjamin, F1 aStringham, Heather, M1 aLi, Man1 aKanoni, Stavroula1 aShrader, Peter1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aQi, Lu1 aTimpson, Nicholas, J1 aGieger, Christian1 aZabena, Carina1 aRocheleau, Ghislain1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aPayne, Felicity1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aArdlie, Kristin1 aAriyurek, Yavuz1 aBalkau, Beverley1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBonnefond, Amélie1 aBonnycastle, Lori, L1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aCharpentier, Guillaume1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCornelis, Marilyn1 aCrawford, Gabe1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aDina, Christian1 aErdos, Michael, R1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFox, Caroline, S1 aFrants, Rune1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGroves, Christopher, J1 aGrundy, Scott1 aGwilliam, Rhian1 aGyllensten, Ulf1 aHadjadj, Samy1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHerder, Christian1 aHicks, Andrew, A1 aHillman, David, R1 aHingorani, Aroon, D1 aHofman, Albert1 aHui, Jennie1 aHung, Joe1 aIsomaa, Bo1 aJohnson, Paul, R V1 aJørgensen, Torben1 aJula, Antti1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aLyssenko, Valeriya1 aMahley, Robert1 aMangino, Massimo1 aManning, Alisa, K1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcCulloch, Laura, J1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, Braxton, D1 aMorken, Mario, A1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNarisu, Narisu1 aNeville, Matthew, J1 aOostra, Ben, A1 aOrrù, Marco1 aPakyz, Ruth1 aPalmer, Colin, N A1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPerola, Markus1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRathmann, Wolfgang1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRoden, Michael1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aScott, Laura, J1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurethsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTanaka, Toshiko1 aThorand, Barbara1 aTichet, Jean1 aTönjes, Anke1 aTuomi, Tiinamaija1 aUitterlinden, André, G1 aDijk, Ko Willems1 aHoek, Mandy1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWalters, Bragi, G1 aWard, Kim, L1 aWatkins, Hugh1 aWeedon, Michael, N1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZeggini, Eleftheria1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aLoos, Ruth, J F1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aHattersley, Andrew, T1 aSilander, Kaisa1 aSalomaa, Veikko1 aSmith, George Davey1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aDedoussis, George, V1 aSerrano-Ríos, Manuel1 aMorris, Andrew, D1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPankow, James, S1 aSampson, Michael, J1 aKuusisto, Johanna1 aLaakso, Markku1 aHansen, Torben1 aPedersen, Oluf1 aPramstaller, Peter Paul1 aWichmann, Erich, H1 aIllig, Thomas1 aRudan, Igor1 aWright, Alan, F1 aStumvoll, Michael1 aCampbell, Harry1 aWilson, James, F1 aBergman, Richard, N1 aBuchanan, Thomas, A1 aCollins, Francis, S1 aMohlke, Karen, L1 aTuomilehto, Jaakko1 aValle, Timo, T1 aAltshuler, David1 aRotter, Jerome, I1 aSiscovick, David, S1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aDeloukas, Panos1 aSpector, Timothy, D1 aFrayling, Timothy, M1 aFerrucci, Luigi1 aKong, Augustine1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAulchenko, Yurii, S1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aWaterworth, Dawn, M1 aVollenweider, Peter1 aPeltonen, Leena1 aMooser, Vincent1 aAbecasis, Goncalo, R1 aWareham, Nicholas, J1 aSladek, Robert1 aFroguel, Philippe1 aWatanabe, Richard, M1 aMeigs, James, B1 aGroop, Leif1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aFlorez, Jose, C1 aBarroso, Inês1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal BPgen Consortium1 aAnders Hamsten on behalf of Procardis Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/116006326nas a2201873 4500008004100000022001400041245007300055210006900128260001300197300001100210490000700221520118400228653001901412653001501431653001501446653000901461653001101470653002001481653003401501653003101535653001101566653001101577653002801588653002001616653001701636100001901653700002201672700002301694700002701717700002001744700002201764700001801786700001601804700001601820700002101836700002601857700001201883700002001895700002001915700001801935700002001953700002001973700002301993700001902016700002202035700002102057700002702078700001802105700001702123700002502140700002902165700002402194700001802218700002202236700001902258700002402277700002202301700002202323700002402345700002502369700001902394700002102413700002302434700002602457700002202483700002602505700002002531700002002551700002302571700001902594700002102613700002002634700002502654700001902679700001802698700002202716700002302738700002302761700002002784700002102804700002102825700002402846700001802870700002202888700002202910700001802932700001802950700002302968700002202991700002103013700001603034700002203050700001803072700002103090700001703111700001903128700001603147700001903163700001903182700002003201700002003221700002203241700002203263700002403285700002103309700002603330700002803356700001903384700001903403700002103422700002503443700002303468700002203491700001803513700002203531700001803553700001803571700002003589700002203609700001903631700002103650700002003671700001703691700001903708700002203727700001903749700002503768700002003793700002403813700002403837700001703861700002003878700001803898700002003916700002403936700002103960700001403981700002403995700002304019700001804042700002204060700002004082700002404102700002304126700002004149700002504169700001604194700002004210700002104230700002804251700002604279700001904305700001704324700002304341700001304364700001804377700002104395856003604416 2010 eng d a1546-171800aNew loci associated with kidney function and chronic kidney disease.0 aNew loci associated with kidney function and chronic kidney dise c2010 May a376-840 v423 aChronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
10aCohort Studies10aCreatinine10aCystatin C10aDiet10aEurope10aGenetic Markers10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aModels, Genetic10aRisk Factors1 aKöttgen, Anna1 aPattaro, Cristian1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aGlazer, Nicole, L1 aParsa, Afshin1 aGao, Xiaoyi1 aYang, Qiong1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aLi, Man1 aSchmidt, Helena1 aTanaka, Toshiko1 aIsaacs, Aaron1 aKetkar, Shamika1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aDehghan, Abbas1 aTeumer, Alexander1 aParé, Guillaume1 aAtkinson, Elizabeth, J1 aZeller, Tanja1 aLohman, Kurt1 aCornelis, Marilyn, C1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aTönjes, Anke1 aHayward, Caroline1 aAspelund, Thor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aRampersaud, Evadnie1 aMitchell, Braxton, D1 aArking, Dan, E1 aBoerwinkle, Eric1 aStruchalin, Maksim1 aCavalieri, Margherita1 aSingleton, Andrew1 aGiallauria, Francesco1 aMetter, Jeffrey1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSiscovick, David1 aPsaty, Bruce, M1 aZillikens, Carola, M1 aOostra, Ben, A1 aFeitosa, Mary1 aProvince, Michael1 ade Andrade, Mariza1 aTurner, Stephen, T1 aSchillert, Arne1 aZiegler, Andreas1 aWild, Philipp, S1 aSchnabel, Renate, B1 aWilde, Sandra1 aMunzel, Thomas, F1 aLeak, Tennille, S1 aIllig, Thomas1 aKlopp, Norman1 aMeisinger, Christa1 aWichmann, H-Erich1 aKoenig, Wolfgang1 aZgaga, Lina1 aZemunik, Tatijana1 aKolcic, Ivana1 aMinelli, Cosetta1 aHu, Frank, B1 aJohansson, Asa1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aSchreiber, Stefan1 aAulchenko, Yurii, S1 aFelix, Janine, F1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aImboden, Medea1 aNitsch, Dorothea1 aBrandstätter, Anita1 aKollerits, Barbara1 aKedenko, Lyudmyla1 aMägi, Reedik1 aStumvoll, Michael1 aKovacs, Peter1 aBoban, Mladen1 aCampbell, Susan1 aEndlich, Karlhans1 aVölzke, Henry1 aKroemer, Heyo, K1 aNauck, Matthias1 aVölker, Uwe1 aPolasek, Ozren1 aVitart, Veronique1 aBadola, Sunita1 aParker, Alexander, N1 aRidker, Paul, M1 aKardia, Sharon, L R1 aBlankenberg, Stefan1 aLiu, Yongmei1 aCurhan, Gary, C1 aFranke, Andre1 aRochat, Thierry1 aPaulweber, Bernhard1 aProkopenko, Inga1 aWang, Wei1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aShlipak, Michael, G1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKrämer, Bernhard, K1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aWitteman, Jacqueline, C1 aPramstaller, Peter, P1 aRettig, Rainer1 aHastie, Nick1 aChasman, Daniel, I1 aKao, W H1 aHeid, Iris, M1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/118304638nas a2200901 4500008004100000022001400041245020700055210006900262260001600331300001200347490000800359520199800367653001002365653001502375653001602390653001102406653003402417653001502451653001102466653000902477653001602486653001402502653003602516653001502552653002602567100002302593700002002616700001902636700002302655700001702678700002002695700002202715700001602737700002502753700001902778700002502797700001602822700001902838700001602857700002702873700002202900700002002922700002302942700002202965700002302987700002203010700002103032700002303053700002103076700002203097700002803119700001803147700002003165700002003185700002103205700001803226700002203244700002203266700002103288700001903309700002103328700002403349700001903373700002003392700001903412700002103431700002203452700002403474700002003498700002103518700002003539700001903559700003003578700001803608700003003626710004403656856003603700 2010 eng d a1524-453900aNovel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.0 aNovel associations of multiple genetic loci with plasma levels o c2010 Mar 30 a1382-920 v1213 aBACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.
METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.
CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.
10aAdult10aFactor VII10aFactor VIII10aFemale10aGenome-Wide Association Study10aHemostasis10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aThrombosis10avon Willebrand Factor1 aSmith, Nicholas, L1 aChen, Ming-Huei1 aDehghan, Abbas1 aStrachan, David, P1 aBasu, Saonli1 aSoranzo, Nicole1 aHayward, Caroline1 aRudan, Igor1 aSabater-Lleal, Maria1 aBis, Joshua, C1 ade Maat, Moniek, P M1 aRumley, Ann1 aKong, Xiaoxiao1 aYang, Qiong1 aWilliams, Frances, M K1 aVitart, Veronique1 aCampbell, Harry1 aMälarstig, Anders1 aWiggins, Kerri, L1 aDuijn, Cornelia, M1 aMcArdle, Wendy, L1 aPankow, James, S1 aJohnson, Andrew, D1 aSilveira, Angela1 aMcKnight, Barbara1 aUitterlinden, André, G1 aAleksic, Nena1 aMeigs, James, B1 aPeters, Annette1 aKoenig, Wolfgang1 aCushman, Mary1 aKathiresan, Sekar1 aRotter, Jerome, I1 aBovill, Edwin, G1 aHofman, Albert1 aBoerwinkle, Eric1 aTofler, Geoffrey, H1 aPeden, John, F1 aPsaty, Bruce, M1 aLeebeek, Frank1 aFolsom, Aaron, R1 aLarson, Martin, G1 aSpector, Timothy, D1 aWright, Alan, F1 aWilson, James, F1 aHamsten, Anders1 aLumley, Thomas1 aWitteman, Jacqueline, C M1 aTang, Weihong1 aO'Donnell, Christopher, J1 aWellcome Trust Case Control Consortium; uhttps://chs-nhlbi.org/node/117603263nas a2200553 4500008004100000022001400041245011200055210006900167260001300236300001100249490000600260520171300266653000901979653002201988653003402010653002102044653001102065653003402076653001102110653000902121653001602130653003602146653002402182100002302206700001602229700002102245700002002266700001902286700001202305700002102317700002302338700002102361700002102382700001602403700001902419700001802438700002302456700001902479700002202498700001702520700001902537700001902556700002102575700001702596700002402613700001702637700001902654856003602673 2011 eng d a1942-326800aAssociation of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.0 aAssociation of genetic variants and incident coronary heart dise c2011 Dec a661-720 v43 aBACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.
METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.
CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.
10aAged10aAged, 80 and over10aContinental Population Groups10aCoronary Disease10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies1 aFranceschini, Nora1 aCarty, Cara1 aBůzková, Petra1 aReiner, Alex, P1 aGarrett, Tiana1 aLin, Yi1 aVöckler, Jens-S1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBoerwinkle, Eric1 aLin, Dan-Yu1 aBookman, Ebony1 aBest, Lyle, G1 aBella, Jonathan, N1 aEaton, Charles1 aGreenland, Philip1 aJenny, Nancy1 aNorth, Kari, E1 aTaverna, Darin1 aYoung, Alicia, M1 aDeelman, Ewa1 aKooperberg, Charles1 aPsaty, Bruce1 aHeiss, Gerardo uhttps://chs-nhlbi.org/node/134704248nas a2200877 4500008004100000022001400041245015200055210006900207260001600276300001200292490000700304520170700311653001002018653002202028653000902050653001902059653001902078653001302097653004002110653001102150653001702161653003402178653001302212653001102225653001702236653000902253653001602262653001402278653003602292653001202328100001802340700002102358700001302379700002502392700002402417700002302441700001502464700002402479700001902503700002102522700002702543700002002570700002402590700002102614700002302635700001902658700002302677700002302700700001602723700002102739700002002760700001902780700002202799700002502821700002102846700002202867700002202889700001902911700001702930700002302947700002302970700002302993700001603016700002003032700002203052700002403074700002203098700002303120700002003143700001803163700002603181700001803207700001703225710009203242856003603334 2011 eng d a1460-208300aAssociation of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.0 aAssociation of genetic variation with systolic and diastolic blo c2011 Jun 01 a2273-840 v203 aThe prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
10aAdult10aAfrican Americans10aAged10aBlood Pressure10aCohort Studies10aDiastole10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aHypertension10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aYoung, Hunter, J1 aLi, Yali1 aDreisbach, Albert, W1 aKeating, Brendan, J1 aMusani, Solomon, K1 aLiu, Kiang1 aMorrison, Alanna, C1 aGanesh, Santhi1 aKutlar, Abdullah1 aRamachandran, Vasan, S1 aPolak, Josef, F1 aFabsitz, Richard, R1 aDries, Daniel, L1 aFarlow, Deborah, N1 aRedline, Susan1 aAdeyemo, Adebowale1 aHirschorn, Joel, N1 aSun, Yan, V1 aWyatt, Sharon, B1 aPenman, Alan, D1 aPalmas, Walter1 aRotter, Jerome, I1 aTownsend, Raymond, R1 aDoumatey, Ayo, P1 aTayo, Bamidele, O1 aMosley, Thomas, H1 aLyon, Helen, N1 aKang, Sun, J1 aRotimi, Charles, N1 aCooper, Richard, S1 aFranceschini, Nora1 aCurb, David1 aMartin, Lisa, W1 aEaton, Charles, B1 aKardia, Sharon, L R1 aTaylor, Herman, A1 aCaulfield, Mark, J1 aEhret, Georg, B1 aJohnson, Toby1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aLevy, Daniel1 aInternational Consortium for Blood Pressure Genome-wide Association Studies (ICBP-GWAS) uhttps://chs-nhlbi.org/node/127303582nas a2200661 4500008004100000022001400041245009700055210006900152260001600221300001100237490000700248520163600255653001001891653000901901653003101910653002301941653003801964653003802002653003402040653001302074653002902087653001102116653001602127653001602143653003102159653003602190653003002226653002602256100002302282700002202305700002402327700002602351700001602377700002002393700002202413700002102435700002002456700002302476700002302499700001602522700002102538700001702559700002002576700002302596700002802619700002202647700002202669700002002691700001902711700002502730700002202755700002002777700002002797700002502817700002202842700002002864856003602884 2011 eng d a1552-578300aAssociation of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.0 aAssociation of polymorphisms in the hepatocyte growth factor gen c2011 Oct 31 a8514-90 v523 aPURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.
METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.
RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).
CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.
10aAdult10aAged10aChromosomes, Human, Pair 710aCorneal Topography10aEnzyme-Linked Immunosorbent Assay10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHepatocyte Growth Factor10aHumans10aKeratoconus10aMiddle Aged10aNucleic Acid Hybridization10aPolymorphism, Single Nucleotide10aPromoter Regions, Genetic10aSequence Tagged Sites1 aBurdon, Kathryn, P1 aMacgregor, Stuart1 aBykhovskaya, Yelena1 aJavadiyan, Sharhbanou1 aLi, Xiaohui1 aLaurie, Kate, J1 aMuszynska, Dorota1 aLindsay, Richard1 aLechner, Judith1 aHaritunians, Talin1 aHenders, Anjali, K1 aDash, Durga1 aSiscovick, David1 aAnand, Seema1 aAldave, Anthony1 aCoster, Douglas, J1 aSzczotka-Flynn, Loretta1 aMills, Richard, A1 aIyengar, Sudha, K1 aTaylor, Kent, D1 aPhillips, Tony1 aMontgomery, Grant, W1 aRotter, Jerome, I1 aHewitt, Alex, W1 aSharma, Shiwani1 aRabinowitz, Yaron, S1 aWilloughby, Colin1 aCraig, Jamie, E uhttps://chs-nhlbi.org/node/134003940nas a2200757 4500008004100000022001400041245008100055210006900136260001300205300001200218490000700230520182400237653001002061653000902071653001102080653003802091653003402129653001302163653001102176653000902187653002702196653002302223653001602246653001402262653003602276100001902312700002202331700002102353700002202374700002902396700002302425700001602448700002302464700001602487700002302503700001802526700001202544700001902556700002102575700002202596700002302618700002802641700002302669700001902692700002202711700001602733700001602749700002202765700002202787700002102809700002102830700002602851700002002877700002102897700002502918700002102943700002402964700001902988700002703007700002103034700002403055700002203079700002203101700002303123856003603146 2011 eng d a1939-327X00aA bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium.0 abivariate genomewide approach to metabolic syndrome STAMPEED con c2011 Apr a1329-390 v603 aOBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
10aAdult10aAged10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMeta-Analysis as Topic10aMetabolic Syndrome10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide1 aKraja, Aldi, T1 aVaidya, Dhananjay1 aPankow, James, S1 aGoodarzi, Mark, O1 aAssimes, Themistocles, L1 aKullo, Iftikhar, J1 aSovio, Ulla1 aMathias, Rasika, A1 aSun, Yan, V1 aFranceschini, Nora1 aAbsher, Devin1 aLi, Guo1 aZhang, Qunyuan1 aFeitosa, Mary, F1 aGlazer, Nicole, L1 aHaritunians, Talin1 aHartikainen, Anna-Liisa1 aKnowles, Joshua, W1 aNorth, Kari, E1 aIribarren, Carlos1 aKral, Brian1 aYanek, Lisa1 aO'Reilly, Paul, F1 aMcCarthy, Mark, I1 aJaquish, Cashell1 aCouper, David, J1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aBecker, Lewis, C1 aProvince, Michael, A1 aBoerwinkle, Eric1 aQuertermous, Thomas1 aPalotie, Leena1 aJarvelin, Marjo-Riitta1 aBecker, Diane, M1 aKardia, Sharon, L R1 aRotter, Jerome, I1 aChen, Yii-Der Ida1 aBorecki, Ingrid, B uhttps://chs-nhlbi.org/node/127404125nas a2200745 4500008004100000022001400041245014300055210006900198260001600267300001300283490000700296520189000303653002802193653003002221653002702251653002502278653003802303653003402341653001302375653001102388653001602399653001502415653001502430653003602445653001702481100001802498700001602516700001702532700002302549700001902572700001902591700001902610700001902629700002002648700001602668700002002684700002202704700002002726700002402746700002402770700002102794700002402815700002102839700002202860700002102882700002302903700001902926700002202945700002102967700001702988700001903005700002203024700001903046700001403065700002203079700002203101700002403123700002503147700001803172700001803190700001803208710007203226710004503298856003603343 2011 eng d a1552-578300aCandidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe).0 aCandidate gene association study for diabetic retinopathy in per c2011 Sep 29 a7593-6020 v523 aPURPOSE: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).
METHODS: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥ 14 and ≥ 30. The χ² analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.
RESULTS: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.
CONCLUSIONS: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.
10aCardiovascular Diseases10aDiabetes Mellitus, Type 210aDiabetic Nephropathies10aDiabetic Retinopathy10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aIduronidase10aOdds Ratio10aP-Selectin10aPolymorphism, Single Nucleotide10aRisk Factors1 aSobrin, Lucia1 aGreen, Todd1 aSim, Xueling1 aJensen, Richard, A1 aTai, Shyong, E1 aTay, Wan, Ting1 aWang, Jie, Jin1 aMitchell, Paul1 aSandholm, Niina1 aLiu, Yiyuan1 aHietala, Kustaa1 aIyengar, Sudha, K1 aBrooks, Matthew1 aBuraczynska, Monika1 aVan Zuydam, Natalie1 aSmith, Albert, V1 aGudnason, Vilmundur1 aDoney, Alex, S F1 aMorris, Andrew, D1 aLeese, Graham, P1 aPalmer, Colin, N A1 aSwaroop, Anand1 aTaylor, Herman, A1 aWilson, James, G1 aPenman, Alan1 aChen, Ching, J1 aGroop, Per-Henrik1 aSaw, Seang-Mei1 aAung, Tin1 aKlein, Barbara, E1 aRotter, Jerome, I1 aSiscovick, David, S1 aCotch, Mary, Frances1 aKlein, Ronald1 aDaly, Mark, J1 aWong, Tien, Y1 aFamily Investigation of Nephropathy and Diabetes-Eye Research Group1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/156703692nas a2200637 4500008004100000022001400041245006800055210006500123260001300188300001000201490000700211520184500218653001002063653000902073653002202082653003402104653002502138653002802163653001102191653002202202653003402224653002802258653001102286653005102297653000902348653001602357653003102373653003602404653001402440653001902454653000902473653004702482653006302529100002602592700001802618700002302636700001902659700001402678700002202692700002002714700001702734700002202751700002202773700002202795700001902817700002202836700001202858700002202870700002002892700002202912700002402934700001802958700002202976700002002998856003603018 2011 eng d a1744-688000aCerivastatin, genetic variants, and the risk of rhabdomyolysis.0 aCerivastatin genetic variants and the risk of rhabdomyolysis c2011 May a280-80 v213 aOBJECTIVE: The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.
METHODS: This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.
RESULTS: Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63).
CONCLUSION: We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.
10aAdult10aAged10aAged, 80 and over10aAryl Hydrocarbon Hydroxylases10aCase-Control Studies10aCytochrome P-450 CYP2C810aFemale10aGenetic Variation10aGenome-Wide Association Study10aGlucuronosyltransferase10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aOrganic Anion Transporters10aPolymorphism, Single Nucleotide10aPyridines10aRhabdomyolysis10aRisk10aRyanodine Receptor Calcium Release Channel10aSolute Carrier Organic Anion Transporter Family Member 1b11 aMarciante, Kristin, D1 aDurda, Jon, P1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Ken1 aMcKnight, Barbara1 aTotah, Rheem, A1 aTamraz, Bani1 aKroetz, Deanna, L1 aFukushima, Hisayo1 aKaspera, Rüdiger1 aBis, Joshua, C1 aGlazer, Nicole, L1 aLi, Guo1 aAustin, Thomas, R1 aTaylor, Kent, D1 aRotter, Jerome, I1 aJaquish, Cashell, E1 aKwok, Pui-Yan1 aTracy, Russell, P1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/127504476nas a2200937 4500008004100000022001400041245014100055210006900196260001300265300001300278490000600291520177500297653002202072653001502094653002102109653002302130653002102153653003002174653001102204653001902215653002202234653002502256653001802281653003402299653001302333653001102346653002702357653000902384653001502393653001402408653003602422653003302458653004702491653001302538100002102551700001802572700002202590700001802612700001702630700002002647700002002667700002002687700002402707700001802731700001702749700002102766700002502787700001602812700002502828700002302853700001902876700002102895700001602916700002802932700002402960700002802984700002003012700002203032700001503054700002003069700002303089700002103112700002203133700001903155700002203174700002403196700002203220700002803242700002303270700001903293700002003312700002403332700002403356700001703380700002703397700001703424700002003441700002103461700002003482856003603502 2011 eng d a1553-740400aEnhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium.0 aEnhanced statistical tests for GWAS in admixed populations asses c2011 Apr ae10013710 v73 aWhile genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.
10aAfrican Americans10aAlgorithms10aBreast Neoplasms10aChromosome Mapping10aCoronary Disease10aDiabetes Mellitus, Type 210aFemale10aGene Frequency10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLinkage Disequilibrium10aMale10aOdds Ratio10aPhenotype10aPolymorphism, Single Nucleotide10aPrincipal Component Analysis10aReceptor, Fibroblast Growth Factor, Type 210aSoftware1 aPasaniuc, Bogdan1 aZaitlen, Noah1 aLettre, Guillaume1 aChen, Gary, K1 aTandon, Arti1 aKao, Linda, W H1 aRuczinski, Ingo1 aFornage, Myriam1 aSiscovick, David, S1 aZhu, Xiaofeng1 aLarkin, Emma1 aLange, Leslie, A1 aCupples, Adrienne, L1 aYang, Qiong1 aAkylbekova, Ermeg, L1 aMusani, Solomon, K1 aDivers, Jasmin1 aMychaleckyj, Joe1 aLi, Mingyao1 aPapanicolaou, George, J1 aMillikan, Robert, C1 aAmbrosone, Christine, B1 aJohn, Esther, M1 aBernstein, Leslie1 aZheng, Wei1 aHu, Jennifer, J1 aZiegler, Regina, G1 aNyante, Sarah, J1 aBandera, Elisa, V1 aIngles, Sue, A1 aPress, Michael, F1 aChanock, Stephen, J1 aDeming, Sandra, L1 aRodriguez-Gil, Jorge, L1 aPalmer, Cameron, D1 aBuxbaum, Sarah1 aEkunwe, Lynette1 aHirschhorn, Joel, N1 aHenderson, Brian, E1 aMyers, Simon1 aHaiman, Christopher, A1 aReich, David1 aPatterson, Nick1 aWilson, James, G1 aPrice, Alkes, L uhttps://chs-nhlbi.org/node/128804453nas a2200889 4500008004100000022001400041245011700055210006900172260001300241300001300254490000600267520190600273653004202179653001002221653003902231653000902270653001202279653001102291653003002302653003202332653001702364653003402381653003102415653001102446653002802457653001102485653002802496653000902524653001602533653002202549653001402571653003602585653001402621100001802635700002202653700001802675700001902693700002302712700002302735700002002758700001702778700002402795700002002819700001902839700002002858700001802878700002102896700002902917700002102946700002202967700001802989700001603007700002303023700001203046700002403058700002503082700002303107700002303130700002303153700002303176700002203199700002203221700002303243700001703266700002403283700002203307700002403329700001803353700002503371700002503396700002303421700002503444700001503469700002103484710002203505856003603527 2011 eng d a1553-740400aGenetic association for renal traits among participants of African ancestry reveals new loci for renal function.0 aGenetic association for renal traits among participants of Afric c2011 Sep ae10022640 v73 aChronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
10aAdaptor Proteins, Vesicular Transport10aAdult10aAfrican Continental Ancestry Group10aAged10aAnimals10aFemale10aGene Knockdown Techniques10aGenetic Association Studies10aGenetic Loci10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKCNQ1 Potassium Channel10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aNeoplasm Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aZebrafish1 aLiu, Ching-Ti1 aGarnaas, Maija, K1 aTin, Adrienne1 aKöttgen, Anna1 aFranceschini, Nora1 aPeralta, Carmen, A1 ade Boer, Ian, H1 aLu, Xiaoning1 aAtkinson, Elizabeth1 aDing, Jingzhong1 aNalls, Michael1 aShriner, Daniel1 aCoresh, Josef1 aKutlar, Abdullah1 aBibbins-Domingo, Kirsten1 aSiscovick, David1 aAkylbekova, Ermeg1 aWyatt, Sharon1 aAstor, Brad1 aMychaleckjy, Josef1 aLi, Man1 aReilly, Muredach, P1 aTownsend, Raymond, R1 aAdeyemo, Adebowale1 aZonderman, Alan, B1 ade Andrade, Mariza1 aTurner, Stephen, T1 aMosley, Thomas, H1 aHarris, Tamara, B1 aRotimi, Charles, N1 aLiu, Yongmei1 aKardia, Sharon, L R1 aEvans, Michele, K1 aShlipak, Michael, G1 aKramer, Holly1 aFlessner, Michael, F1 aDreisbach, Albert, W1 aGoessling, Wolfram1 aCupples, Adrienne, L1 aKao, Linda1 aFox, Caroline, S1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/132704377nas a2200829 4500008004100000022001400041245014300055210006900198260001300267300001300280490000600293520197700299653001502276653001002291653000902301653002202310653003402332653001102366653001902377653002502396653003402421653001102455653002702466653002102493653002202514653002202536653000902558653001602567653002702583653003602610653002802646653001702674653001802691653001602709100002202725700001902747700001702766700002802783700002302811700002102834700002102855700001802876700002602894700002102920700002802941700002102969700002102990700002503011700001703036700002203053700002003075700002303095700001903118700002303137700002203160700001903182700002503201700001803226700002203244700002103266700002603287700002103313700002103334700002203355700002703377700002303404700001903427700002403446700001903470700002203489856003603511 2011 eng d a1553-740400aGenetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.0 aGenetic determinants of lipid traits in diverse populations from c2011 Jun ae10021380 v73 aFor the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aContinental Population Groups10aFemale10aGene Frequency10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aLipid Metabolism10aLipoproteins, HDL10aLipoproteins, LDL10aMale10aMiddle Aged10aMolecular Epidemiology10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors10aTriglycerides10aYoung Adult1 aDumitrescu, Logan1 aCarty, Cara, L1 aTaylor, Kira1 aSchumacher, Fredrick, R1 aHindorff, Lucia, A1 aAmbite, José, L1 aAnderson, Garnet1 aBest, Lyle, G1 aBrown-Gentry, Kristin1 aBůzková, Petra1 aCarlson, Christopher, S1 aCochran, Barbara1 aCole, Shelley, A1 aDevereux, Richard, B1 aDuggan, Dave1 aEaton, Charles, B1 aFornage, Myriam1 aFranceschini, Nora1 aHaessler, Jeff1 aHoward, Barbara, V1 aJohnson, Karen, C1 aLaston, Sandra1 aKolonel, Laurence, N1 aLee, Elisa, T1 aMacCluer, Jean, W1 aManolio, Teri, A1 aPendergrass, Sarah, A1 aQuibrera, Miguel1 aShohet, Ralph, V1 aWilkens, Lynne, R1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aBuyske, Steven1 aKooperberg, Charles1 aNorth, Kari, E1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/130303576nas a2200673 4500008004100000022001400041245014900055210006900204260001300273300001300286490000600299520159100305653001201896653003401908653002501942653001101967653001701978653003401995653001102029653000902040653003602049653003602085100002402121700002002145700001802165700002102183700001902204700002502223700002702248700001902275700001802294700002602312700002502338700001902363700002102382700002102403700002302424700002202447700001802469700001702487700001802504700002102522700001902543700002302562700002002585700002102605700002502626700001802651700001802669700002402687700002802711700002102739700002002760700002002780700002102800700002502821700002002846856003602866 2011 eng d a1553-740400aGenetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.0 aGenetic loci associated with plasma phospholipid n3 fatty acids c2011 Jul ae10021930 v73 aLong-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻⁶⁴) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻⁵⁸) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹⁵⁴). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻⁴³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹⁵). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻⁸). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.
10aAlleles10aContinental Population Groups10aFatty Acids, Omega-310aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide1 aLemaitre, Rozenn, N1 aTanaka, Toshiko1 aTang, Weihong1 aManichaikul, Ani1 aFoy, Millennia1 aKabagambe, Edmond, K1 aNettleton, Jennifer, A1 aKing, Irena, B1 aWeng, Lu-Chen1 aBhattacharya, Sayanti1 aBandinelli, Stefania1 aBis, Joshua, C1 aRich, Stephen, S1 aJacobs, David, R1 aCherubini, Antonio1 aMcKnight, Barbara1 aLiang, Shuang1 aGu, Xiangjun1 aRice, Kenneth1 aLaurie, Cathy, C1 aLumley, Thomas1 aBrowning, Brian, L1 aPsaty, Bruce, M1 aChen, Yii-der, I1 aFriedlander, Yechiel1 aDjoussé, Luc1 aH Y Wu, Jason1 aSiscovick, David, S1 aUitterlinden, André, G1 aArnett, Donna, K1 aFerrucci, Luigi1 aFornage, Myriam1 aTsai, Michael, Y1 aMozaffarian, Dariush1 aSteffen, Lyn, M uhttps://chs-nhlbi.org/node/131104787nas a2201105 4500008004100000022001400041245006700055210006500122260001600187300001200203490000800215520177000223653001001993653000902003653002202012653004002034653001302074653001102087653004302098653001502141653002002156653003402176653001102210653000902221653001602230653002102246653001902267100002302286700002502309700002302334700001502357700001902372700002002391700002002411700001802431700001802449700002202467700001902489700001902508700001602527700001602543700002802559700002002587700001702607700002202624700002102646700001902667700002202686700002002708700002402728700002002752700002402772700002102796700002002817700002002837700001902857700002502876700002202901700002202923700002002945700001402965700001702979700002202996700002303018700001703041700001903058700001903077700001803096700002003114700002303134700002003157700001803177700001603195700002103211700002003232700002203252700002103274700001903295700002603314700001903340700002003359700001903379700002403398700002003422700002103442700002203463700003003485700003003515700001903545700001803564700002003582700002103602700002203623856003603645 2011 eng d a1524-453900aGenetic predictors of fibrin D-dimer levels in healthy adults.0 aGenetic predictors of fibrin Ddimer levels in healthy adults c2011 May 03 a1864-720 v1233 aBACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.
METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.
CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
10aAdult10aAged10aBlood Coagulation10aEuropean Continental Ancestry Group10aFactor V10aFemale10aFibrin Fibrinogen Degradation Products10aFibrinogen10aGenetic Testing10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aReference Values10aThromboplastin1 aSmith, Nicholas, L1 aHuffman, Jennifer, E1 aStrachan, David, P1 aHuang, Jie1 aDehghan, Abbas1 aTrompet, Stella1 aLopez, Lorna, M1 aShin, So-Youn1 aBaumert, Jens1 aVitart, Veronique1 aBis, Joshua, C1 aWild, Sarah, H1 aRumley, Ann1 aYang, Qiong1 aUitterlinden, André, G1 aStott, David, J1 aDavies, Gail1 aCarter, Angela, M1 aThorand, Barbara1 aPolasek, Ozren1 aMcKnight, Barbara1 aCampbell, Harry1 aRudnicka, Alicja, R1 aChen, Ming-Huei1 aBuckley, Brendan, M1 aHarris, Sarah, E1 aPeters, Annette1 aPulanic, Drazen1 aLumley, Thomas1 ade Craen, Anton, J M1 aLiewald, David, C1 aGieger, Christian1 aCampbell, Susan1 aFord, Ian1 aGow, Alan, J1 aLuciano, Michelle1 aPorteous, David, J1 aGuo, Xiuqing1 aSattar, Naveed1 aTenesa, Albert1 aCushman, Mary1 aSlagboom, Eline1 aVisscher, Peter, M1 aSpector, Tim, D1 aIllig, Thomas1 aRudan, Igor1 aBovill, Edwin, G1 aWright, Alan, F1 aMcArdle, Wendy, L1 aTofler, Geoffrey1 aHofman, Albert1 aWestendorp, Rudi, G J1 aStarr, John, M1 aGrant, Peter, J1 aKarakas, Mahir1 aHastie, Nicholas, D1 aPsaty, Bruce, M1 aWilson, James, F1 aLowe, Gordon, D O1 aO'Donnell, Christopher, J1 aWitteman, Jacqueline, C M1 aJukema, Wouter1 aDeary, Ian, J1 aSoranzo, Nicole1 aKoenig, Wolfgang1 aHayward, Caroline uhttps://chs-nhlbi.org/node/128413785nas a2204513 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2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium uhttps://chs-nhlbi.org/node/132506039nas a2201765 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2011 eng d a1546-171800aGenetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.0 aGenetic variation near IRS1 associates with reduced adiposity an c2011 Jun 26 a753-600 v433 aGenome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
10aAdiponectin10aAdiposity10aAlleles10aBody Fat Distribution10aBody Mass Index10aBody Weight10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aInsulin Receptor Substrate Proteins10aIntracellular Signaling Peptides and Proteins10aMale10aMembrane Proteins10aMeta-Analysis as Topic10aMetabolome10aObesity10aPolymorphism, Single Nucleotide10aSubcutaneous Fat1 aKilpeläinen, Tuomas, O1 aZillikens, Carola, M1 aStančáková, Alena1 aFinucane, Francis, M1 aRied, Janina, S1 aLangenberg, Claudia1 aZhang, Weihua1 aBeckmann, Jacques, S1 aLuan, Jian'an1 aVandenput, Liesbeth1 aStyrkarsdottir, Unnur1 aZhou, Yanhua1 aSmith, Albert, Vernon1 aZhao, Jing-Hua1 aAmin, Najaf1 aVedantam, Sailaja1 aShin, So-Youn1 aHaritunians, Talin1 aFu, Mao1 aFeitosa, Mary, F1 aKumari, Meena1 aHalldorsson, Bjarni, V1 aTikkanen, Emmi1 aMangino, Massimo1 aHayward, Caroline1 aSong, Ci1 aArnold, Alice, M1 aAulchenko, Yurii, S1 aOostra, Ben, A1 aCampbell, Harry1 aCupples, Adrienne, L1 aDavis, Kathryn, E1 aDöring, Angela1 aEiriksdottir, Gudny1 aEstrada, Karol1 aFernández-Real, José, Manuel1 aGarcia, Melissa1 aGieger, Christian1 aGlazer, Nicole, L1 aGuiducci, Candace1 aHofman, Albert1 aHumphries, Steve, E1 aIsomaa, Bo1 aJacobs, Leonie, C1 aJula, Antti1 aKarasik, David1 aKarlsson, Magnus, K1 aKhaw, Kay-Tee1 aKim, Lauren, J1 aKivimaki, Mika1 aKlopp, Norman1 aKuhnel, Brigitte1 aKuusisto, Johanna1 aLiu, Yongmei1 aLjunggren, Osten1 aLorentzon, Mattias1 aLuben, Robert, N1 aMcKnight, Barbara1 aMellström, Dan1 aMitchell, Braxton, D1 aMooser, Vincent1 aMoreno, José, Maria1 aMännistö, Satu1 aO'Connell, Jeffery, R1 aPascoe, Laura1 aPeltonen, Leena1 aPeral, Belén1 aPerola, Markus1 aPsaty, Bruce, M1 aSalomaa, Veikko1 aSavage, David, B1 aSemple, Robert, K1 aSkaric-Juric, Tatjana1 aSigurdsson, Gunnar1 aSong, Kijoung, S1 aSpector, Timothy, D1 aSyvänen, Ann-Christine1 aTalmud, Philippa, J1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVidal-Puig, Antonio1 aWild, Sarah, H1 aWright, Alan, F1 aClegg, Deborah, J1 aSchadt, Eric1 aWilson, James, F1 aRudan, Igor1 aRipatti, Samuli1 aBorecki, Ingrid, B1 aShuldiner, Alan, R1 aIngelsson, Erik1 aJansson, John-Olov1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aGroop, Leif1 aKiel, Douglas, P1 aRivadeneira, Fernando1 aWalker, Mark1 aBarroso, Inês1 aVollenweider, Peter1 aWaeber, Gérard1 aChambers, John, C1 aKooner, Jaspal, S1 aSoranzo, Nicole1 aHirschhorn, Joel, N1 aStefansson, Kari1 aWichmann, H-Erich1 aOhlsson, Claes1 aO'Rahilly, Stephen1 aWareham, Nicholas, J1 aSpeliotes, Elizabeth, K1 aFox, Caroline, S1 aLaakso, Markku1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/130102615nas a2200481 4500008004100000022001400041245014100055210006900196260001300265300001300278490000600291520118600297653002701483653001901510653001101529653001901540653001701559653001801576653003401594653001301628653001101641653002101652653003801673653001101711653002201722653002001744653003101764653003601795653001301831653003001844100002101874700002001895700001601915700001901931700001901950700001901969700001901988700002402007700001802031700002502049700002302074856003602097 2011 eng d a1553-740400aGenome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci.0 aGenomewide association analysis of soluble ICAM1 concentration r c2011 Apr ae10013740 v73 aSoluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P = 5.8 × 10(-9)), RELA (rs1049728, P = 2.7 × 10(-16)), and SH2B3 (rs3184504, P = 2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.
10aABO Blood-Group System10aCohort Studies10aFemale10aGene Frequency10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aI-kappa B Kinase10aIntercellular Adhesion Molecule-110aLipase10aMembrane Proteins10aModels, Genetic10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide10aProteins10aTranscription Factor RelA1 aParé, Guillaume1 aRidker, Paul, M1 aRose, Lynda1 aBarbalic, Maja1 aDupuis, Josée1 aDehghan, Abbas1 aBis, Joshua, C1 aBenjamin, Emelia, J1 aShiffman, Dov1 aParker, Alexander, N1 aChasman, Daniel, I uhttps://chs-nhlbi.org/node/128707169nas a2202257 4500008004100000022001400041245010400055210006900159260001600228300001200244490000700256520086500263653001001128653004001138653003401178653001101212653004301223653003101266100002601297700001801323700002001341700002001361700001901381700001601400700001801416700001901434700002601453700002501479700001801504700002601522700002001548700001701568700002001585700002101605700002001626700001801646700002401664700001901688700001901707700002001726700002501746700002101771700002401792700002301816700002001839700002201859700002901881700001901910700002801929700002101957700002201978700002602000700002302026700002402049700001802073700001902091700001902110700002102129700002302150700002102173700001802194700001602212700002802228700002202256700001702278700002002295700001702315700002002332700001902352700002602371700001602397700001702413700001702430700002002447700001802467700001902485700001902504700002102523700002202544700001802566700001902584700002002603700001802623700001802641700002202659700001902681700001902700700002002719700001702739700002302756700001902779700002102798700002002819700001802839700002402857700001902881700002102900700001602921700002302937700001902960700002202979700001903001700001803020700002403038700001803062700002303080700002103103700002203124700002103146700002303167700002203190700002103212700001903233700002603252700002003278700002203298700001603320700001803336700002403354700001703378700001903395700002803414700002003442700002203462700002203484700002003506700001903526700001703545700002103562700002603583700002203609700001903631700002403650700001903674700001903693700002003712700002703732700001803759700002603777700001803803700002003821700002803841700002003869700002003889700002203909700001603931700002403947700001903971700001803990700002004008700001704028700002204045700001904067700002504086700002604111700002204137700001904159700001904178700001904197700002004216700001604236700002204252700002204274700002004296700001504316700002204331700001904353700002204372700002304394700002604417700001904443700002104462700002204483700002004505700002204525700002004547700002304567700001804590700002704608700002604635700001804661700002404679700002304703700002504726700001704751700002404768700002104792710004104813710002104854856003604875 2011 eng d a1546-171800aGenome-wide association and large-scale follow up identifies 16 new loci influencing lung function.0 aGenomewide association and largescale follow up identifies 16 ne c2011 Sep 25 a1082-900 v433 aPulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
10aChild10aEuropean Continental Ancestry Group10aGenome-Wide Association Study10aHumans10aPulmonary Disease, Chronic Obstructive10aRespiratory Function Tests1 aArtigas, Maria, Soler1 aLoth, Daan, W1 aWain, Louise, V1 aGharib, Sina, A1 aObeidat, Ma'en1 aTang, Wenbo1 aZhai, Guangju1 aZhao, Jing Hua1 aSmith, Albert, Vernon1 aHuffman, Jennifer, E1 aAlbrecht, Eva1 aJackson, Catherine, M1 aEvans, David, M1 aCadby, Gemma1 aFornage, Myriam1 aManichaikul, Ani1 aLopez, Lorna, M1 aJohnson, Toby1 aAldrich, Melinda, C1 aAspelund, Thor1 aBarroso, Inês1 aCampbell, Harry1 aCassano, Patricia, A1 aCouper, David, J1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aGarcia, Melissa1 aGieger, Christian1 aGislason, Gauti, Kjartan1 aGrkovic, Ivica1 aHammond, Christopher, J1 aHancock, Dana, B1 aHarris, Tamara, B1 aRamasamy, Adaikalavan1 aHeckbert, Susan, R1 aHeliövaara, Markku1 aHomuth, Georg1 aHysi, Pirro, G1 aJames, Alan, L1 aJankovic, Stipan1 aJoubert, Bonnie, R1 aKarrasch, Stefan1 aKlopp, Norman1 aKoch, Beate1 aKritchevsky, Stephen, B1 aLauner, Lenore, J1 aLiu, Yongmei1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aLumley, Thomas1 aBalushi, Khalid, A Al1 aAng, Wei, Q1 aBarr, Graham1 aBeilby, John1 aBlakey, John, D1 aBoban, Mladen1 aBoraska, Vesna1 aBrisman, Jonas1 aBritton, John, R1 aBrusselle, Guy, G1 aCooper, Cyrus1 aCurjuric, Ivan1 aDahgam, Santosh1 aDeary, Ian, J1 aEbrahim, Shah1 aEijgelsheim, Mark1 aFrancks, Clyde1 aGaysina, Darya1 aGranell, Raquel1 aGu, Xiangjun1 aHankinson, John, L1 aHardy, Rebecca1 aHarris, Sarah, E1 aHenderson, John1 aHenry, Amanda1 aHingorani, Aroon, D1 aHofman, Albert1 aHolt, Patrick, G1 aHui, Jennie1 aHunter, Michael, L1 aImboden, Medea1 aJameson, Karen, A1 aKerr, Shona, M1 aKolcic, Ivana1 aKronenberg, Florian1 aLiu, Jason, Z1 aMarchini, Jonathan1 aMcKeever, Tricia1 aMorris, Andrew, D1 aOlin, Anna-Carin1 aPorteous, David, J1 aPostma, Dirkje, S1 aRich, Stephen, S1 aRing, Susan, M1 aRivadeneira, Fernando1 aRochat, Thierry1 aSayer, Avan Aihie1 aSayers, Ian1 aSly, Peter, D1 aSmith, George Davey1 aSood, Akshay1 aStarr, John, M1 aUitterlinden, André, G1 aVonk, Judith, M1 aWannamethee, Goya1 aWhincup, Peter, H1 aWijmenga, Cisca1 aWilliams, Dale1 aWong, Andrew1 aMangino, Massimo1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aNorth, Kari, E1 aOmenaas, Ernst1 aPalmer, Lyle, J1 aPietiläinen, Kirsi, H1 aPin, Isabelle1 aEk, Ozren, Pola Sbrev1 aPouta, Anneli1 aPsaty, Bruce, M1 aHartikainen, Anna-Liisa1 aRantanen, Taina1 aRipatti, Samuli1 aRotter, Jerome, I1 aRudan, Igor1 aRudnicka, Alicja, R1 aSchulz, Holger1 aShin, So-Youn1 aSpector, Tim, D1 aSurakka, Ida1 aVitart, Veronique1 aVölzke, Henry1 aWareham, Nicholas, J1 aWarrington, Nicole, M1 aWichmann, H-Erich1 aWild, Sarah, H1 aWilk, Jemma, B1 aWjst, Matthias1 aWright, Alan, F1 aZgaga, Lina1 aZemunik, Tatijana1 aPennell, Craig, E1 aNyberg, Fredrik1 aKuh, Diana1 aHolloway, John, W1 aBoezen, Marike1 aLawlor, Debbie, A1 aMorris, Richard, W1 aProbst-Hensch, Nicole1 aKaprio, Jaakko1 aWilson, James, F1 aHayward, Caroline1 aKähönen, Mika1 aHeinrich, Joachim1 aMusk, Arthur, W1 aJarvis, Deborah, L1 aGläser, Sven1 aJarvelin, Marjo-Riitta1 aStricker, Bruno, H Ch1 aElliott, Paul1 aO'Connor, George, T1 aStrachan, David, P1 aLondon, Stephanie, J1 aHall, Ian, P1 aGudnason, Vilmundur1 aTobin, Martin, D1 aInternational Lung Cancer Consortium1 aGIANT Consortium uhttps://chs-nhlbi.org/node/609605055nas a2201153 4500008004100000022001400041245009900055210006900154260001300223300001100236490000700247520175600254653000902010653002202019653002002041653003202061653002402093653001902117653004002136653001102176653001902187653003802206653003402244653001302278653001102291653002602302653003102328653000902359653001602368653002302384653002902407653003602436653003002472653001902502100002002521700002302541700001902564700002002583700002002603700002002623700002502643700001902668700002402687700001902711700002202730700002102752700002202773700002002795700002102815700002102836700002002857700001802877700002102895700001902916700002302935700002402958700002202982700001803004700002203022700002603044700002103070700002203091700002003113700002003133700001403153700002603167700001903193700002603212700002003238700002303258700002103281700002403302700002803326700001603354700002303370700001903393700002003412700001803432700002003450700002203470700002203492700002103514700002303535700002203558700002003580700002403600700002203624700002103646700002003667700002003687700002403707700002703731700002203758700002203780700002003802700002103822700002203843856003603865 2011 eng d a1531-824900aGenome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.0 aGenomewide association studies of cerebral white matter lesion b c2011 Jun a928-390 v693 aOBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).
INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
10aAged10aAged, 80 and over10aCerebral Cortex10aChromosomes, Human, Pair 1710aCognition Disorders10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLeukoencephalopathies10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aMovement Disorders10aNerve Fibers, Myelinated10aPolymorphism, Single Nucleotide10aResidence Characteristics10aRNA, Messenger1 aFornage, Myriam1 aDebette, Stephanie1 aBis, Joshua, C1 aSchmidt, Helena1 aIkram, Arfan, M1 aDufouil, Carole1 aSigurdsson, Sigurdur1 aLumley, Thomas1 aDeStefano, Anita, L1 aFazekas, Franz1 aVrooman, Henri, A1 aShibata, Dean, K1 aMaillard, Pauline1 aZijdenbos, Alex1 aSmith, Albert, V1 aGudnason, Haukur1 ade Boer, Renske1 aCushman, Mary1 aMazoyer, Bernard1 aHeiss, Gerardo1 aVernooij, Meike, W1 aEnzinger, Christian1 aGlazer, Nicole, L1 aBeiser, Alexa1 aKnopman, David, S1 aCavalieri, Margherita1 aNiessen, Wiro, J1 aHarris, Tamara, B1 aPetrovic, Katja1 aLopez, Oscar, L1 aAu, Rhoda1 aLambert, Jean-Charles1 aHofman, Albert1 aGottesman, Rebecca, F1 aGarcia, Melissa1 aHeckbert, Susan, R1 aAtwood, Larry, D1 aCatellier, Diane, J1 aUitterlinden, André, G1 aYang, Qiong1 aSmith, Nicholas, L1 aAspelund, Thor1 aRomero, Jose, R1 aRice, Kenneth1 aTaylor, Kent, D1 aNalls, Michael, A1 aRotter, Jerome, I1 aSharrett, Richey1 aDuijn, Cornelia, M1 aAmouyel, Philippe1 aWolf, Philip, A1 aGudnason, Vilmundur1 avan der Lugt, Aad1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aTzourio, Christophe1 aBreteler, Monique, M B1 aMosley, Thomas, H1 aSchmidt, Reinhold1 aLongstreth, W T1 aDeCarli, Charles1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/129803920nas a2200721 4500008004100000022001400041245017000055210006900225260001600294300001200310490000700322520181400329653001002143653002202153653000902175653001202184653001402196653001502210653004002225653001102265653001702276653003802293653003402331653001302365653000902378653001102387653002702398653000902425653001602434653003102450653003802481653003602519653001402555653001602569100001802585700002202603700002402625700001802649700001702667700002202684700002002706700001802726700002502744700002102769700002002790700001602810700002302826700002602849700002002875700001402895700002102909700002402930700002102954700002202975700002302997700002503020700002203045700002503067700002103092700001903113710003003132856003603162 2011 eng d a1460-208300aGenome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.0 aGenomewide association study for serum urate concentrations and c2011 Oct 15 a4056-680 v203 aSerum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.
10aAdult10aAfrican Americans10aAged10aAnimals10aCHO Cells10aCricetinae10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGout10aHumans10aLoss of Heterozygosity10aMale10aMiddle Aged10aOrganic Anion Transporters10aOrganic Cation Transport Proteins10aPolymorphism, Single Nucleotide10aUric Acid10aYoung Adult1 aTin, Adrienne1 aWoodward, Owen, M1 aKao, Wen Hong Linda1 aLiu, Ching-Ti1 aLu, Xiaoning1 aNalls, Michael, A1 aShriner, Daniel1 aSemmo, Mariam1 aAkylbekova, Ermeg, L1 aWyatt, Sharon, B1 aHwang, Shih-Jen1 aYang, Qiong1 aZonderman, Alan, B1 aAdeyemo, Adebowale, A1 aPalmer, Cameron1 aMeng, Yan1 aReilly, Muredach1 aShlipak, Michael, G1 aSiscovick, David1 aEvans, Michele, K1 aRotimi, Charles, N1 aFlessner, Michael, F1 aKöttgen, Michael1 aCupples, Adrienne, L1 aFox, Caroline, S1 aKöttgen, Anna1 aCARe and CHARGE Consortia uhttps://chs-nhlbi.org/node/130504132nas a2200709 4500008004100000022001400041245010500055210006900160260001600229300001200245490000700257520206100264653000902325653003102334653001902365653004002384653001102424653003402435653001102469653004902480653003302529653000902562653003602571100002202607700002602629700002002655700002202675700002202697700002002719700002202739700002002761700001702781700002102798700001602819700001802835700001802853700001802871700001702889700001902906700002002925700002202945700002302967700001902990700002203009700002203031700002203053700001903075700001803094700002303112700002103135700001903156700002403175700002003199700002503219700002203244700002003266700002303286700002503309700002703334700002503361856003603386 2011 eng d a1460-208300aA genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.0 agenomewide association study identifies novel loci associated wi c2011 Mar 15 a1241-510 v203 aInsulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
10aAged10aChromosomes, Human, Pair 710aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aInsulin-Like Growth Factor Binding Protein 310aInsulin-Like Growth Factor I10aMale10aPolymorphism, Single Nucleotide1 aKaplan, Robert, C1 aPetersen, Ann-Kristin1 aChen, Ming-Huei1 aTeumer, Alexander1 aGlazer, Nicole, L1 aDöring, Angela1 aLam, Carolyn, S P1 aFriedrich, Nele1 aNewman, Anne1 aMüller, Martina1 aYang, Qiong1 aHomuth, Georg1 aCappola, Anne1 aKlopp, Norman1 aSmith, Holly1 aErnst, Florian1 aPsaty, Bruce, M1 aWichmann, H-Erich1 aSawyer, Douglas, B1 aBiffar, Reiner1 aRotter, Jerome, I1 aGieger, Christian1 aSullivan, Lisa, S1 aVölzke, Henry1 aRice, Kenneth1 aSpyroglou, Ariadni1 aKroemer, Heyo, K1 aChen, Y-D, Ida1 aManolopoulou, Jenny1 aNauck, Matthias1 aStrickler, Howard, D1 aGoodarzi, Mark, O1 aReincke, Martin1 aPollak, Michael, N1 aBidlingmaier, Martin1 aVasan, Ramachandran, S1 aWallaschofski, Henri uhttps://chs-nhlbi.org/node/126109449nas a2203037 4500008004100000022001400041245011300055210006900168260001600237300001200253490000700265520102300272653001301295653001901308653002501327653002201352653001701374653003401391653001101425653001701436653002701453653003601480100002001516700002601536700002201562700001401584700001801598700002301616700002101639700002101660700002001681700002101701700002001722700001601742700002201758700002001780700001801800700001801818700001901836700001901855700001601874700002601890700001901916700001701935700001601952700001701968700002001985700001802005700001802023700001702041700002002058700001902078700002102097700002402118700001602142700001902158700002002177700002002197700002002217700001602237700002102253700002402274700002202298700002302320700002002343700003102363700002502394700002202419700001702441700002202458700002102480700002002501700001902521700001802540700002702558700002402585700001702609700002202626700001902648700001702667700003302684700002602717700002502743700002802768700002002796700002702816700002002843700001902863700002402882700002002906700002002926700001802946700001902964700002202983700002103005700001703026700001903043700002203062700002003084700002203104700002003126700001903146700001503165700002403180700002103204700001903225700001803244700001703262700002003279700001803299700002403317700001403341700001703355700001603372700001903388700002303407700001803430700002303448700001703471700001603488700002403504700001903528700003003547700002003577700002403597700002403621700002003645700001803665700002603683700002303709700002403732700002403756700002003780700001703800700001803817700002103835700001803856700002003874700001803894700001503912700002003927700001803947700002303965700002103988700002004009700002104029700001704050700001904067700002204086700002204108700001904130700002304149700002004172700001904192700002104211700001704232700001704249700001704266700003004283700001804313700001704331700001704348700002204365700002204387700002004409700001904429700002004448700002204468700001704490700001904507700002004526700001804546700002104564700002404585700002004609700002104629700001904650700002304669700001704692700002204709700002304731700002404754700002004778700002204798700002304820700001604843700002104859700002504880700002804905700002204933700002004955700001604975700002204991700001805013700002205031700002305053700001905076700002205095700002105117700001905138700002005157700002305177700002505200700002305225700002105248700002005269700002205289700002005311700002005331700002005351700002305371700001805394700002105412700002105433700002105454700002005475700002105495700002005516700002205536700002005558700002505578700001905603700002105622700001905643700001905662700002305681700002505704700003005729700002205759700002105781700002105802700002105823700002005844700002705864700002605891700002505917700002405942700002905966700001705995700002406012700002006036700002306056700002006079700002106099700001806120700002306138710002706161710002306188710002406211710005006235710002506285710002206310710002806332710001506360856003606375 2011 eng d a1546-171800aGenome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.0 aGenomewide association study identifies six new loci influencing c2011 Sep 11 a1005-110 v433 aNumerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
10aArteries10aBlood Pressure10aCase-Control Studies10aFollow-Up Studies10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide1 aWain, Louise, V1 aVerwoert, Germaine, C1 aO'Reilly, Paul, F1 aShi, Gang1 aJohnson, Toby1 aJohnson, Andrew, D1 aBochud, Murielle1 aRice, Kenneth, M1 aHenneman, Peter1 aSmith, Albert, V1 aEhret, Georg, B1 aAmin, Najaf1 aLarson, Martin, G1 aMooser, Vincent1 aHadley, David1 aDörr, Marcus1 aBis, Joshua, C1 aAspelund, Thor1 aEsko, Tõnu1 aJanssens, Cecile, J W1 aZhao, Jing Hua1 aHeath, Simon1 aLaan, Maris1 aFu, Jingyuan1 aPistis, Giorgio1 aLuan, Jian'an1 aArora, Pankaj1 aLucas, Gavin1 aPirastu, Nicola1 aPichler, Irene1 aJackson, Anne, U1 aWebster, Rebecca, J1 aZhang, Feng1 aPeden, John, F1 aSchmidt, Helena1 aTanaka, Toshiko1 aCampbell, Harry1 aIgl, Wilmar1 aMilaneschi, Yuri1 aHottenga, Jouke-Jan1 aVitart, Veronique1 aChasman, Daniel, I1 aTrompet, Stella1 aBragg-Gresham, Jennifer, L1 aAlizadeh, Behrooz, Z1 aChambers, John, C1 aGuo, Xiuqing1 aLehtimäki, Terho1 aKuhnel, Brigitte1 aLopez, Lorna, M1 aPolasek, Ozren1 aBoban, Mladen1 aNelson, Christopher, P1 aMorrison, Alanna, C1 aPihur, Vasyl1 aGanesh, Santhi, K1 aHofman, Albert1 aKundu, Suman1 aMattace-Raso, Francesco, U S1 aRivadeneira, Fernando1 aSijbrands, Eric, J G1 aUitterlinden, André, G1 aHwang, Shih-Jen1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aLaitinen, Jaana1 aPouta, Anneli1 aZitting, Paavo1 aMcArdle, Wendy, L1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGlazer, Nicole, L1 aTaylor, Kent, D1 aHarris, Tamara, B1 aAlavere, Helene1 aHaller, Toomas1 aKeis, Aime1 aTammesoo, Mari-Liis1 aAulchenko, Yurii1 aBarroso, Inês1 aKhaw, Kay-Tee1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aEyheramendy, Susana1 aOrg, Elin1 aSõber, Siim1 aLu, Xiaowen1 aNolte, Ilja, M1 aPenninx, Brenda, W1 aCorre, Tanguy1 aMasciullo, Corrado1 aSala, Cinzia1 aGroop, Leif1 aVoight, Benjamin, F1 aMelander, Olle1 aO'Donnell, Christopher, J1 aSalomaa, Veikko1 ad'Adamo, Adamo, Pio1 aFabretto, Antonella1 aFaletra, Flavio1 aUlivi, Sheila1 aDel Greco, Fabiola, M1 aFacheris, Maurizio1 aCollins, Francis, S1 aBergman, Richard, N1 aBeilby, John, P1 aHung, Joseph1 aMusk, William1 aMangino, Massimo1 aShin, So-Youn1 aSoranzo, Nicole1 aWatkins, Hugh1 aGoel, Anuj1 aHamsten, Anders1 aGider, Pierre1 aLoitfelder, Marisa1 aZeginigg, Marion1 aHernandez, Dena1 aNajjar, Samer, S1 aNavarro, Pau1 aWild, Sarah, H1 aCorsi, Anna Maria1 aSingleton, Andrew1 aGeus, Eco, J C1 aWillemsen, Gonneke1 aParker, Alex, N1 aRose, Lynda, M1 aBuckley, Brendan1 aStott, David1 aOrrù, Marco1 aUda, Manuela1 avan der Klauw, Melanie, M1 aZhang, Weihua1 aLi, Xinzhong1 aScott, James1 aChen, Yii-Der Ida1 aBurke, Gregory, L1 aKähönen, Mika1 aViikari, Jorma1 aDöring, Angela1 aMeitinger, Thomas1 aDavies, Gail1 aStarr, John, M1 aEmilsson, Valur1 aPlump, Andrew1 aLindeman, Jan, H1 aHoen, Peter, A C 't1 aKönig, Inke, R1 aFelix, Janine, F1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aBreteler, Monique1 aDebette, Stephanie1 aDeStefano, Anita, L1 aFornage, Myriam1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aHolm, Hilma1 aStefansson, Kari1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aSamani, Nilesh, J1 aPreuss, Michael1 aRudan, Igor1 aHayward, Caroline1 aDeary, Ian, J1 aWichmann, H-Erich1 aRaitakari, Olli, T1 aPalmas, Walter1 aKooner, Jaspal, S1 aStolk, Ronald, P1 aJukema, Wouter1 aWright, Alan, F1 aBoomsma, Dorret, I1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWilson, James, F1 aFerrucci, Luigi1 aSchmidt, Reinhold1 aFarrall, Martin1 aSpector, Tim, D1 aPalmer, Lyle, J1 aTuomilehto, Jaakko1 aPfeufer, Arne1 aGasparini, Paolo1 aSiscovick, David1 aAltshuler, David1 aLoos, Ruth, J F1 aToniolo, Daniela1 aSnieder, Harold1 aGieger, Christian1 aMeneton, Pierre1 aWareham, Nicholas, J1 aOostra, Ben, A1 aMetspalu, Andres1 aLauner, Lenore1 aRettig, Rainer1 aStrachan, David, P1 aBeckmann, Jacques, S1 aWitteman, Jacqueline, C M1 aErdmann, Jeanette1 aDijk, Ko Willems1 aBoerwinkle, Eric1 aBoehnke, Michael1 aRidker, Paul, M1 aJarvelin, Marjo-Riitta1 aChakravarti, Aravinda1 aAbecasis, Goncalo, R1 aGudnason, Vilmundur1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aRao, Dabeeru, C1 aTobin, Martin, D1 aElliott, Paul1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aEchoGen consortium1 aAortaGen Consortium1 aCHARGE Consortium Heart Failure Working Group1 aKidneyGen Consortium1 aCKDGen Consortium1 aCardiogenics consortium1 aCardioGram uhttps://chs-nhlbi.org/node/132403421nas a2200829 4500008004100000022001400041245004600055210004200101260001300143300001600156490000700172520116200179653001001341653003801351653003401389653001301423653001101436653001401447100001901461700001601480700002301496700002301519700002201542700001801564700002401582700002101606700002001627700002301647700001701670700001201687700001801699700002401717700001901741700002101760700002101781700001801802700002401820700002001844700002201864700002301886700001901909700001901928700002101947700001901968700002001987700002202007700002002029700002202049700002202071700002302093700002002116700002002136700002202156700002002178700002602198700002102224700002002245700002002265700002502285700002502310700002902335700002202364700002002386700002402406700001902430700001702449700002402466700002002490700002202510700002302532856003602555 2011 eng d a1558-149700aA genome-wide association study of aging.0 agenomewide association study of aging c2011 Nov a2109.e15-280 v323 aHuman longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.
10aAging10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLongevity1 aWalter, Stefan1 aAtzmon, Gil1 aDemerath, Ellen, W1 aGarcia, Melissa, E1 aKaplan, Robert, C1 aKumari, Meena1 aLunetta, Kathryn, L1 aMilaneschi, Yuri1 aTanaka, Toshiko1 aTranah, Gregory, J1 aVölker, Uwe1 aYu, Lei1 aArnold, Alice1 aBenjamin, Emelia, J1 aBiffar, Reiner1 aBuchman, Aron, S1 aBoerwinkle, Eric1 aCouper, David1 aDe Jager, Philip, L1 aEvans, Denis, A1 aHarris, Tamara, B1 aHoffmann, Wolfgang1 aHofman, Albert1 aKarasik, David1 aKiel, Douglas, P1 aKocher, Thomas1 aKuningas, Maris1 aLauner, Lenore, J1 aLohman, Kurt, K1 aLutsey, Pamela, L1 aMackenbach, Johan1 aMarciante, Kristin1 aPsaty, Bruce, M1 aReiman, Eric, M1 aRotter, Jerome, I1 aSeshadri, Sudha1 aShardell, Michelle, D1 aSmith, Albert, V1 aDuijn, Cornelia1 aWalston, Jeremy1 aZillikens, Carola, M1 aBandinelli, Stefania1 aBaumeister, Sebastian, E1 aBennett, David, A1 aFerrucci, Luigi1 aGudnason, Vilmundur1 aKivimaki, Mika1 aLiu, Yongmei1 aMurabito, Joanne, M1 aNewman, Anne, B1 aTiemeier, Henning1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/130704122nas a2201045 4500008004100000022001400041245014200055210006900197260001300266300001300279490000600292520107900298653001001377653000901387653001201396653003101408653002701439653004001466653001101506653001701517653003801534653003401572653001101606653000901617653001601626653002701642653003601669100001901705700002101724700002201745700002901767700002201796700002101818700002901839700002201868700002301890700002301913700002501936700002301961700002901984700002302013700002202036700001502058700001902073700002002092700002602112700001902138700003002157700002802187700002102215700001702236700002402253700002302277700001902300700002002319700002202339700001602361700001702377700002302394700001202417700001902429700001702448700002102465700001802486700002002504700002002524700002502544700002202569700002402591700001902615700002102634700002202655700002502677700001802702700001802720700002502738700002302763700002402786700003002810700002302840700001802863700002702881700001802908700002502926700002602951700001902977700002302996700002103019856003603040 2011 eng d a1553-740400aIdentification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.0 aIdentification of a sudden cardiac death susceptibility locus at c2011 Jun ae10021580 v73 aSudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).
10aAdult10aAged10aAlleles10aChromosomes, Human, Pair 210aDeath, Sudden, Cardiac10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMyocardial Contraction10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aJunttila, Juhani1 aGoyette, Philippe1 aHuertas-Vazquez, Adriana1 aEijgelsheim, Mark1 aBlom, Marieke, T1 aNewton-Cheh, Christopher1 aReinier, Kyndaron1 aTeodorescu, Carmen1 aUy-Evanado, Audrey1 aCarter-Monroe, Naima1 aKaikkonen, Kari, S1 aKortelainen, Marja-Leena1 aBoucher, Gabrielle1 aLagacé, Caroline1 aMoes, Anna1 aZhao, XiaoQing1 aKolodgie, Frank1 aRivadeneira, Fernando1 aHofman, Albert1 aWitteman, Jacqueline, C M1 aUitterlinden, André, G1 aMarsman, Roos, F1 aPazoki, Raha1 aBardai, Abdennasser1 aKoster, Rudolph, W1 aDehghan, Abbas1 aHwang, Shih-Jen1 aBhatnagar, Pallav1 aPost, Wendy1 aHilton, Gina1 aPrineas, Ronald, J1 aLi, Man1 aKöttgen, Anna1 aEhret, Georg1 aBoerwinkle, Eric1 aCoresh, Josef1 aKao, Linda, W H1 aPsaty, Bruce, M1 aTomaselli, Gordon, F1 aSotoodehnia, Nona1 aSiscovick, David, S1 aBurke, Greg, L1 aMarbán, Eduardo1 aSpooner, Peter, M1 aCupples, Adrienne, L1 aJui, Jonathan1 aGunson, Karen1 aKesaniemi, Antero, Y1 aWilde, Arthur, A M1 aTardif, Jean-Claude1 aO'Donnell, Christopher, J1 aBezzina, Connie, R1 aVirmani, Renu1 aStricker, Bruno, H C H1 aTan, Hanno, L1 aAlbert, Christine, M1 aChakravarti, Aravinda1 aRioux, John, D1 aHuikuri, Heikki, V1 aChugh, Sumeet, S uhttps://chs-nhlbi.org/node/130403188nas a2200553 4500008004100000022001400041245012300055210006900178260001300247300000900260490000700269520163300276653001001909653000901919653002001928653002501948653003001973653001602003653001202019653001102031653001802042653003402060653001302094653001102107653001202118653002702130653000902157653002702166653002702193653001602220653003602236653001502272100002202287700002202309700001802331700001802349700001302367700001702380700001902397700002802416700002202444700002502466700002302491700002002514700002002534700002502554700001902579856003602598 2011 eng d a1098-227200aMeta-analysis of gene-environment interaction: joint estimation of SNP and SNP × environment regression coefficients.0 aMetaanalysis of geneenvironment interaction joint estimation of c2011 Jan a11-80 v353 aINTRODUCTION: Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies.
METHODS: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples.
RESULTS: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.
10aAdult10aAged10aBody Mass Index10aConfidence Intervals10aDiabetes Mellitus, Type 210aEnvironment10aFasting10aFemale10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aInsulin10aLeast-Squares Analysis10aMale10aMathematical Computing10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aPPAR gamma1 aManning, Alisa, K1 aLaValley, Michael1 aLiu, Ching-Ti1 aRice, Kenneth1 aAn, Ping1 aLiu, Yongmei1 aMiljkovic, Iva1 aRasmussen-Torvik, Laura1 aHarris, Tamara, B1 aProvince, Michael, A1 aBorecki, Ingrid, B1 aFlorez, Jose, C1 aMeigs, James, B1 aCupples, Adrienne, L1 aDupuis, Josée uhttps://chs-nhlbi.org/node/125805459nas a2201501 4500008004100000022001400041245016600055210006900221260001600290300001000306490000700316520120500323653001001528653000901538653001001547653002001557653003501577653001901612653002801631653004001659653001701699653003801716653001801754653003401772653001301806653001001819653001101829653001601840653001401856653002801870653003601898653001701934100001901951700002001970700002301990700001802013700002502031700001802056700001902074700002102093700002502114700002002139700002202159700002502181700002202206700001802228700002002246700002302266700001902289700001602308700001602324700001702340700002502357700002202382700002002404700002302424700002002447700001802467700001902485700002002504700002002524700002102544700001802565700002602583700001702609700001902626700002302645700002002668700002302688700002402711700001802735700001802753700001902771700002302790700002202813700002402835700001702859700002402876700002102900700002102921700002002942700001802962700002102980700001703001700001903018700002303037700002403060700002203084700002203106700001903128700002103147700001803168700002003186700001903206700002203225700002503247700002303272700002503295700002003320700002103340700002303361700002703384700002203411700002003433700002003453700002103473700001203494700002303506700001703529700002103546700001803567700002003585700002103605700001903626700002103645700002403666700002003690700002503710700001903735700002403754700002003778700001803798700002503816700002403841700003003865710002603895856003603921 2011 eng d a1546-171800aMeta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.0 aMetaanalysis of genomewide association studies from the CHARGE c c2011 Sep 11 a940-70 v433 aCarotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
10aAdult10aAged10aAging10aAtherosclerosis10aCarotid Intima-Media Thickness10aCohort Studies10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMiddle Aged10aPhenotype10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aRisk Factors1 aBis, Joshua, C1 aKavousi, Maryam1 aFranceschini, Nora1 aIsaacs, Aaron1 aAbecasis, Goncalo, R1 aSchminke, Ulf1 aPost, Wendy, S1 aSmith, Albert, V1 aCupples, Adrienne, L1 aMarkus, Hugh, S1 aSchmidt, Reinhold1 aHuffman, Jennifer, E1 aLehtimäki, Terho1 aBaumert, Jens1 aMünzel, Thomas1 aHeckbert, Susan, R1 aDehghan, Abbas1 aNorth, Kari1 aOostra, Ben1 aBevan, Steve1 aStoegerer, Eva-Maria1 aHayward, Caroline1 aRaitakari, Olli1 aMeisinger, Christa1 aSchillert, Arne1 aSanna, Serena1 aVölzke, Henry1 aCheng, Yu-Ching1 aThorsson, Bolli1 aFox, Caroline, S1 aRice, Kenneth1 aRivadeneira, Fernando1 aNambi, Vijay1 aHalperin, Eran1 aPetrovic, Katja, E1 aPeltonen, Leena1 aWichmann, Erich, H1 aSchnabel, Renate, B1 aDörr, Marcus1 aParsa, Afshin1 aAspelund, Thor1 aDemissie, Serkalem1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTaylor, Kent1 aUitterlinden, Andre1 aCouper, David, J1 aSitzer, Matthias1 aKähönen, Mika1 aIllig, Thomas1 aWild, Philipp, S1 aOrrù, Marco1 aLüdemann, Jan1 aShuldiner, Alan, R1 aEiriksdottir, Gudny1 aWhite, Charles, C1 aRotter, Jerome, I1 aHofman, Albert1 aSeissler, Jochen1 aZeller, Tanja1 aUsala, Gianluca1 aErnst, Florian1 aLauner, Lenore, J1 aD'Agostino, Ralph, B1 aO'Leary, Daniel, H1 aBallantyne, Christie1 aThiery, Joachim1 aZiegler, Andreas1 aLakatta, Edward, G1 aChilukoti, Ravi, Kumar1 aHarris, Tamara, B1 aWolf, Philip, A1 aPsaty, Bruce, M1 aPolak, Joseph, F1 aLi, Xia1 aRathmann, Wolfgang1 aUda, Manuela1 aBoerwinkle, Eric1 aKlopp, Norman1 aSchmidt, Helena1 aWilson, James, F1 aViikari, Jorma1 aKoenig, Wolfgang1 aBlankenberg, Stefan1 aNewman, Anne, B1 aWitteman, Jacqueline1 aHeiss, Gerardo1 avan Duijn, Cornelia1 aScuteri, Angelo1 aHomuth, Georg1 aMitchell, Braxton, D1 aGudnason, Vilmundur1 aO'Donnell, Christopher, J1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/132306092nas a2201597 4500008004100000022001400041245012900055210006900184260001600253300001000269490000800279520159300287653001501880653002301895653002801918653003801946653003401984653001102018653001702029653001502046100001902061700001902080700001902099700001902118700002402137700001302161700002002174700002502194700002302219700002002242700001802262700002302280700002702303700002202330700002102352700002102373700001902394700002102413700001702434700001902451700002502470700001902495700002002514700002002534700002102554700002402575700001702599700002002616700002002636700002002656700002302676700002102699700002002720700001702740700001702757700001902774700001902793700002202812700002202834700002302856700002202879700002202901700002202923700002102945700002602966700002102992700002503013700001803038700001803056700002003074700001303094700002303107700002103130700001903151700001903170700001903189700001803208700001703226700002203243700001703265700004103282700002003323700002003343700001903363700002003382700002403402700001903426700002503445700001903470700001703489700001803506700001403524700002403538700001703562700002203579700001703601700002403618700001603642700002103658700002303679700002103702700002203723700001603745700002303761700002203784700002803806700002703834700001803861700001803879700002003897700002603917700002103943700002703964700002003991700002204011700002504033700002004058700002304078700001904101700002004120700002204140700002604162700002304188700002004211700002004231700002404251700002004275700001804295700002104313700002804334700003004362700002404392700001904416700002304435856003604458 2011 eng d a1524-453900aMeta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.0 aMetaanalysis of genomewide association studies in 80 000 subject c2011 Feb 22 a731-80 v1233 aBACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.
METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.
CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aRisk Factors10aVasculitis1 aDehghan, Abbas1 aDupuis, Josée1 aBarbalic, Maja1 aBis, Joshua, C1 aEiriksdottir, Gudny1 aLu, Chen1 aPellikka, Niina1 aWallaschofski, Henri1 aKettunen, Johannes1 aHenneman, Peter1 aBaumert, Jens1 aStrachan, David, P1 aFuchsberger, Christian1 aVitart, Veronique1 aWilson, James, F1 aParé, Guillaume1 aNaitza, Silvia1 aRudock, Megan, E1 aSurakka, Ida1 aGeus, Eco, J C1 aAlizadeh, Behrooz, Z1 aGuralnik, Jack1 aShuldiner, Alan1 aTanaka, Toshiko1 aZee, Robert, Y L1 aSchnabel, Renate, B1 aNambi, Vijay1 aKavousi, Maryam1 aRipatti, Samuli1 aNauck, Matthias1 aSmith, Nicholas, L1 aSmith, Albert, V1 aSundvall, Jouko1 aScheet, Paul1 aLiu, Yongmei1 aRuokonen, Aimo1 aRose, Lynda, M1 aLarson, Martin, G1 aHoogeveen, Ron, C1 aFreimer, Nelson, B1 aTeumer, Alexander1 aTracy, Russell, P1 aLauner, Lenore, J1 aBuring, Julie, E1 aYamamoto, Jennifer, F1 aFolsom, Aaron, R1 aSijbrands, Eric, J G1 aPankow, James1 aElliott, Paul1 aKeaney, John, F1 aSun, Wei1 aSarin, Antti-Pekka1 aFontes, João, D1 aBadola, Sunita1 aAstor, Brad, C1 aHofman, Albert1 aPouta, Anneli1 aWerdan, Karl1 aGreiser, Karin, H1 aKuss, Oliver1 aMeyer zu Schwabedissen, Henriette, E1 aThiery, Joachim1 aJamshidi, Yalda1 aNolte, Ilja, M1 aSoranzo, Nicole1 aSpector, Timothy, D1 aVölzke, Henry1 aParker, Alexander, N1 aAspelund, Thor1 aBates, David1 aYoung, Lauren1 aTsui, Kim1 aSiscovick, David, S1 aGuo, Xiuqing1 aRotter, Jerome, I1 aUda, Manuela1 aSchlessinger, David1 aRudan, Igor1 aHicks, Andrew, A1 aPenninx, Brenda, W1 aThorand, Barbara1 aGieger, Christian1 aCoresh, Joe1 aWillemsen, Gonneke1 aHarris, Tamara, B1 aUitterlinden, André, G1 aJarvelin, Marjo-Riitta1 aRice, Kenneth1 aRadke, Dörte1 aSalomaa, Veikko1 avan Dijk, Ko, Willems1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aFerrucci, Luigi1 aGibson, Quince, D1 aBandinelli, Stefania1 aSnieder, Harold1 aBoomsma, Dorret, I1 aXiao, Xiangjun1 aCampbell, Harry1 aHayward, Caroline1 aPramstaller, Peter, P1 aDuijn, Cornelia, M1 aPeltonen, Leena1 aPsaty, Bruce, M1 aGudnason, Vilmundur1 aRidker, Paul, M1 aHomuth, Georg1 aKoenig, Wolfgang1 aBallantyne, Christie, M1 aWitteman, Jacqueline, C M1 aBenjamin, Emelia, J1 aPerola, Markus1 aChasman, Daniel, I uhttps://chs-nhlbi.org/node/126707496nas a2202305 4500008004100000022001400041245006700055210006600122260001600188300001000204490000800214520114000222653001201362653002001374653001401394653002801408653002401436653001101460653003001471653001901501653001801520653003401538653001801572653001101590653001901601653001901620653002901639653002701668653001401695653002301709100002201732700002601754700001601780700001801796700002001814700002001834700002901854700001901883700002301902700001801925700002001943700001801963700002001981700002002001700002002021700002102041700002202062700001702084700001802101700002602119700001902145700002202164700002002186700002402206700002402230700001802254700002202272700001802294700001602312700002002328700002202348700002102370700001802391700002302409700001502432700002602447700002002473700002002493700002102513700002502534700001702559700002902576700001902605700001902624700002302643700002202666700002202688700002102710700001702731700001702748700002302765700001902788700002002807700001802827700002202845700002002867700001802887700001402905700002102919700001902940700002202959700002202981700001903003700002803022700002303050700002803073700001803101700001803119700002003137700002103157700001903178700002103197700003103218700002003249700002503269700001903294700002103313700002003334700002403354700002203378700001803400700002503418700002503443700002103468700002003489700001803509700002003527700001903547700002303566700001803589700002603607700001803633700001903651700002203670700002203692700001903714700001703733700002203750700002303772700002403795700002203819700002403841700001703865700002303882700002003905700001903925700002203944700002303966700002203989700001704011700001904028700002104047700001804068700001704086700001804103700002804121700002304149700001704172700002204189700002204211700002304233700001804256700002004274700001904294700002104313700002504334700002104359700002204380700002104402700001904423700002304442700002004465700002304485700002304508700001804531700001804549700002204567700002204589700002704611700002404638700002304662700002004685700002404705700002504729700002804754700001904782700002004801700002404821700001604845700002204861700001904883700002204902700002104924700002104945700001904966700002104985700002105006700001805027700002105045700002005066700002405086700002405110700002005134856003605154 2011 eng d a1476-468700aNew gene functions in megakaryopoiesis and platelet formation.0 aNew gene functions in megakaryopoiesis and platelet formation c2011 Nov 30 a201-80 v4803 aPlatelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
10aAnimals10aBlood Platelets10aCell Size10aDrosophila melanogaster10aDrosophila Proteins10aEurope10aGene Expression Profiling10aGene Silencing10aGenome, Human10aGenome-Wide Association Study10aHematopoiesis10aHumans10aMegakaryocytes10aPlatelet Count10aProtein Interaction Maps10aTranscription, Genetic10aZebrafish10aZebrafish Proteins1 aGieger, Christian1 aRadhakrishnan, Aparna1 aCvejic, Ana1 aTang, Weihong1 aPorcu, Eleonora1 aPistis, Giorgio1 aSerbanovic-Canic, Jovana1 aElling, Ulrich1 aGoodall, Alison, H1 aLabrune, Yann1 aLopez, Lorna, M1 aMägi, Reedik1 aMeacham, Stuart1 aOkada, Yukinori1 aPirastu, Nicola1 aSorice, Rossella1 aTeumer, Alexander1 aVoss, Katrin1 aZhang, Weihua1 aRamirez-Solis, Ramiro1 aBis, Joshua, C1 aEllinghaus, David1 aGögele, Martin1 aHottenga, Jouke-Jan1 aLangenberg, Claudia1 aKovacs, Peter1 aO'Reilly, Paul, F1 aShin, So-Youn1 aEsko, Tõnu1 aHartiala, Jaana1 aKanoni, Stavroula1 aMurgia, Federico1 aParsa, Afshin1 aStephens, Jonathan1 aHarst, Pim1 avan der Schoot, Ellen1 aAllayee, Hooman1 aAttwood, Antony1 aBalkau, Beverley1 aBastardot, François1 aBasu, Saonli1 aBaumeister, Sebastian, E1 aBiino, Ginevra1 aBomba, Lorenzo1 aBonnefond, Amélie1 aCambien, Francois1 aChambers, John, C1 aCucca, Francesco1 aD'Adamo, Pio1 aDavies, Gail1 ade Boer, Rudolf, A1 aGeus, Eco, J C1 aDöring, Angela1 aElliott, Paul1 aErdmann, Jeanette1 aEvans, David, M1 aFalchi, Mario1 aFeng, Wei1 aFolsom, Aaron, R1 aFrazer, Ian, H1 aGibson, Quince, D1 aGlazer, Nicole, L1 aHammond, Chris1 aHartikainen, Anna-Liisa1 aHeckbert, Susan, R1 aHengstenberg, Christian1 aHersch, Micha1 aIllig, Thomas1 aLoos, Ruth, J F1 aJolley, Jennifer1 aKhaw, Kay, Tee1 aKuhnel, Brigitte1 aKyrtsonis, Marie-Christine1 aLagou, Vasiliki1 aLloyd-Jones, Heather1 aLumley, Thomas1 aMangino, Massimo1 aMaschio, Andrea1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMemari, Yasin1 aMitchell, Braxton, D1 aMontgomery, Grant, W1 aNakamura, Yusuke1 aNauck, Matthias1 aNavis, Gerjan1 aNöthlings, Ute1 aNolte, Ilja, M1 aPorteous, David, J1 aPouta, Anneli1 aPramstaller, Peter, P1 aPullat, Janne1 aRing, Susan, M1 aRotter, Jerome, I1 aRuggiero, Daniela1 aRuokonen, Aimo1 aSala, Cinzia1 aSamani, Nilesh, J1 aSambrook, Jennifer1 aSchlessinger, David1 aSchreiber, Stefan1 aSchunkert, Heribert1 aScott, James1 aSmith, Nicholas, L1 aSnieder, Harold1 aStarr, John, M1 aStumvoll, Michael1 aTakahashi, Atsushi1 aTang, W, H Wilson1 aTaylor, Kent1 aTenesa, Albert1 aThein, Swee, Lay1 aTönjes, Anke1 aUda, Manuela1 aUlivi, Sheila1 avan Veldhuisen, Dirk, J1 aVisscher, Peter, M1 aVölker, Uwe1 aWichmann, H-Erich1 aWiggins, Kerri, L1 aWillemsen, Gonneke1 aYang, Tsun-Po1 aZhao, Jing, Hua1 aZitting, Paavo1 aBradley, John, R1 aDedoussis, George, V1 aGasparini, Paolo1 aHazen, Stanley, L1 aMetspalu, Andres1 aPirastu, Mario1 aShuldiner, Alan, R1 avan Pelt, Joost1 aZwaginga, Jaap-Jan1 aBoomsma, Dorret, I1 aDeary, Ian, J1 aFranke, Andre1 aFroguel, Philippe1 aGanesh, Santhi, K1 aJarvelin, Marjo-Riitta1 aMartin, Nicholas, G1 aMeisinger, Christa1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aWareham, Nicholas, J1 aAkkerman, Jan-Willem, N1 aCiullo, Marina1 aDeloukas, Panos1 aGreinacher, Andreas1 aJupe, Steve1 aKamatani, Naoyuki1 aKhadake, Jyoti1 aKooner, Jaspal, S1 aPenninger, Josef1 aProkopenko, Inga1 aStemple, Derek1 aToniolo, Daniela1 aWernisch, Lorenz1 aSanna, Serena1 aHicks, Andrew, A1 aRendon, Augusto1 aFerreira, Manuel, A1 aOuwehand, Willem, H1 aSoranzo, Nicole uhttps://chs-nhlbi.org/node/135503344nas a2200517 4500008004100000022001400041245014800055210006900203260001600272300001100288490000800299520172900307653002602036653003402062653001802096653003202114653002502146653003402171653001102205653003302216653003102249653005202280653001402332653001902346653002002365653001702385653001802402100002002420700002302440700001902463700002802482700002102510700002202531700002702553700001902580700002402599700002202623700002102645700001902666700001902685700002402704700002302728700002402751710001502775856003602790 2011 eng d a1476-625600aThe Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study.0 aNext PAGE in understanding complex traits design for the analysi c2011 Oct 01 a849-590 v1743 aGenetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the "phenome-wide association study" approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser.
10aEpidemiologic Methods10aEpidemiologic Research Design10aEthnic Groups10aGenetic Association Studies10aGenetics, Population10aGenome-Wide Association Study10aHumans10aInterinstitutional Relations10aMultifactorial Inheritance10aNational Human Genome Research Institute (U.S.)10aPhenotype10aPilot Projects10aResearch Design10aRisk Factors10aUnited States1 aMatise, Tara, C1 aAmbite, Jose, Luis1 aBuyske, Steven1 aCarlson, Christopher, S1 aCole, Shelley, A1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aHeiss, Gerardo1 aKooperberg, Charles1 aLe Marchand, Loic1 aManolio, Teri, A1 aNorth, Kari, E1 aPeters, Ulrike1 aRitchie, Marylyn, D1 aHindorff, Lucia, A1 aHaines, Jonathan, L1 aPAGE Study uhttps://chs-nhlbi.org/node/131305540nas a2201357 4500008004100000022001400041245007400055210006900129260001300198300001200211490000700223520169700230653001701927653001901944653001101963653001001974653003401984653001102018653000902029653002702038653003602065653002802101653003102129653002402160100001802184700001902202700003102221700001602252700002502268700001202293700002102305700002402326700002502350700001402375700001702389700001802406700001802424700001902442700002802461700001902489700002502508700002402533700002302557700002502580700002102605700001602626700002602642700001902668700002102687700001902708700002002727700002102747700002102768700002402789700001702813700002002830700001302850700002102863700002502884700001802909700002002927700003002947700002102977700002702998700002203025700002903047700002103076700002303097700001603120700002003136700001903156700002003175700002303195700002203218700002403240700002003264700001703284700002703301700003103328700002303359700002003382700002103402700001503423700002803438700001903466700002303485700002503508700002403533700001903557700001903576700001703595700002503612700002603637700001903663700002203682700002103704700002703725700002603752700002803778700002503806700002403831700002003855700002203875700002403897700002003921700002103941700002503962700002603987700002304013700001904036700002604055700002104081700002504102700001904127856003604146 2012 eng d a1523-468100aAssessment of gene-by-sex interaction effect on bone mineral density.0 aAssessment of genebysex interaction effect on bone mineral densi c2012 Oct a2051-640 v273 aSexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.
10aBone Density10aCohort Studies10aFemale10aGenes10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aReproducibility of Results10aSex Characteristics1 aLiu, Ching-Ti1 aEstrada, Karol1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aEvangelou, Evangelos1 aLi, Guo1 aMinster, Ryan, L1 aCarless, Melanie, A1 aKammerer, Candace, M1 aOei, Ling1 aZhou, Yanhua1 aAlonso, Nerea1 aDailiana, Zoe1 aEriksson, Joel1 aGarcía-Giralt, Natalia1 aGiroux, Sylvie1 aHusted, Lise, Bjerre1 aKhusainova, Rita, I1 aKoromila, Theodora1 aKung, Annie, Waichee1 aLewis, Joshua, R1 aMasi, Laura1 aMencej-Bedrac, Simona1 aNogues, Xavier1 aPatel, Millan, S1 aPrezelj, Janez1 aRichards, Brent1 aSham, Pak, Chung1 aSpector, Timothy1 aVandenput, Liesbeth1 aXiao, Su-Mei1 aZheng, Hou-Feng1 aZhu, Kun1 aBalcells, Susana1 aBrandi, Maria, Luisa1 aFrost, Morten1 aGoltzman, David1 aGonzález-Macías, Jesús1 aKarlsson, Magnus1 aKhusnutdinova, Elza, K1 aKollia, Panagoula1 aLangdahl, Bente, Lomholt1 aLjunggren, Osten1 aLorentzon, Mattias1 aMarc, Janja1 aMellström, Dan1 aOhlsson, Claes1 aOlmos, José, M1 aRalston, Stuart, H1 aRiancho, José, A1 aRousseau, François1 aUrreizti, Roser1 aVan Hul, Wim1 aZarrabeitia, María, T1 aCastano-Betancourt, Martha1 aDemissie, Serkalem1 aGrundberg, Elin1 aHerrera, Lizbeth1 aKwan, Tony1 aMedina-Gómez, Carolina1 aPastinen, Tomi1 aSigurdsson, Gunnar1 aThorleifsson, Gudmar1 aVanmeurs, Joyce, Bj1 aBlangero, John1 aHofman, Albert1 aLiu, Yongmei1 aMitchell, Braxton, D1 aO'Connell, Jeffrey, R1 aOostra, Ben, A1 aRotter, Jerome, I1 aStefansson, Kari1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aThorsteinsdottir, Unnur1 aTylavsky, Frances, A1 aUitterlinden, Andre1 aCauley, Jane, A1 aHarris, Tamara, B1 aIoannidis, John, Pa1 aPsaty, Bruce, M1 aRobbins, John, A1 aZillikens, Carola, M1 aVanduijn, Cornelia, M1 aPrince, Richard, L1 aKarasik, David1 aRivadeneira, Fernando1 aKiel, Douglas, P1 aCupples, Adrienne, L1 aHsu, Yi-Hsiang uhttps://chs-nhlbi.org/node/155607377nas a2201945 4500008004100000022001400041245014700055210006900202260001600271300001100287490000600298520192200304653001002226653001602236653000902252653002202261653001202283653002502295653003102320653001902351653004202370653001102412653003402423653001302457653001902470653001102489653002002500653000902520653001602529653003302545653001402578653003602592653001702628653001602645100002402661700002202685700002002707700001602727700002102743700001702764700002002781700002002801700002002821700001902841700001702860700002202877700002302899700002502922700001702947700002202964700002502986700002003011700001903031700002303050700002203073700001903095700002103114700001803135700002203153700001503175700002203190700002203212700002003234700002503254700002103279700002403300700001603324700001803340700002703358700002103385700002503406700001903431700001803450700002603468700002103494700002303515700001903538700002403557700002503581700002003606700001803626700003003644700002203674700002003696700002103716700002203737700001903759700002003778700001803798700002403816700001903840700001903859700001803878700002703896700001803923700002303941700002803964700002103992700001604013700001904029700001704048700002304065700001804088700002104106700001804127700002004145700001804165700002904183700002104212700002004233700003004253700001904283700002304302700002304325700001904348700002004367700002104387700001404408700002604422700002204448700002204470700002204492700002104514700002004535700002604555700002804581700001904609700002304628700001904651700002104670700002004691700001804711700002204729700001604751700002904767700002404796700002104820700002004841700001904861700002504880700002204905700002404927700002504951700001704976700002004993700002005013700001905033700001605052700002305068700002005091700002305111700001705134700002005151700002205171700002105193700003005214700001705244700002205261700002305283700002105306700001905327700002505346700002405371856003605395 2012 eng d a1942-326800aAssociation between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.0 aAssociation between chromosome 9p21 variants and the anklebrachi c2012 Feb 01 a100-120 v53 aBACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).
CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
10aAdult10aAge Factors10aAged10aAged, 80 and over10aAlleles10aAnkle Brachial Index10aChromosomes, Human, Pair 910aCohort Studies10aCyclin-Dependent Kinase Inhibitor p1510aFemale10aGenome-Wide Association Study10aGenotype10aHapMap Project10aHumans10aLogistic Models10aMale10aMiddle Aged10aPeripheral Vascular Diseases10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aSex Factors1 aMurabito, Joanne, M1 aWhite, Charles, C1 aKavousi, Maryam1 aSun, Yan, V1 aFeitosa, Mary, F1 aNambi, Vijay1 aLamina, Claudia1 aSchillert, Arne1 aCoassin, Stefan1 aBis, Joshua, C1 aBroer, Linda1 aCrawford, Dana, C1 aFranceschini, Nora1 aFrikke-Schmidt, Ruth1 aHaun, Margot1 aHolewijn, Suzanne1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aKiechl, Stefan1 aKollerits, Barbara1 aMontasser, May, E1 aNolte, Ilja, M1 aRudock, Megan, E1 aSenft, Andrea1 aTeumer, Alexander1 aHarst, Pim1 aVitart, Veronique1 aWaite, Lindsay, L1 aWood, Andrew, R1 aWassel, Christina, L1 aAbsher, Devin, M1 aAllison, Matthew, A1 aAmin, Najaf1 aArnold, Alice1 aAsselbergs, Folkert, W1 aAulchenko, Yurii1 aBandinelli, Stefania1 aBarbalic, Maja1 aBoban, Mladen1 aBrown-Gentry, Kristin1 aCouper, David, J1 aCriqui, Michael, H1 aDehghan, Abbas1 aHeijer, Martin, den1 aDieplinger, Benjamin1 aDing, Jingzhong1 aDörr, Marcus1 aEspinola-Klein, Christine1 aFelix, Stephan, B1 aFerrucci, Luigi1 aFolsom, Aaron, R1 aFraedrich, Gustav1 aGibson, Quince1 aGoodloe, Robert1 aGunjaca, Grgo1 aHaltmayer, Meinhard1 aHeiss, Gerardo1 aHofman, Albert1 aKieback, Arne1 aKiemeney, Lambertus, A1 aKolcic, Ivana1 aKullo, Iftikhar, J1 aKritchevsky, Stephen, B1 aLackner, Karl, J1 aLi, Xiaohui1 aLieb, Wolfgang1 aLohman, Kurt1 aMeisinger, Christa1 aMelzer, David1 aMohler, Emile, R1 aMudnic, Ivana1 aMueller, Thomas1 aNavis, Gerjan1 aOberhollenzer, Friedrich1 aOlin, Jeffrey, W1 aO'Connell, Jeff1 aO'Donnell, Christopher, J1 aPalmas, Walter1 aPenninx, Brenda, W1 aPetersmann, Astrid1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRantner, Barbara1 aRice, Ken1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSeldenrijk, Adrie1 aStadler, Marietta1 aSummerer, Monika1 aTanaka, Toshiko1 aTybjaerg-Hansen, Anne1 aUitterlinden, André, G1 aGilst, Wiek, H1 aVermeulen, Sita, H1 aWild, Sarah, H1 aWild, Philipp, S1 aWilleit, Johann1 aZeller, Tanja1 aZemunik, Tatijana1 aZgaga, Lina1 aAssimes, Themistocles, L1 aBlankenberg, Stefan1 aBoerwinkle, Eric1 aCampbell, Harry1 aCooke, John, P1 ade Graaf, Jacqueline1 aHerrington, David1 aKardia, Sharon, L R1 aMitchell, Braxton, D1 aMurray, Anna1 aMünzel, Thomas1 aNewman, Anne, B1 aOostra, Ben, A1 aRudan, Igor1 aShuldiner, Alan, R1 aSnieder, Harold1 aDuijn, Cornelia, M1 aVölker, Uwe1 aWright, Alan, F1 aWichmann, H-Erich1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aLiu, Yongmei1 aHayward, Caroline1 aBorecki, Ingrid, B1 aZiegler, Andreas1 aNorth, Kari, E1 aCupples, Adrienne, L1 aKronenberg, Florian uhttps://chs-nhlbi.org/node/135903420nas a2200517 4500008004100000022001400041245023700055210006900292260001600361300001000377490000600387520182700393653000902220653002202229653002802251653002102279653002102300653004002321653001102361653002502372653003402397653001302431653001102444653000902455653001602464653003602480653001702516653001102533653001802544100001902562700002102581700002002602700002302622700001802645700001902663700002302682700002302705700001402728700002002742700001602762700002002778700001902798700002502817700002402842856003602866 2012 eng d a1942-326800aAssociations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study.0 aAssociations between incident ischemic stroke events and stroke c2012 Apr 01 a210-60 v53 aBACKGROUND: Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.
METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomics and Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were significantly associated with [corrected] IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.
CONCLUSIONS: Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aFemale10aGenetics, Population10aGenome-Wide Association Study10aGenomics10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke10aTriglycerides1 aCarty, Cara, L1 aBůzková, Petra1 aFornage, Myriam1 aFranceschini, Nora1 aCole, Shelley1 aHeiss, Gerardo1 aHindorff, Lucia, A1 aHoward, Barbara, V1 aMann, Sue1 aMartin, Lisa, W1 aZhang, Ying1 aMatise, Tara, C1 aPrentice, Ross1 aReiner, Alexander, P1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/137103141nas a2200685 4500008004100000022001400041245018100055210006900236260001300305300001100318490000700329520115600336653001001492653000901502653002201511653001201533653003001545653001101575653003801586653003401624653001301658653001101671653000901682653001701691653001601708653002201724653000901746653001701755100002701772700002501799700002201824700002101846700002201867700001501889700001901904700002301923700002401946700002301970700002401993700002002017700002502037700001902062700002302081700001502104700002102119700002002140700001802160700002402178700002602202700001902228700002202247700002302269700002302292700001902315700001902334700002202353700002302375700002102398856003602419 2012 eng d a1939-327X00aConsistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium.0 aConsistent directions of effect for established type 2 diabetes c2012 Jun a1642-70 v613 aCommon genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.
10aAdult10aAged10aAged, 80 and over10aAlleles10aDiabetes Mellitus, Type 210aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMetagenomics10aMiddle Aged10aPopulation Groups10aRisk10aRisk Factors1 aHaiman, Christopher, A1 aFesinmeyer, Megan, D1 aSpencer, Kylee, L1 aBůzková, Petra1 aVoruganti, Saroja1 aWan, Peggy1 aHaessler, Jeff1 aFranceschini, Nora1 aMonroe, Kristine, R1 aHoward, Barbara, V1 aJackson, Rebecca, D1 aFlorez, Jose, C1 aKolonel, Laurence, N1 aBuyske, Steven1 aGoodloe, Robert, J1 aLiu, Simin1 aManson, JoAnn, E1 aMeigs, James, B1 aWaters, Kevin1 aMukamal, Kenneth, J1 aPendergrass, Sarah, A1 aShrader, Peter1 aWilkens, Lynne, R1 aHindorff, Lucia, A1 aAmbite, Jose, Luis1 aNorth, Kari, E1 aPeters, Ulrike1 aCrawford, Dana, C1 aLe Marchand, Loïc1 aPankow, James, S uhttps://chs-nhlbi.org/node/663304113nas a2200817 4500008004100000022001400041245022200055210006900277260001300346300001100359490000700370520161000377653005101987653000902038653002802047653002102075653001102096653001702107653003402124653001102158653000902169653001602178653002202194653003602216100002102252700001902273700001902292700001902311700001902330700001802349700001302367700002302380700002802403700002002431700002502451700002402476700002102500700002602521700002202547700002602569700002302595700002002618700002102638700002402659700002702683700001902710700002202729700002302751700002402774700002002798700002402818700002302842700003202865700002002897700002202917700002102939700001902960700001802979700001802997700002603015700002203041700002203063700002803085700002103113700003003134700002203164700002103186700002403207700002803231856003603259 2012 eng d a1522-964500aEight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies.0 aEight genetic loci associated with variation in lipoproteinassoc c2012 Jan a238-510 v333 aAIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.
CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aCoronary Artery Disease10aCoronary Disease10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPhospholipases A210aPolymorphism, Single Nucleotide1 aGrallert, Harald1 aDupuis, Josée1 aBis, Joshua, C1 aDehghan, Abbas1 aBarbalic, Maja1 aBaumert, Jens1 aLu, Chen1 aSmith, Nicholas, L1 aUitterlinden, André, G1 aRoberts, Robert1 aKhuseyinova, Natalie1 aSchnabel, Renate, B1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aHoogeveen, Ron, C1 aFontes, João, Daniel1 aMeisinger, Christa1 aKeaney, John, F1 aLemaitre, Rozenn1 aAulchenko, Yurii, S1 aVasan, Ramachandran, S1 aEllis, Stephen1 aHazen, Stanley, L1 aDuijn, Cornelia, M1 aNelson, Jeanenne, J1 aMärz, Winfried1 aSchunkert, Heribert1 aMcPherson, Ruth, M1 aStirnadel-Farrant, Heide, A1 aPsaty, Bruce, M1 aGieger, Christian1 aSiscovick, David1 aHofman, Albert1 aIllig, Thomas1 aCushman, Mary1 aYamamoto, Jennifer, F1 aRotter, Jerome, I1 aLarson, Martin, G1 aStewart, Alexandre, F R1 aBoerwinkle, Eric1 aWitteman, Jacqueline, C M1 aTracy, Russell, P1 aKoenig, Wolfgang1 aBenjamin, Emelia, J1 aBallantyne, Christie, M uhttps://chs-nhlbi.org/node/134103528nas a2200721 4500008004100000022001400041245014600055210006900201260000900270300001100279490000600290520139200296653002201688653002801710653004001738653002101778653002101799653002301820653001901843653001901862653003401881653001301915653001101928653002301939653003601962653002801998100001902026700001302045700001902058700001602077700002902093700002202122700002302144700002202167700002302189700002102212700002102233700002202254700002102276700001802297700002202315700002502337700002302362700002202385700001702407700002002424700002402444700001202468700002302480700002002503700002602523700002202549700002802571700002402599700001802623700002102641700002102662700002702683700001902710700002202729700001902751856003602770 2012 eng d a1932-620300aEvaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.0 aEvaluation of the metabochip genotyping array in African America c2012 ae356510 v73 aThe Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
10aAfrican Americans10aCardiovascular Diseases10aCholesterol Ester Transfer Proteins10aCholesterol, HDL10aCholesterol, LDL10aChromosomes, Human10aCohort Studies10aGene Frequency10aGenome-Wide Association Study10aGenotype10aHumans10aMetabolic Diseases10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aBuyske, Steven1 aWu, Ying1 aCarty, Cara, L1 aCheng, Iona1 aAssimes, Themistocles, L1 aDumitrescu, Logan1 aHindorff, Lucia, A1 aMitchell, Sabrina1 aAmbite, Jose, Luis1 aBoerwinkle, Eric1 aBůzková, Petra1 aCarlson, Chris, S1 aCochran, Barbara1 aDuggan, David1 aEaton, Charles, B1 aFesinmeyer, Megan, D1 aFranceschini, Nora1 aHaessler, Jeffrey1 aJenny, Nancy1 aKang, Hyun, Min1 aKooperberg, Charles1 aLin, Yi1 aLe Marchand, Loïc1 aMatise, Tara, C1 aRobinson, Jennifer, G1 aRodriguez, Carlos1 aSchumacher, Fredrick, R1 aVoight, Benjamin, F1 aYoung, Alicia1 aManolio, Teri, A1 aMohlke, Karen, L1 aHaiman, Christopher, A1 aPeters, Ulrike1 aCrawford, Dana, C1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/663403996nas a2200625 4500008004100000022001400041245008800055210006900143260000900212300001300221490000600234520220300240653002202443653000902465653002602474653002402500653004002524653001102564653003802575653003402613653001102647653002702658653000902685653001702694653001602711653003602727653002802763653003402791653001702825653001602842653001802858100002202876700002402898700001902922700001802941700001602959700001902975700001902994700001803013700002503031700002303056700002003079700001703099700002303116700001903139700002103158700002203179700002103201700002403222700002703246700002103273700002103294700001903315856003603334 2012 eng d a1553-740400aFine-mapping and initial characterization of QT interval loci in African Americans.0 aFinemapping and initial characterization of QT interval loci in c2012 ae10028700 v83 aThe QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.
10aAfrican Americans10aAged10aComputational Biology10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMale10aMetagenomics10aMiddle Aged10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRisk Factors10aTachycardia10aUnited States1 aAvery, Christy, L1 aSethupathy, Praveen1 aBuyske, Steven1 aHe, Qianchuan1 aLin, Dan-Yu1 aArking, Dan, E1 aCarty, Cara, L1 aDuggan, David1 aFesinmeyer, Megan, D1 aHindorff, Lucia, A1 aJeff, Janina, M1 aKlein, Liviu1 aPatton, Kristen, K1 aPeters, Ulrike1 aShohet, Ralph, V1 aSotoodehnia, Nona1 aYoung, Alicia, M1 aKooperberg, Charles1 aHaiman, Christopher, A1 aMohlke, Karen, L1 aWhitsel, Eric, A1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/608308598nas a2202365 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520193500238653005002173653001602223653002002239653002602259653001102285653002202296653003402318653001102352653000902363653002602372653001402398653003602412653001302448653002302461100001502484700002002499700002202519700002202541700002802563700002302591700001902614700002502633700003202658700001802690700001902708700002602727700003102753700001902784700001802803700002002821700001202841700001702853700002202870700002502892700002002917700002002937700001602957700002002973700001902993700001903012700001803031700002103049700001803070700002603088700001903114700002103133700002003154700002103174700001903195700002103214700002003235700001903255700003503274700002403309700002103333700001803354700001503372700002803387700001903415700003403434700001803468700001803486700002003504700002203524700002103546700002103567700002503588700002903613700002303642700001603665700002003681700002203701700001403723700002303737700001603760700001803776700001903794700002203813700001903835700002103854700002203875700002203897700002003919700002103939700002303960700002003983700002004003700001804023700002104041700002304062700002404085700001904109700001804128700002704146700001804173700001704191700002204208700001904230700001904249700002404268700002604292700002104318700001704339700002004356700001904376700002004395700002004415700002004435700002504455700002004480700002404500700002204524700002004546700001604566700001904582700002104601700001904622700002304641700002304664700002504687700002504712700002404737700002304761700002504784700002104809700002104830700002104851700002404872700002104896700002204917700002404939700002804963700001704991700002305008700001905031700001805050700002105068700003005089700002605119700002205145700002405167700002005191700002705211700001905238700002305257700002005280700002105300700002005321700002405341700001505365700002005380700001805400700001905418700002805437700002505465700002805490700002605518700002505544700002705569700002305596700002505619700002405644700001905668700002205687700001805709700002005727700001905747700002205766700002205788700002105810700002105831700002405852700002005876700002505896700002405921700002205945700002305967700002105990700002006011700002006031700002806051700002106079700002506100700002406125700002406149700002306173856003606196 2012 eng d a1476-468700aFTO genotype is associated with phenotypic variability of body mass index.0 aFTO genotype is associated with phenotypic variability of body m c2012 Oct 11 a267-720 v4903 aThere is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Height10aBody Mass Index10aCo-Repressor Proteins10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteins10aRepressor Proteins1 aYang, Jian1 aLoos, Ruth, J F1 aPowell, Joseph, E1 aMedland, Sarah, E1 aSpeliotes, Elizabeth, K1 aChasman, Daniel, I1 aRose, Lynda, M1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aMägi, Reedik1 aWaite, Lindsay1 aSmith, Albert, Vernon1 aYerges-Armstrong, Laura, M1 aMonda, Keri, L1 aHadley, David1 aMahajan, Anubha1 aLi, Guo1 aKapur, Karen1 aVitart, Veronique1 aHuffman, Jennifer, E1 aWang, Sophie, R1 aPalmer, Cameron1 aEsko, Tõnu1 aFischer, Krista1 aZhao, Jing Hua1 aDemirkan, Ayse1 aIsaacs, Aaron1 aFeitosa, Mary, F1 aLuan, Jian'an1 aHeard-Costa, Nancy, L1 aWhite, Charles1 aJackson, Anne, U1 aPreuss, Michael1 aZiegler, Andreas1 aEriksson, Joel1 aKutalik, Zoltán1 aFrau, Francesca1 aNolte, Ilja, M1 avan Vliet-Ostaptchouk, Jana, V1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aVerweij, Niek1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aEstrada, Karol1 aBragg-Gresham, Jennifer, Lynn1 aSanna, Serena1 aSidore, Carlo1 aTyrer, Jonathan1 aTeumer, Alexander1 aProkopenko, Inga1 aMangino, Massimo1 aLindgren, Cecilia, M1 aAssimes, Themistocles, L1 aShuldiner, Alan, R1 aHui, Jennie1 aBeilby, John, P1 aMcArdle, Wendy, L1 aHall, Per1 aHaritunians, Talin1 aZgaga, Lina1 aKolcic, Ivana1 aPolasek, Ozren1 aZemunik, Tatijana1 aOostra, Ben, A1 aJunttila, Juhani1 aGrönberg, Henrik1 aSchreiber, Stefan1 aPeters, Annette1 aHicks, Andrew, A1 aStephens, Jonathan1 aFoad, Nicola, S1 aLaitinen, Jaana1 aPouta, Anneli1 aKaakinen, Marika1 aWillemsen, Gonneke1 aVink, Jacqueline, M1 aWild, Sarah, H1 aNavis, Gerjan1 aAsselbergs, Folkert, W1 aHomuth, Georg1 aJohn, Ulrich1 aIribarren, Carlos1 aHarris, Tamara1 aLauner, Lenore1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBoerwinkle, Eric1 aCadby, Gemma1 aPalmer, Lyle, J1 aJames, Alan, L1 aMusk, Arthur, W1 aIngelsson, Erik1 aPsaty, Bruce, M1 aBeckmann, Jacques, S1 aWaeber, Gérard1 aVollenweider, Peter1 aHayward, Caroline1 aWright, Alan, F1 aRudan, Igor1 aGroop, Leif, C1 aMetspalu, Andres1 aKhaw, Kay, Tee1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aProvince, Michael, A1 aWareham, Nicholas, J1 aTardif, Jean-Claude1 aHuikuri, Heikki, V1 aCupples, Adrienne, L1 aAtwood, Larry, D1 aFox, Caroline, S1 aBoehnke, Michael1 aCollins, Francis, S1 aMohlke, Karen, L1 aErdmann, Jeanette1 aSchunkert, Heribert1 aHengstenberg, Christian1 aStark, Klaus1 aLorentzon, Mattias1 aOhlsson, Claes1 aCusi, Daniele1 aStaessen, Jan, A1 avan der Klauw, Melanie, M1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aJolley, Jennifer, D1 aRipatti, Samuli1 aJarvelin, Marjo-Riitta1 aGeus, Eco, J C1 aBoomsma, Dorret, I1 aPenninx, Brenda1 aWilson, James, F1 aCampbell, Harry1 aChanock, Stephen, J1 aHarst, Pim1 aHamsten, Anders1 aWatkins, Hugh1 aHofman, Albert1 aWitteman, Jacqueline, C1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aZillikens, Carola, M1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aAbecasis, Goncalo, R1 aSchlessinger, David1 aSchipf, Sabine1 aStumvoll, Michael1 aTönjes, Anke1 aSpector, Tim, D1 aNorth, Kari, E1 aLettre, Guillaume1 aMcCarthy, Mark, I1 aBerndt, Sonja, I1 aHeath, Andrew, C1 aMadden, Pamela, A F1 aNyholt, Dale, R1 aMontgomery, Grant, W1 aMartin, Nicholas, G1 aMcKnight, Barbara1 aStrachan, David, P1 aHill, William, G1 aSnieder, Harold1 aRidker, Paul, M1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N1 aGoddard, Michael, E1 aVisscher, Peter, M uhttps://chs-nhlbi.org/node/617506059nas a2201225 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2012 eng d a1474-446500aGenetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.0 aGenetic risk factors for ischaemic stroke and its subtypes the M c2012 Nov a951-620 v113 aBACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.
METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.
FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.
INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.
FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).
10aBrain Ischemia10aDatabases, Genetic10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aRisk Factors10aStroke1 aTraylor, Matthew1 aFarrall, Martin1 aHolliday, Elizabeth, G1 aSudlow, Cathie1 aHopewell, Jemma, C1 aCheng, Yu-Ching1 aFornage, Myriam1 aIkram, Arfan, M1 aMalik, Rainer1 aBevan, Steve1 aThorsteinsdottir, Unnur1 aNalls, Mike, A1 aLongstreth, Wt1 aWiggins, Kerri, L1 aYadav, Sunaina1 aParati, Eugenio, A1 aDeStefano, Anita, L1 aWorrall, Bradford, B1 aKittner, Steven, J1 aKhan, Muhammad, Saleem1 aReiner, Alex, P1 aHelgadottir, Anna1 aAchterberg, Sefanja1 aFernandez-Cadenas, Israel1 aAbboud, Sherine1 aSchmidt, Reinhold1 aWalters, Matthew1 aChen, Wei-Min1 aRingelstein, Bernd1 aO'Donnell, Martin1 aHo, Weang, Kee1 aPera, Joanna1 aLemmens, Robin1 aNorrving, Bo1 aHiggins, Peter1 aBenn, Marianne1 aSale, Michele1 aKuhlenbäumer, Gregor1 aDoney, Alexander, S F1 aVicente, Astrid, M1 aDelavaran, Hossein1 aAlgra, Ale1 aDavies, Gail1 aOliveira, Sofia, A1 aPalmer, Colin, N A1 aDeary, Ian1 aSchmidt, Helena1 aPandolfo, Massimo1 aMontaner, Joan1 aCarty, Cara1 ade Bakker, Paul, I W1 aKostulas, Konstantinos1 aFerro, Jose, M1 avan Zuydam, Natalie, R1 aValdimarsson, Einar1 aNordestgaard, Børge, G1 aLindgren, Arne1 aThijs, Vincent1 aSlowik, Agnieszka1 aSaleheen, Danish1 aParé, Guillaume1 aBerger, Klaus1 aThorleifsson, Gudmar1 aHofman, Albert1 aMosley, Thomas, H1 aMitchell, Braxton, D1 aFurie, Karen1 aClarke, Robert1 aLevi, Christopher1 aSeshadri, Sudha1 aGschwendtner, Andreas1 aBoncoraglio, Giorgio, B1 aSharma, Pankaj1 aBis, Joshua, C1 aGretarsdottir, Solveig1 aPsaty, Bruce, M1 aRothwell, Peter, M1 aRosand, Jonathan1 aMeschia, James, F1 aStefansson, Kari1 aDichgans, Martin1 aMarkus, Hugh, S1 aAustralian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2)1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/586307422nas a2202413 4500008004100000022001400041245009100055210006900146260000900215300001300224490000600237520076400243653002201007653000901029653001201038653001401050653002901064653002701093653001801120653004001138653001101178653002201189653003001211653003401241653003101275653001101306653001101317653002801328653000901356653001601365653003401381653001401415100002201429700001901451700002201470700001901492700002301511700002701534700002001561700002001581700001801601700001901619700001201638700001601650700002001666700001601686700002501702700002401727700002601751700001901777700001801796700001801814700002101832700002601853700002301879700002001902700001201922700002301934700002201957700001801979700002001997700002702017700001702044700002502061700001902086700001802105700001902123700002202142700002702164700002102191700002102212700002202233700001602255700002202271700001802293700001902311700002102330700002002351700001902371700002302390700002002413700002202433700002202455700001902477700002402496700002502520700002102545700002002566700002602586700002002612700001702632700001902649700001902668700002302687700002302710700002002733700002502753700002302778700002102801700001802822700002002840700002202860700001802882700002202900700001802922700002102940700002402961700001602985700001903001700001903020700002003039700002003059700002203079700002003101700001903121700001903140700002203159700001903181700001803200700002103218700002003239700002003259700001703279700001903296700001803315700002203333700001803355700001903373700002803392700002603420700002403446700001903470700001703489700002203506700002203528700001903550700002203569700001903591700002003610700001903630700002203649700002203671700002003693700001903713700001603732700002303748700002303771700002503794700001803819700001403837700002403851700001703875700002103892700002403913700001703937700001703954700001903971700001903990700001904009700001904028700002404047700002004071700002104091700001804112700002104130700001904151700001904170700002904189700002404218700002104242700002404263700002304287700001804310700002204328700002004350700002404370700002304394700002004417700002404437700001704461700002004478700001604498700002004514700002104534700001804555700002604573700001904599700002104618700003004639700002204669700001704691700001804708700002104726700001804747700002304765700002304788700002004811700002104831710002604852710002004878710002004898710005404918856003604972 2012 eng d a1553-740400aGenome-wide association and functional follow-up reveals new loci for kidney function.0 aGenomewide association and functional followup reveals new loci c2012 ae10025840 v83 aChronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
10aAfrican Americans10aAged10aAnimals10aCaspase 910aCyclin-Dependent Kinases10aDEAD-box RNA Helicases10aDNA Helicases10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGene Knockdown Techniques10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aPhosphoric Diester Hydrolases10aZebrafish1 aPattaro, Cristian1 aKöttgen, Anna1 aTeumer, Alexander1 aGarnaas, Maija1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aTaliun, Daniel1 aLi, Man1 aGao, Xiaoyi1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aO'Seaghdha, Conall, M1 aGlazer, Nicole1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aJohnson, Andrew, D1 aGierman, Hinco, J1 aFeitosa, Mary1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aChouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aCavalieri, Margherita1 aRao, Madhumathi1 aHu, Frank, B1 aDemirkan, Ayse1 aOostra, Ben, A1 ade Andrade, Mariza1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aKolcic, Ivana1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aEndlich, Karlhans1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aKetkar, Shamika1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aGiulianini, Franco1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMetzger, Marie1 aMitchell, Paul1 aCiullo, Marina1 aKim, Stuart, K1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aSiscovick, David, S1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline, C M1 aHayward, Caroline1 aRidker, Paul1 aParsa, Afshin1 aBochud, Murielle1 aHeid, Iris, M1 aGoessling, Wolfram1 aChasman, Daniel, I1 aKao, Linda, W H1 aFox, Caroline, S1 aCARDIoGRAM consortium1 aICBP Consortium1 aCARe Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2) uhttps://chs-nhlbi.org/node/137705378nas a2201249 4500008004100000022001400041245010600055210006900161260001600230300001100246490000800257520186000265653000902125653001102134653002902145653003402174653001102208653000902219653001602228653002602244653003602270653004302306653002502349653003202374653001202406653001902418100001902437700002202456700002002478700001902498700002102517700002002538700002602558700002302584700002202607700001602629700001802645700001902663700001602682700002002698700002602718700002102744700002102765700001502786700002002801700002002821700002302841700002202864700002402886700001902910700001802929700002002947700001702967700001902984700002303003700001903026700002103045700002203066700001903088700001903107700001903126700001803145700001903163700002203182700002203204700001703226700002003243700002003263700001903283700002603302700002203328700001903350700002403369700002003393700002203413700001903435700002203454700002003476700002103496700002603517700002003543700002203563700002603585700001903611700002803630700002503658700002003683700001803703700002503721700002403746700001803770700002003788700002503808700002403833700001703857700002003874700002303894700002503917700001903942700002603961700002003987700001704007700002404024700002104048700002304069856003604092 2012 eng d a1535-497000aGenome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.0 aGenomewide association studies identify CHRNA53 and HTR4 in the c2012 Oct 01 a622-320 v1863 aRATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.
MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
10aAged10aFemale10aForced Expiratory Volume10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPulmonary Disease, Chronic Obstructive10aReceptors, Nicotinic10aReceptors, Serotonin, 5-HT410aSmoking10aVital Capacity1 aWilk, Jemma, B1 aShrine, Nick, R G1 aLoehr, Laura, R1 aZhao, Jing Hua1 aManichaikul, Ani1 aLopez, Lorna, M1 aSmith, Albert, Vernon1 aHeckbert, Susan, R1 aSmolonska, Joanna1 aTang, Wenbo1 aLoth, Daan, W1 aCurjuric, Ivan1 aHui, Jennie1 aCho, Michael, H1 aLatourelle, Jeanne, C1 aHenry, Amanda, P1 aAldrich, Melinda1 aBakke, Per1 aBeaty, Terri, H1 aBentley, Amy, R1 aBorecki, Ingrid, B1 aBrusselle, Guy, G1 aBurkart, Kristin, M1 aChen, Ting-Hsu1 aCouper, David1 aCrapo, James, D1 aDavies, Gail1 aDupuis, Josée1 aFranceschini, Nora1 aGulsvik, Amund1 aHancock, Dana, B1 aHarris, Tamara, B1 aHofman, Albert1 aImboden, Medea1 aJames, Alan, L1 aKhaw, Kay-Tee1 aLahousse, Lies1 aLauner, Lenore, J1 aLitonjua, Augusto1 aLiu, Yongmei1 aLohman, Kurt, K1 aLomas, David, A1 aLumley, Thomas1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aMusk, Arthur, W1 aMyers, Richard, H1 aNorth, Kari, E1 aPostma, Dirkje, S1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRivadeneira, Fernando1 aRochat, Thierry1 aRotter, Jerome, I1 aArtigas, Maria, Soler1 aStarr, John, M1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aZanen, Pieter1 aProvince, Michael, A1 aSilverman, Edwin, K1 aDeary, Ian, J1 aPalmer, Lyle, J1 aCassano, Patricia, A1 aGudnason, Vilmundur1 aBarr, Graham1 aLoos, Ruth, J F1 aStrachan, David, P1 aLondon, Stephanie, J1 aBoezen, Marike1 aProbst-Hensch, Nicole1 aGharib, Sina, A1 aHall, Ian, P1 aO'Connor, George, T1 aTobin, Martin, D1 aStricker, Bruno, H uhttps://chs-nhlbi.org/node/609205960nas a2201525 4500008004100000022001400041245011100055210006900166260001600235300001200251490000800263520152700271653004101798653003201839653005601871653001401927653002101941653001901962653002801981653003002009653003002039653003102069653001902100653003402119653001302153653001102166653002402177653002702201653001402228653001202242653003802254653003602292653001502328653003702343653002102380653002602401100001502427700002502442700002702467700002002494700001802514700002002532700001802552700002802570700002102598700002302619700002302642700002302665700002302688700002202711700002102733700001702754700002602771700001802797700001602815700002002831700002002851700002702871700001902898700002602917700003102943700001802974700001902992700002403011700002103035700002103056700001703077700002003094700002003114700001503134700002303149700002203172700002103194700001803215700002003233700002503253700002303278700002203301700002303323700001903346700001903365700002203384700001703406700001703423700002703440700001703467700001803484700002803502700002803530700002303558700001903581700001803600700003003618700002103648700001703669700002003686700001903706700002203725700001903747700001703766700001903783700002003802700002203822700002403844700001803868700002203886700002803908700002003936700002103956700001803977700002403995700002104019700002204040700002004062700002804082700001804110700002204128700002904150700002104179700002004200700001504220700001704235700003004252700002004282710002304302710002604325710001904351710002804370856003604398 2012 eng d a1528-002000aGenome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.0 aGenomewide association study for circulating levels of PAI1 prov c2012 Dec 06 a4873-810 v1203 aWe conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
10aAdaptor Proteins, Signal Transducing10aARNTL Transcription Factors10aATPases Associated with Diverse Cellular Activities10aCell Line10aCell Line, Tumor10aCohort Studies10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aGene Expression Profiling10aGene Expression Regulation10aGene Frequency10aGenome-Wide Association Study10aGenotype10aHumans10aLIM Domain Proteins10aMeta-Analysis as Topic10aMonocytes10aMucin-310aPlasminogen Activator Inhibitor 110aPolymorphism, Single Nucleotide10aPPAR gamma10aProteasome Endopeptidase Complex10aRNA Interference10aTranscription Factors1 aHuang, Jie1 aSabater-Lleal, Maria1 aAsselbergs, Folkert, W1 aTregouet, David1 aShin, So-Youn1 aDing, Jingzhong1 aBaumert, Jens1 aOudot-Mellakh, Tiphaine1 aFolkersen, Lasse1 aJohnson, Andrew, D1 aSmith, Nicholas, L1 aWilliams, Scott, M1 aIkram, Mohammad, A1 aKleber, Marcus, E1 aBecker, Diane, M1 aTruong, Vinh1 aMychaleckyj, Josyf, C1 aTang, Weihong1 aYang, Qiong1 aSennblad, Bengt1 aMoore, Jason, H1 aWilliams, Frances, M K1 aDehghan, Abbas1 aSilbernagel, Günther1 aSchrijvers, Elisabeth, M C1 aSmith, Shelly1 aKarakas, Mahir1 aTofler, Geoffrey, H1 aSilveira, Angela1 aNavis, Gerjan, J1 aLohman, Kurt1 aChen, Ming-Huei1 aPeters, Annette1 aGoel, Anuj1 aHopewell, Jemma, C1 aChambers, John, C1 aSaleheen, Danish1 aLundmark, Per1 aPsaty, Bruce, M1 aStrawbridge, Rona, J1 aBoehm, Bernhard, O1 aCarter, Angela, M1 aMeisinger, Christa1 aPeden, John, F1 aBis, Joshua, C1 aMcKnight, Barbara1 aOhrvik, John1 aTaylor, Kent1 aFranzosi, Maria Grazia1 aSeedorf, Udo1 aCollins, Rory1 aFranco-Cereceda, Anders1 aSyvänen, Ann-Christine1 aGoodall, Alison, H1 aYanek, Lisa, R1 aCushman, Mary1 aMüller-Nurasyid, Martina1 aFolsom, Aaron, R1 aBasu, Saonli1 aMatijevic, Nena1 aGilst, Wiek, H1 aKooner, Jaspal, S1 aHofman, Albert1 aDanesh, John1 aClarke, Robert1 aMeigs, James, B1 aKathiresan, Sekar1 aReilly, Muredach, P1 aKlopp, Norman1 aHarris, Tamara, B1 aWinkelmann, Bernhard, R1 aGrant, Peter, J1 aHillege, Hans, L1 aWatkins, Hugh1 aSpector, Timothy, D1 aBecker, Lewis, C1 aTracy, Russell, P1 aMärz, Winfried1 aUitterlinden, André, G1 aEriksson, Per1 aCambien, Francois1 aMorange, Pierre-Emmanuel1 aKoenig, Wolfgang1 aSoranzo, Nicole1 aHarst, Pim1 aLiu, Yongmei1 aO'Donnell, Christopher, J1 aHamsten, Anders1 aDIAGRAM Consortium1 aCARDIoGRAM consortium1 aC4D Consortium1 aCardiogenics consortium uhttps://chs-nhlbi.org/node/608903084nas a2200361 4500008004100000022001400041245017300055210006900228260001600297300001000313490000700323520191100330653002502241653003102266653001902297653002802316653002402344653003402368653001102402653001602413653003602429100001602465700002402481700002302505700002102528700002002549700002802569700002202597700002202619700002002641700002502661856003602686 2012 eng d a1460-208300aA genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries.0 agenomewide association study identifies a potential novel gene l c2012 Jan 15 a421-90 v213 aKeratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10(-8), 2.4 × 10(-7) and 3.1 × 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 × 10(-5) and 2.6 × 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10(-7) (unadjusted P= 1.2 × 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.
10aCase-Control Studies10aChromosomes, Human, Pair 210aCohort Studies10aCorneal Transplantation10aDeveloped Countries10aGenome-Wide Association Study10aHumans10aKeratoconus10aPolymorphism, Single Nucleotide1 aLi, Xiaohui1 aBykhovskaya, Yelena1 aHaritunians, Talin1 aSiscovick, David1 aAldave, Anthony1 aSzczotka-Flynn, Loretta1 aIyengar, Sudha, K1 aRotter, Jerome, I1 aTaylor, Kent, D1 aRabinowitz, Yaron, S uhttps://chs-nhlbi.org/node/155505536nas a2201405 4500008004100000022001400041245012000055210006900175260000900244300001300253490000600266520151700272653002901789653002001818653001801838653003401856653002001890653002301910653001101933653000901944653002601953653003601979653004402015653004302059653002802102653001202130653003002142653001902172100002102191700002602212700002002238700001802258700002102276700002602297700001802323700001902341700001602360700002202376700002102398700002202419700001702441700001602458700001902474700001802493700001902511700002002530700002402550700001902574700002202593700001802615700001702633700002202650700002102672700001802693700001902711700001802730700002002748700001702768700002002785700002202805700002602827700001902853700002202872700002402894700002202918700001902940700002402959700002302983700002203006700002203028700002003050700001903070700002003089700001903109700002103128700001903149700002403168700002303192700002603215700002103241700002803262700001703290700001903307700002003326700002003346700002803366700002003394700002103414700002003435700002403455700001903479700002103498700001903519700002203538700001803560700002803578700002803606700001803634700002303652700001703675700002503692700001903717700002503736700002403761700002903785700002003814700002703834700002303861700002403884700001903908700001703927700002503944700002303969700002003992700001704012700001904029700002104048700002504069856003604094 2012 eng d a1553-740400aGenome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.0 aGenomewide joint metaanalysis of SNP and SNPbysmoking interactio c2012 ae10030980 v83 aGenome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
10aForced Expiratory Volume10aGene Expression10aGenome, Human10aGenome-Wide Association Study10aHLA-DQ Antigens10aHLA-DQ beta-Chains10aHumans10aLung10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels, Inwardly Rectifying10aPulmonary Disease, Chronic Obstructive10aReceptors, Cell Surface10aSmoking10aSOX9 Transcription Factor10aVital Capacity1 aHancock, Dana, B1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aHenry, Amanda1 aManichaikul, Ani1 aRamasamy, Adaikalavan1 aLoth, Daan, W1 aImboden, Medea1 aKoch, Beate1 aMcArdle, Wendy, L1 aSmith, Albert, V1 aSmolonska, Joanna1 aSood, Akshay1 aTang, Wenbo1 aWilk, Jemma, B1 aZhai, Guangju1 aZhao, Jing Hua1 aAschard, Hugues1 aBurkart, Kristin, M1 aCurjuric, Ivan1 aEijgelsheim, Mark1 aElliott, Paul1 aGu, Xiangjun1 aHarris, Tamara, B1 aJanson, Christer1 aHomuth, Georg1 aHysi, Pirro, G1 aLiu, Jason, Z1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aManning, Alisa, K1 aMarciante, Kristin, D1 aObeidat, Ma'en1 aPostma, Dirkje, S1 aAldrich, Melinda, C1 aBrusselle, Guy, G1 aChen, Ting-Hsu1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aHeinrich, Joachim1 aRotter, Jerome, I1 aWijmenga, Cisca1 aWilliams, Dale1 aBentley, Amy, R1 aHofman, Albert1 aLaurie, Cathy, C1 aLumley, Thomas1 aMorrison, Alanna, C1 aJoubert, Bonnie, R1 aRivadeneira, Fernando1 aCouper, David, J1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aWjst, Matthias1 aWain, Louise, V1 aVonk, Judith, M1 aUitterlinden, André, G1 aRochat, Thierry1 aRich, Stephen, S1 aPsaty, Bruce, M1 aO'Connor, George, T1 aNorth, Kari, E1 aMirel, Daniel, B1 aMeibohm, Bernd1 aLauner, Lenore, J1 aKhaw, Kay-Tee1 aHartikainen, Anna-Liisa1 aHammond, Christopher, J1 aGläser, Sven1 aMarchini, Jonathan1 aKraft, Peter1 aWareham, Nicholas, J1 aVölzke, Henry1 aStricker, Bruno, H C1 aSpector, Timothy, D1 aProbst-Hensch, Nicole, M1 aJarvis, Deborah1 aJarvelin, Marjo-Riitta1 aHeckbert, Susan, R1 aGudnason, Vilmundur1 aBoezen, Marike1 aBarr, Graham1 aCassano, Patricia, A1 aStrachan, David, P1 aFornage, Myriam1 aHall, Ian, P1 aDupuis, Josée1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/608805038nas a2201333 4500008004100000022001400041245007300055210006900128260000900197300000900206490000600215520172900221653001001950653002201960653000901982653003201991653003202023653001102055653001702066653003802083653002202121653003402143653001302177653001102190653000902201653001602210653002602226653001402252653003602266653001802302653002502320653001202345653002402357100001602381700001702397700001502414700001702429700001402446700002002460700001602480700001802496700001802514700001102532700001602543700001702559700001502576700002002591700001402611700001802625700001702643700001402660700001702674700001702691700001502708700001602723700001802739700001602757700001302773700001802786700001702804700001602821700001602837700001602853700001602869700001502885700002002900700001602920700002002936700002002956700001502976700001302991700001503004700001703019700001503036700001503051700001203066700001803078700001903096700001103115700001703126700001603143700001903159700001403178700002103192700001403213700001303227700001503240700001403255700001503269700002403284700001803308700002103326700002003347700001503367700001503382700001403397700001903411700001603430700001503446700001703461700001503478700001703493700001603510700001603526700001603542700001003558700001303568700001803581700002003599700001703619700001703636700001503653856003603668 2012 eng d a2158-318800aGenome-wide meta-analyses of smoking behaviors in African Americans.0 aGenomewide metaanalyses of smoking behaviors in African American c2012 ae1190 v23 aThe identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.
10aAdult10aAfrican Americans10aAged10aChromosomes, Human, Pair 1010aChromosomes, Human, Pair 1510aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteoglycans10aReceptors, Nicotinic10aSmoking10aStatistics as Topic1 aDavid, S, P1 aHamidovic, A1 aChen, G, K1 aBergen, A, W1 aWessel, J1 aKasberger, J, L1 aBrown, W, M1 aPetruzella, S1 aThacker, E, L1 aKim, Y1 aNalls, M, A1 aTranah, G, J1 aSung, Y, J1 aAmbrosone, C, B1 aArnett, D1 aBandera, E, V1 aBecker, D, M1 aBecker, L1 aBerndt, S, I1 aBernstein, L1 aBlot, W, J1 aBroeckel, U1 aBuxbaum, S, G1 aCaporaso, N1 aCasey, G1 aChanock, S, J1 aDeming, S, L1 aDiver, W, R1 aEaton, C, B1 aEvans, D, S1 aEvans, M, K1 aFornage, M1 aFranceschini, N1 aHarris, T B1 aHenderson, B, E1 aHernandez, D, G1 aHitsman, B1 aHu, J, J1 aHunt, S, C1 aIngles, S, A1 aJohn, E, M1 aKittles, R1 aKolb, S1 aKolonel, L, N1 aLe Marchand, L1 aLiu, Y1 aLohman, K, K1 aMcKnight, B1 aMillikan, R, C1 aMurphy, A1 aNeslund-Dudas, C1 aNyante, S1 aPress, M1 aPsaty, B M1 aRao, D, C1 aRedline, S1 aRodriguez-Gil, J, L1 aRybicki, B, A1 aSignorello, L, B1 aSingleton, A, B1 aSmoller, J1 aSnively, B1 aSpring, B1 aStanford, J, L1 aStrom, S, S1 aSwan, G, E1 aTaylor, K, D1 aThun, M, J1 aWilson, A, F1 aWitte, J, S1 aYamamura, Y1 aYanek, L, R1 aYu, K1 aZheng, W1 aZiegler, R, G1 aZonderman, A, B1 aJorgenson, E1 aHaiman, C, A1 aFurberg, H uhttps://chs-nhlbi.org/node/680408678nas a2202593 4500008004100000022001400041245012400055210006900179260001600248300001200264490000700276520126400283653001701547653002601564653004001590653003401630653001101664653001501675653002001690653003001710653003801740653003401778653001301812653001801825653001101843653005001854653005501904653002101959653000901980653004601989653001702035653002002052653003602072653002802108653001702136653001302153100001902166700002602185700002502211700001902236700002002255700002502275700001402300700002302314700001602337700001802353700002202371700001202393700001802405700002102423700002202444700002402466700001802490700001702508700003102525700002002556700001802576700001902594700002502613700002402638700001702662700002502679700002102704700002102725700001702746700001702763700002202780700001902802700002602821700001802847700002102865700002002886700002802906700001902934700002102953700002202974700002502996700002203021700002103043700001703064700002403081700002303105700001703128700002203145700002303167700002003190700001903210700002103229700001603250700002603266700002003292700001903312700002103331700001903352700001903371700002003390700002803410700002103438700001903459700002003478700002003498700002703518700001403545700001303559700002103572700002503593700002403618700001703642700002403659700001803683700002203701700001403723700001803737700002003755700003003775700002003805700002103825700002403846700001803870700002203888700002903910700002303939700001503962700002103977700002103998700001604019700002004035700003104055700002004086700003004106700001904136700002204155700002004177700002404197700002004221700002204241700002004263700001704283700001904300700002704319700002404346700003104370700002004401700002104421700002704442700002604469700001504495700001204510700001804522700002804540700002404568700001604592700002204608700002304630700002604653700002304679700002704702700002004729700001704749700002204766700001904788700002504807700002004832700002304852700002104875700002404896700001904920700002404939700002104963700002004984700002405004700001905028700002405047700001805071700001905089700001805108700002205126700001705148700002305165700002205188700002505210700002705235700002705262700001905289700001905308700002305327700002305350700002005373700001705393700001805410700002405428700002105452700002305473700002505496700002305521700002105544700002505565700002205590700002005612700002205632700002605654700002005680700002005700700002405720700002705744700002505771700002805796700001905824700001905843700002005862700002205882700002105904700002805925700002305953700002505976700002106001700002606022856003606048 2012 eng d a1546-171800aGenome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.0 aGenomewide metaanalysis identifies 56 bone mineral density loci c2012 Apr 15 a491-5010 v443 aBone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
10aBone Density10aComputational Biology10aEuropean Continental Ancestry Group10aExtracellular Matrix Proteins10aFemale10aFemur Neck10aFractures, Bone10aGene Expression Profiling10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGlycoproteins10aHumans10aIntercellular Signaling Peptides and Proteins10aLow Density Lipoprotein Receptor-Related Protein-510aLumbar Vertebrae10aMale10aMitochondrial Membrane Transport Proteins10aOsteoporosis10aPhosphoproteins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors10aSpectrin1 aEstrada, Karol1 aStyrkarsdottir, Unnur1 aEvangelou, Evangelos1 aHsu, Yi-Hsiang1 aDuncan, Emma, L1 aNtzani, Evangelia, E1 aOei, Ling1 aAlbagha, Omar, M E1 aAmin, Najaf1 aKemp, John, P1 aKoller, Daniel, L1 aLi, Guo1 aLiu, Ching-Ti1 aMinster, Ryan, L1 aMoayyeri, Alireza1 aVandenput, Liesbeth1 aWillner, Dana1 aXiao, Su-Mei1 aYerges-Armstrong, Laura, M1 aZheng, Hou-Feng1 aAlonso, Nerea1 aEriksson, Joel1 aKammerer, Candace, M1 aKaptoge, Stephen, K1 aLeo, Paul, J1 aThorleifsson, Gudmar1 aWilson, Scott, G1 aWilson, James, F1 aAalto, Ville1 aAlen, Markku1 aAragaki, Aaron, K1 aAspelund, Thor1 aCenter, Jacqueline, R1 aDailiana, Zoe1 aDuggan, David, J1 aGarcia, Melissa1 aGarcía-Giralt, Natalia1 aGiroux, Sylvie1 aHallmans, Göran1 aHocking, Lynne, J1 aHusted, Lise, Bjerre1 aJameson, Karen, A1 aKhusainova, Rita1 aKim, Ghi, Su1 aKooperberg, Charles1 aKoromila, Theodora1 aKruk, Marcin1 aLaaksonen, Marika1 aLaCroix, Andrea, Z1 aLee, Seung, Hun1 aLeung, Ping, C1 aLewis, Joshua, R1 aMasi, Laura1 aMencej-Bedrac, Simona1 aNguyen, Tuan, V1 aNogues, Xavier1 aPatel, Millan, S1 aPrezelj, Janez1 aRose, Lynda, M1 aScollen, Serena1 aSiggeirsdottir, Kristin1 aSmith, Albert, V1 aSvensson, Olle1 aTrompet, Stella1 aTrummer, Olivia1 avan Schoor, Natasja, M1 aWoo, Jean1 aZhu, Kun1 aBalcells, Susana1 aBrandi, Maria, Luisa1 aBuckley, Brendan, M1 aCheng, Sulin1 aChristiansen, Claus1 aCooper, Cyrus1 aDedoussis, George1 aFord, Ian1 aFrost, Morten1 aGoltzman, David1 aGonzález-Macías, Jesús1 aKähönen, Mika1 aKarlsson, Magnus1 aKhusnutdinova, Elza1 aKoh, Jung-Min1 aKollia, Panagoula1 aLangdahl, Bente, Lomholt1 aLeslie, William, D1 aLips, Paul1 aLjunggren, Osten1 aLorenc, Roman, S1 aMarc, Janja1 aMellström, Dan1 aObermayer-Pietsch, Barbara1 aOlmos, José, M1 aPettersson-Kymmer, Ulrika1 aReid, David, M1 aRiancho, José, A1 aRidker, Paul, M1 aRousseau, François1 aSlagboom, Eline1 aTang, Nelson, L S1 aUrreizti, Roser1 aVan Hul, Wim1 aViikari, Jorma1 aZarrabeitia, María, T1 aAulchenko, Yurii, S1 aCastano-Betancourt, Martha1 aGrundberg, Elin1 aHerrera, Lizbeth1 aIngvarsson, Thorvaldur1 aJohannsdottir, Hrefna1 aKwan, Tony1 aLi, Rui1 aLuben, Robert1 aMedina-Gómez, Carolina1 aPalsson, Stefan, Th1 aReppe, Sjur1 aRotter, Jerome, I1 aSigurdsson, Gunnar1 avan Meurs, Joyce, B J1 aVerlaan, Dominique1 aWilliams, Frances, M K1 aWood, Andrew, R1 aZhou, Yanhua1 aGautvik, Kaare, M1 aPastinen, Tomi1 aRaychaudhuri, Soumya1 aCauley, Jane, A1 aChasman, Daniel, I1 aClark, Graeme, R1 aCummings, Steven, R1 aDanoy, Patrick1 aDennison, Elaine, M1 aEastell, Richard1 aEisman, John, A1 aGudnason, Vilmundur1 aHofman, Albert1 aJackson, Rebecca, D1 aJones, Graeme1 aJukema, Wouter1 aKhaw, Kay-Tee1 aLehtimäki, Terho1 aLiu, Yongmei1 aLorentzon, Mattias1 aMcCloskey, Eugene1 aMitchell, Braxton, D1 aNandakumar, Kannabiran1 aNicholson, Geoffrey, C1 aOostra, Ben, A1 aPeacock, Munro1 aPols, Huibert, A P1 aPrince, Richard, L1 aRaitakari, Olli1 aReid, Ian, R1 aRobbins, John1 aSambrook, Philip, N1 aSham, Pak, Chung1 aShuldiner, Alan, R1 aTylavsky, Frances, A1 aDuijn, Cornelia, M1 aWareham, Nick, J1 aCupples, Adrienne, L1 aEcons, Michael, J1 aEvans, David, M1 aHarris, Tamara, B1 aKung, Annie, Wai Chee1 aPsaty, Bruce, M1 aReeve, Jonathan1 aSpector, Timothy, D1 aStreeten, Elizabeth, A1 aZillikens, Carola, M1 aThorsteinsdottir, Unnur1 aOhlsson, Claes1 aKarasik, David1 aRichards, Brent1 aBrown, Matthew, A1 aStefansson, Kari1 aUitterlinden, André, G1 aRalston, Stuart, H1 aIoannidis, John, P A1 aKiel, Douglas, P1 aRivadeneira, Fernando uhttps://chs-nhlbi.org/node/801603248nas a2200673 4500008004100000022001400041245010800055210006900163260001600232300001200248490000700260520130900267653003401576653001101610653003901621653001301660653002501673653003001698100002101728700002001749700002401769700002001793700002101813700002801834700002301862700001901885700002101904700001901925700001401944700002801958700002001986700002202006700002202028700002702050700002302077700002402100700001902124700001802143700002002161700002102181700002102202700002502223700002102248700002202269700001702291700001902308700002002327700002102347700001402368700002002382700001902402700002202421700002002443700001602463700002402479700001702503700001802520856003602538 2012 eng d a1460-208300aGenome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.0 aGenomewide metaanalysis points to CTC1 and ZNF676 as genes regul c2012 Dec 15 a5385-940 v213 aLeukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.
10aGenome-Wide Association Study10aHumans10aKruppel-Like Transcription Factors10aTelomere10aTelomere Homeostasis10aTelomere-Binding Proteins1 aMangino, Massimo1 aHwang, Shih-Jen1 aSpector, Timothy, D1 aHunt, Steven, C1 aKimura, Masayuki1 aFitzpatrick, Annette, L1 aChristiansen, Lene1 aPetersen, Inge1 aElbers, Clara, C1 aHarris, Tamara1 aChen, Wei1 aSrinivasan, Sathanur, R1 aKark, Jeremy, D1 aBenetos, Athanase1 aShamieh, Said, El1 aVisvikis-Siest, Sophie1 aChristensen, Kaare1 aBerenson, Gerald, S1 aValdes, Ana, M1 aViñuela, Ana1 aGarcia, Melissa1 aArnett, Donna, K1 aBroeckel, Ulrich1 aProvince, Michael, A1 aPankow, James, S1 aKammerer, Candace1 aLiu, Yongmei1 aNalls, Michael1 aTishkoff, Sarah1 aThomas, Fridtjof1 aZiv, Elad1 aPsaty, Bruce, M1 aBis, Joshua, C1 aRotter, Jerome, I1 aTaylor, Kent, D1 aSmith, Erin1 aSchork, Nicholas, J1 aLevy, Daniel1 aAviv, Abraham uhttps://chs-nhlbi.org/node/609004494nas a2200925 4500008004100000022001400041245008800055210006900143260001300212300001100225490000600236520191100242653001002153653002202163653000902185653002402194653004002218653001102258653002702269653002202296653001802318653003402336653001102370653000902381653001602390653003602406100001802442700002202460700002102482700002202503700001702525700001902542700002002561700002002581700001702601700002002618700001802638700002202656700002202678700002402700700002402724700001202748700002402760700002202784700001402806700001902820700001602839700001902855700002202874700001702896700002002913700002402933700001902957700002502976700002103001700002403022700002503046700002003071700002403091700002203115700002803137700001903165700002003184700001903204700002003223700001903243700002303262700002203285700002103307700002003328700001903348700002203367700001803389700002203407700002303429700002103452700002903473710003003502856003603532 2012 eng d a1942-326800aImpact of ancestry and common genetic variants on QT interval in African Americans.0 aImpact of ancestry and common genetic variants on QT interval in c2012 Dec a647-550 v53 aBACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.
METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.
CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.
10aAdult10aAfrican Americans10aAged10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aGenealogy and Heraldry10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aSmith, Gustav1 aAvery, Christy, L1 aEvans, Daniel, S1 aNalls, Michael, A1 aMeng, Yan, A1 aSmith, Erin, N1 aPalmer, Cameron1 aTanaka, Toshiko1 aMehra, Reena1 aButler, Anne, M1 aYoung, Taylor1 aBuxbaum, Sarah, G1 aKerr, Kathleen, F1 aBerenson, Gerald, S1 aSchnabel, Renate, B1 aLi, Guo1 aEllinor, Patrick, T1 aMagnani, Jared, W1 aChen, Wei1 aBis, Joshua, C1 aCurb, David1 aHsueh, Wen-Chi1 aRotter, Jerome, I1 aLiu, Yongmei1 aNewman, Anne, B1 aLimacher, Marian, C1 aNorth, Kari, E1 aReiner, Alexander, P1 aQuibrera, Miguel1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSolomon, Allen, J1 aSrinivasan, Sathanur, R1 aAlonso, Alvaro1 aWallace, Robert1 aRedline, Susan1 aZhang, Zhu-Ming1 aPost, Wendy, S1 aZonderman, Alan, B1 aTaylor, Herman, A1 aMurray, Sarah, S1 aFerrucci, Luigi1 aArking, Dan, E1 aEvans, Michele, K1 aFox, Ervin, R1 aSotoodehnia, Nona1 aHeckbert, Susan, R1 aWhitsel, Eric, A1 aNewton-Cheh, Christopher1 aCARe and COGENT consortia uhttps://chs-nhlbi.org/node/617908958nas a2202881 4500008004100000022001400041245014400055210006900199260001300268300001300281490000700294520091900301653001001220653001201230653001801242653001201260653001101272653001901283653003401302653001101336653001201347653000901359653003601368653000901404653002601413653002801439100002101467700002001488700001901508700002101527700002201548700001801570700001801588700002501606700001901631700002301650700002201673700003101695700001601726700002101742700002001763700001801783700001801801700002301819700001901842700001801861700002001879700001801899700002501917700002401942700001601966700002101982700002002003700002202023700001702045700001902062700002502081700002002106700002302126700001302149700002502162700001602187700002402203700001402227700002202241700001702263700001802280700002602298700002302324700002202347700002202369700001602391700002102407700002002428700001502448700002402463700002502487700001402512700002502526700002202551700002102573700002002594700001702614700001802631700002502649700002102674700002102695700002102716700002002737700002602757700001802783700002002801700001902821700001502840700002102855700001302876700003002889700002802919700002102947700002102968700002002989700002903009700002403038700002103062700001903083700002103102700002003123700001803143700002003161700002103181700001703202700002103219700002203240700002003262700001403282700002503296700002003321700001803341700001903359700002203378700002403400700002003424700001603444700002103460700001803481700001903499700001703518700002003535700001903555700001903574700002603593700002803619700002303647700002103670700002303691700002203714700002003736700001903756700002503775700002003800700002103820700002403841700002203865700001803887700002203905700002203927700002503949700001903974700002303993700002304016700002104039700002004060700002204080700002304102700002004125700002604145700002504171700002304196700002404219700001604243700002004259700001804279700002004297700002204317700002004339700002404359700002404383700002404407700002304431700002504454700001904479700002304498700001904521700001904540700002004559700002404579700002104603700002004624700001804644700002104662700002004683700002704703700002204730700001904752700002104771700002504792700002004817700002004837700001504857700002104872700002304893700002304916700002204939700001804961700002404979700002005003700001905023700002205042700001905064700002505083700002405108700001905132700002105151700002005172700002405192700002005216700001805236700001805254700002005272700002405292700001905316700002105335700003705356700002205393700002305415700002105438700001505459700001905474700002305493700001905516700002205535700002105557700002005578700002005598700002105618700002105639700002205660700001805682700002705700700002505727700002505752700002205777700002005799700002005819700002405839700002005863700002405883700002005907700002105927700001905948710007305967856003606040 2012 eng d a1546-171800aLarge-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.0 aLargescale association analyses identify new loci influencing gl c2012 Sep a991-10050 v443 aThrough genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
10aAdult10aAnimals10aBlood Glucose10aFasting10aFemale10aGene Frequency10aGenome-Wide Association Study10aHumans10aInsulin10aMale10aMetabolic Networks and Pathways10aMice10aOsmolar Concentration10aQuantitative Trait Loci1 aScott, Robert, A1 aLagou, Vasiliki1 aWelch, Ryan, P1 aWheeler, Eleanor1 aMontasser, May, E1 aLuan, Jian'an1 aMägi, Reedik1 aStrawbridge, Rona, J1 aRehnberg, Emil1 aGustafsson, Stefan1 aKanoni, Stavroula1 aRasmussen-Torvik, Laura, J1 aYengo, Loic1 aLecoeur, Cécile1 aShungin, Dmitry1 aSanna, Serena1 aSidore, Carlo1 aJohnson, Paul, C D1 aJukema, Wouter1 aJohnson, Toby1 aMahajan, Anubha1 aVerweij, Niek1 aThorleifsson, Gudmar1 aHottenga, Jouke-Jan1 aShah, Sonia1 aSmith, Albert, V1 aSennblad, Bengt1 aGieger, Christian1 aSalo, Perttu1 aPerola, Markus1 aTimpson, Nicholas, J1 aEvans, David, M1 aSt Pourcain, Beate1 aWu, Ying1 aAndrews, Jeanette, S1 aHui, Jennie1 aBielak, Lawrence, F1 aZhao, Wei1 aHorikoshi, Momoko1 aNavarro, Pau1 aIsaacs, Aaron1 aO'Connell, Jeffrey, R1 aStirrups, Kathleen1 aVitart, Veronique1 aHayward, Caroline1 aEsko, Tõnu1 aMihailov, Evelin1 aFraser, Ross, M1 aFall, Tove1 aVoight, Benjamin, F1 aRaychaudhuri, Soumya1 aChen, Han1 aLindgren, Cecilia, M1 aMorris, Andrew, P1 aRayner, Nigel, W1 aRobertson, Neil1 aRybin, Denis1 aLiu, Ching-Ti1 aBeckmann, Jacques, S1 aWillems, Sara, M1 aChines, Peter, S1 aJackson, Anne, U1 aKang, Hyun, Min1 aStringham, Heather, M1 aSong, Kijoung1 aTanaka, Toshiko1 aPeden, John, F1 aGoel, Anuj1 aHicks, Andrew, A1 aAn, Ping1 aMüller-Nurasyid, Martina1 aFranco-Cereceda, Anders1 aFolkersen, Lasse1 aMarullo, Letizia1 aJansen, Hanneke1 aOldehinkel, Albertine, J1 aBruinenberg, Marcel1 aPankow, James, S1 aNorth, Kari, E1 aForouhi, Nita, G1 aLoos, Ruth, J F1 aEdkins, Sarah1 aVarga, Tibor, V1 aHallmans, Göran1 aOksa, Heikki1 aAntonella, Mulas1 aNagaraja, Ramaiah1 aTrompet, Stella1 aFord, Ian1 aBakker, Stephan, J L1 aKong, Augustine1 aKumari, Meena1 aGigante, Bruna1 aHerder, Christian1 aMunroe, Patricia, B1 aCaulfield, Mark1 aAntti, Jula1 aMangino, Massimo1 aSmall, Kerrin1 aMiljkovic, Iva1 aLiu, Yongmei1 aAtalay, Mustafa1 aKiess, Wieland1 aJames, Alan, L1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aPalmer, Colin, N A1 aDoney, Alex, S F1 aWillemsen, Gonneke1 aSmit, Johannes, H1 aCampbell, Susan1 aPolasek, Ozren1 aBonnycastle, Lori, L1 aHercberg, Serge1 aDimitriou, Maria1 aBolton, Jennifer, L1 aFowkes, Gerard, R1 aKovacs, Peter1 aLindström, Jaana1 aZemunik, Tatijana1 aBandinelli, Stefania1 aWild, Sarah, H1 aBasart, Hanneke, V1 aRathmann, Wolfgang1 aGrallert, Harald1 aMaerz, Winfried1 aKleber, Marcus, E1 aBoehm, Bernhard, O1 aPeters, Annette1 aPramstaller, Peter, P1 aProvince, Michael, A1 aBorecki, Ingrid, B1 aHastie, Nicholas, D1 aRudan, Igor1 aCampbell, Harry1 aWatkins, Hugh1 aFarrall, Martin1 aStumvoll, Michael1 aFerrucci, Luigi1 aWaterworth, Dawn, M1 aBergman, Richard, N1 aCollins, Francis, S1 aTuomilehto, Jaakko1 aWatanabe, Richard, M1 aGeus, Eco, J C1 aPenninx, Brenda, W1 aHofman, Albert1 aOostra, Ben, A1 aPsaty, Bruce, M1 aVollenweider, Peter1 aWilson, James, F1 aWright, Alan, F1 aHovingh, Kees1 aMetspalu, Andres1 aUusitupa, Matti1 aMagnusson, Patrik, K E1 aKyvik, Kirsten, O1 aKaprio, Jaakko1 aPrice, Jackie, F1 aDedoussis, George, V1 aDeloukas, Panos1 aMeneton, Pierre1 aLind, Lars1 aBoehnke, Michael1 aShuldiner, Alan, R1 aDuijn, Cornelia, M1 aMorris, Andrew, D1 aToenjes, Anke1 aPeyser, Patricia, A1 aBeilby, John, P1 aKörner, Antje1 aKuusisto, Johanna1 aLaakso, Markku1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aLakka, Timo, A1 aRauramaa, Rainer1 aAdair, Linda, S1 aSmith, George Davey1 aSpector, Tim, D1 aIllig, Thomas1 ade Faire, Ulf1 aHamsten, Anders1 aGudnason, Vilmundur1 aKivimaki, Mika1 aHingorani, Aroon1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aBoomsma, Dorret, I1 aStefansson, Kari1 aHarst, Pim1 aDupuis, Josée1 aPedersen, Nancy, L1 aSattar, Naveed1 aHarris, Tamara, B1 aCucca, Francesco1 aRipatti, Samuli1 aSalomaa, Veikko1 aMohlke, Karen, L1 aBalkau, Beverley1 aFroguel, Philippe1 aPouta, Anneli1 aJarvelin, Marjo-Riitta1 aWareham, Nicholas, J1 aBouatia-Naji, Nabila1 aMcCarthy, Mark, I1 aFranks, Paul, W1 aMeigs, James, B1 aTeslovich, Tanya, M1 aFlorez, Jose, C1 aLangenberg, Claudia1 aIngelsson, Erik1 aProkopenko, Inga1 aBarroso, Inês1 aDIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium uhttps://chs-nhlbi.org/node/609107748nas a2202497 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2012 eng d a1546-171800aMeta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.0 aMetaanalyses identify 13 loci associated with age at menopause a c2012 Jan 22 a260-80 v443 aTo newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
10aAge Factors10aDNA Helicases10aDNA Polymerase gamma10aDNA Primase10aDNA Repair10aDNA Repair Enzymes10aDNA-Directed DNA Polymerase10aEuropean Continental Ancestry Group10aExodeoxyribonucleases10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aImmunity10aMenopause10aPolymorphism, Single Nucleotide10aProteins1 aStolk, Lisette1 aPerry, John, R B1 aChasman, Daniel, I1 aHe, Chunyan1 aMangino, Massimo1 aSulem, Patrick1 aBarbalic, Maja1 aBroer, Linda1 aByrne, Enda, M1 aErnst, Florian1 aEsko, Tõnu1 aFranceschini, Nora1 aGudbjartsson, Daniel, F1 aHottenga, Jouke-Jan1 aKraft, Peter1 aMcArdle, Patrick, F1 aPorcu, Eleonora1 aShin, So-Youn1 aSmith, Albert, V1 avan Wingerden, Sophie1 aZhai, Guangju1 aZhuang, Wei, V1 aAlbrecht, Eva1 aAlizadeh, Behrooz, Z1 aAspelund, Thor1 aBandinelli, Stefania1 aLauc, Lovorka, Barac1 aBeckmann, Jacques, S1 aBoban, Mladen1 aBoerwinkle, Eric1 aBroekmans, Frank, J1 aBurri, Andrea1 aCampbell, Harry1 aChanock, Stephen, J1 aChen, Constance1 aCornelis, Marilyn, C1 aCorre, Tanguy1 aCoviello, Andrea, D1 aD'Adamo, Pio1 aDavies, Gail1 ade Faire, Ulf1 aGeus, Eco, J C1 aDeary, Ian, J1 aDedoussis, George, V Z1 aDeloukas, Panagiotis1 aEbrahim, Shah1 aEiriksdottir, Gudny1 aEmilsson, Valur1 aEriksson, Johan, G1 aFauser, Bart, C J M1 aFerreli, Liana1 aFerrucci, Luigi1 aFischer, Krista1 aFolsom, Aaron, R1 aGarcia, Melissa, E1 aGasparini, Paolo1 aGieger, Christian1 aGlazer, Nicole1 aGrobbee, Diederick, E1 aHall, Per1 aHaller, Toomas1 aHankinson, Susan, E1 aHass, Merli1 aHayward, Caroline1 aHeath, Andrew, C1 aHofman, Albert1 aIngelsson, Erik1 aJanssens, Cecile, J W1 aJohnson, Andrew, D1 aKarasik, David1 aKardia, Sharon, L R1 aKeyzer, Jules1 aKiel, Douglas, P1 aKolcic, Ivana1 aKutalik, Zoltán1 aLahti, Jari1 aLai, Sandra1 aLaisk, Triin1 aLaven, Joop, S E1 aLawlor, Debbie, A1 aLiu, Jianjun1 aLopez, Lorna, M1 aLouwers, Yvonne, V1 aMagnusson, Patrik, K E1 aMarongiu, Mara1 aMartin, Nicholas, G1 aKlaric, Irena, Martinovic1 aMasciullo, Corrado1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMelzer, David1 aMooser, Vincent1 aNavarro, Pau1 aNewman, Anne, B1 aNyholt, Dale, R1 aOnland-Moret, Charlotte, N1 aPalotie, Aarno1 aParé, Guillaume1 aParker, Alex, N1 aPedersen, Nancy, L1 aPeeters, Petra, H M1 aPistis, Giorgio1 aPlump, Andrew, S1 aPolasek, Ozren1 aPop, Victor, J M1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRehnberg, Emil1 aRotter, Jerome, I1 aRudan, Igor1 aSala, Cinzia1 aSalumets, Andres1 aScuteri, Angelo1 aSingleton, Andrew1 aSmith, Jennifer, A1 aSnieder, Harold1 aSoranzo, Nicole1 aStacey, Simon, N1 aStarr, John, M1 aStathopoulou, Maria, G1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStyrkarsdottir, Unnur1 aSun, Yan, V1 aTenesa, Albert1 aThorand, Barbara1 aToniolo, Daniela1 aTryggvadottir, Laufey1 aTsui, Kim1 aUlivi, Sheila1 avan Dam, Rob, M1 aSchouw, Yvonne, T1 avan Gils, Carla, H1 avan Nierop, Peter1 aVink, Jacqueline, M1 aVisscher, Peter, M1 aVoorhuis, Marlies1 aWaeber, Gérard1 aWallaschofski, Henri1 aWichmann, Erich, H1 aWiden, Elisabeth1 avan Gent, Colette, J M Wijnan1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZemunik, Tatijana1 aZgaga, Lina1 aZillikens, Carola, M1 aZygmunt, Marek1 aArnold, Alice, M1 aBoomsma, Dorret, I1 aBuring, Julie, E1 aCrisponi, Laura1 aDemerath, Ellen, W1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHu, Frank, B1 aHunter, David, J1 aLauner, Lenore, J1 aMetspalu, Andres1 aMontgomery, Grant, W1 aOostra, Ben, A1 aRidker, Paul, M1 aSanna, Serena1 aSchlessinger, David1 aSpector, Tim, D1 aStefansson, Kari1 aStreeten, Elizabeth, A1 aThorsteinsdottir, Unnur1 aUda, Manuela1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aMurray, Anna1 aMurabito, Joanne, M1 aVisser, Jenny, A1 aLunetta, Kathryn, L1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/136004917nas a2201453 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2012 eng d a1546-171800aMeta-analysis identifies six new susceptibility loci for atrial fibrillation.0 aMetaanalysis identifies six new susceptibility loci for atrial f c2012 Apr 29 a670-50 v443 aAtrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChild10aChild, Preschool10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aAlbert, Christine, M1 aGlazer, Nicole, L1 aRitchie, Marylyn, D1 aSmith, Albert, V1 aArking, Dan, E1 aMüller-Nurasyid, Martina1 aKrijthe, Bouwe, P1 aLubitz, Steven, A1 aBis, Joshua, C1 aChung, Mina, K1 aDörr, Marcus1 aOzaki, Kouichi1 aRoberts, Jason, D1 aSmith, Gustav1 aPfeufer, Arne1 aSinner, Moritz, F1 aLohman, Kurt1 aDing, Jingzhong1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aRienstra, Michiel1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aMagnani, Jared, W1 aWakili, Reza1 aClauss, Sebastian1 aRotter, Jerome, I1 aSteinbeck, Gerhard1 aLauner, Lenore, J1 aDavies, Robert, W1 aBorkovich, Matthew1 aHarris, Tamara, B1 aLin, Honghuang1 aVölker, Uwe1 aVölzke, Henry1 aMilan, David, J1 aHofman, Albert1 aBoerwinkle, Eric1 aChen, Lin, Y1 aSoliman, Elsayed, Z1 aVoight, Benjamin, F1 aLi, Guo1 aChakravarti, Aravinda1 aKubo, Michiaki1 aTedrow, Usha, B1 aRose, Lynda, M1 aRidker, Paul, M1 aConen, David1 aTsunoda, Tatsuhiko1 aFurukawa, Tetsushi1 aSotoodehnia, Nona1 aXu, Siyan1 aKamatani, Naoyuki1 aLevy, Daniel1 aNakamura, Yusuke1 aParvez, Babar1 aMahida, Saagar1 aFurie, Karen, L1 aRosand, Jonathan1 aMuhammad, Raafia1 aPsaty, Bruce, M1 aMeitinger, Thomas1 aPerz, Siegfried1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aKao, Linda, W H1 aKathiresan, Sekar1 aRoden, Dan, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aMcKnight, Barbara1 aSjögren, Marketa1 aNewman, Anne, B1 aLiu, Yongmei1 aGollob, Michael, H1 aMelander, Olle1 aTanaka, Toshihiro1 aStricker, Bruno, H Ch1 aFelix, Stephan, B1 aAlonso, Alvaro1 aDarbar, Dawood1 aBarnard, John1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aKääb, Stefan uhttps://chs-nhlbi.org/node/138304310nas a2200901 4500008004100000022001400041245011000055210006900165260001300234300001100247490000600258520179200264653001002056653002202066653001902088653002402107653001102131653001702142653003402159653001102193653000902204653002702213653001602240653003602256100002002292700001702312700002102329700002202350700001902372700002002391700001202411700002202423700002102445700001902466700001902485700002402504700002402528700001702552700001402569700001502583700002402598700002302622700001902645700001902664700002402683700002202707700001202729700002402741700001702765700002202782700002602804700001702830700001702847700002002864700002902884700001902913700002302932700002002955700002102975700001902996700002003015700002203035700002403057700002403081700002503105700001803130700002403148700002803172700002003200700002303220700002003243700002103263700002203284700002203306700002203328700002203350856003603372 2012 eng d a1942-326800aNovel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.0 aNovel loci associated with PR interval in a genomewide associati c2012 Dec a639-460 v53 aBACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.
METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).
CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
10aAdult10aAfrican Americans10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide1 aButler, Anne, M1 aYin, Xiaoyan1 aEvans, Daniel, S1 aNalls, Michael, A1 aSmith, Erin, N1 aTanaka, Toshiko1 aLi, Guo1 aBuxbaum, Sarah, G1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBenjamin, Emelia, J1 aBerenson, Gerald, S1 aBis, Josh, C1 aChen, Wei1 aDeo, Rajat1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHsueh, Wen-Chi1 aKeating, Brendan, J1 aKerr, Kathleen, F1 aLi, Yun1 aLimacher, Marian, C1 aLiu, Yongmei1 aLubitz, Steven, A1 aMarciante, Kristin, D1 aMehra, Reena1 aMeng, Yan, A1 aNewman, Anne, B1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPalmer, Cameron, D1 aPsaty, Bruce, M1 aQuibrera, Miguel1 aRedline, Susan1 aReiner, Alex, P1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aSmith, Gustav1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aFerrucci, Luigi1 aMurray, Sarah, S1 aEvans, Michele, K1 aSotoodehnia, Nona1 aMagnani, Jared, W1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/608421848nas a2207177 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2012 eng d a1553-740400aNovel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.0 aNovel loci for adiponectin levels and their influence on type 2 c2012 ae10026070 v83 aCirculating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
10aAdiponectin10aAfrican Americans10aAsian Continental Ancestry Group10aCholesterol, HDL10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGene Expression10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlucose Tolerance Test10aHumans10aInsulin Resistance10aMale10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aDastani, Zari1 aHivert, Marie-France1 aTimpson, Nicholas1 aPerry, John, R B1 aYuan, Xin1 aScott, Robert, A1 aHenneman, Peter1 aHeid, Iris, M1 aKizer, Jorge, R1 aLyytikäinen, Leo-Pekka1 aFuchsberger, Christian1 aTanaka, Toshiko1 aMorris, Andrew, P1 aSmall, Kerrin1 aIsaacs, Aaron1 aBeekman, Marian1 aCoassin, Stefan1 aLohman, Kurt1 aQi, Lu1 aKanoni, Stavroula1 aPankow, James, S1 aUh, Hae-Won1 aWu, Ying1 aBidulescu, Aurelian1 aRasmussen-Torvik, Laura, J1 aGreenwood, Celia, M T1 aLadouceur, Martin1 aGrimsby, Jonna1 aManning, Alisa, K1 aLiu, Ching-Ti1 aKooner, Jaspal1 aMooser, Vincent, E1 aVollenweider, Peter1 aKapur, Karen, A1 aChambers, John1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aFrants, Rune1 aWillems-Vandijk, Ko1 aOostra, Ben, A1 aWillems, Sara, M1 aLamina, Claudia1 aWinkler, Thomas, W1 aPsaty, Bruce, M1 aTracy, Russell, P1 aBrody, Jennifer1 aChen, Ida1 aViikari, Jorma1 aKähönen, Mika1 aPramstaller, Peter, P1 aEvans, David, M1 aSt Pourcain, Beate1 aSattar, Naveed1 aWood, Andrew, R1 aBandinelli, Stefania1 aCarlson, Olga, D1 aEgan, Josephine, M1 aBöhringer, Stefan1 avan Heemst, Diana1 aKedenko, Lyudmyla1 aKristiansson, Kati1 aNuotio, Marja-Liisa1 aLoo, Britt-Marie1 aHarris, Tamara1 aGarcia, Melissa1 aKanaya, Alka1 aHaun, Margot1 aKlopp, Norman1 aWichmann, H-Erich1 aDeloukas, Panos1 aKatsareli, Efi1 aCouper, David, J1 aDuncan, Bruce, B1 aKloppenburg, Margreet1 aAdair, Linda, S1 aBorja, Judith, B1 aWilson, James, G1 aMusani, Solomon1 aGuo, Xiuqing1 aJohnson, Toby1 aSemple, Robert1 aTeslovich, Tanya, M1 aAllison, Matthew, A1 aRedline, Susan1 aBuxbaum, Sarah, G1 aMohlke, Karen, L1 aMeulenbelt, Ingrid1 aBallantyne, Christie, M1 aDedoussis, George, V1 aHu, Frank, B1 aLiu, Yongmei1 aPaulweber, Bernhard1 aSpector, Timothy, D1 aSlagboom, Eline1 aFerrucci, Luigi1 aJula, Antti1 aPerola, Markus1 aRaitakari, Olli1 aFlorez, Jose, C1 aSalomaa, Veikko1 aEriksson, Johan, G1 aFrayling, Timothy, M1 aHicks, Andrew, A1 aLehtimäki, Terho1 aSmith, George Davey1 aSiscovick, David, S1 aKronenberg, Florian1 aDuijn, Cornelia1 aLoos, Ruth, J F1 aWaterworth, Dawn, M1 aMeigs, James, B1 aDupuis, Josée1 aRichards, Brent1 aVoight, Benjamin, F1 aScott, Laura, J1 aSteinthorsdottir, Valgerdur1 aDina, Christian1 aWelch, Ryan, P1 aZeggini, Eleftheria1 aHuth, Cornelia1 aAulchenko, Yurii, S1 aThorleifsson, Gudmar1 aMcCulloch, Laura, J1 aFerreira, Teresa1 aGrallert, Harald1 aAmin, Najaf1 aWu, Guanming1 aWiller, Cristen, J1 aRaychaudhuri, Soumya1 aMcCarroll, Steve, A1 aHofmann, Oliver, M1 aSegrè, Ayellet, V1 aHoek, Mandy1 aNavarro, Pau1 aArdlie, Kristin1 aBalkau, Beverley1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBlagieva, Roza1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBoström, Kristina, Bengtsson1 aBravenboer, Bert1 aBumpstead, Suzannah1 aBurtt, Noel, P1 aCharpentier, Guillaume1 aChines, Peter, S1 aCornelis, Marilyn1 aCrawford, Gabe1 aDoney, Alex, S F1 aElliott, Katherine, S1 aElliott, Amanda, L1 aErdos, Michael, R1 aFox, Caroline, S1 aFranklin, Christopher, S1 aGanser, Martha1 aGieger, Christian1 aGrarup, Niels1 aGreen, Todd1 aGriffin, Simon1 aGroves, Christopher, J1 aGuiducci, Candace1 aHadjadj, Samy1 aHassanali, Neelam1 aHerder, Christian1 aIsomaa, Bo1 aJackson, Anne, U1 aJohnson, Paul, R V1 aJørgensen, Torben1 aKao, Wen, H L1 aKong, Augustine1 aKraft, Peter1 aKuusisto, Johanna1 aLauritzen, Torsten1 aLi, Man1 aLieverse, Aloysius1 aLindgren, Cecilia, M1 aLyssenko, Valeriya1 aMarre, Michel1 aMeitinger, Thomas1 aMidthjell, Kristian1 aMorken, Mario, A1 aNarisu, Narisu1 aNilsson, Peter1 aOwen, Katharine, R1 aPayne, Felicity1 aPetersen, Ann-Kristin1 aPlatou, Carl1 aProença, Christine1 aProkopenko, Inga1 aRathmann, Wolfgang1 aRayner, William1 aRobertson, Neil, R1 aRocheleau, Ghislain1 aRoden, Michael1 aSampson, Michael, J1 aSaxena, Richa1 aShields, Beverley, M1 aShrader, Peter1 aSigurdsson, Gunnar1 aSparsø, Thomas1 aStrassburger, Klaus1 aStringham, Heather, M1 aSun, Qi1 aSwift, Amy, J1 aThorand, Barbara1 aTichet, Jean1 aTuomi, Tiinamaija1 avan Dam, Rob, M1 avan Haeften, Timon, W1 avan Herpt, Thijs1 avan Vliet-Ostaptchouk, Jana, V1 aWalters, Bragi, G1 aWeedon, Michael, N1 aWijmenga, Cisca1 aWitteman, Jacqueline1 aBergman, Richard, N1 aCauchi, Stephane1 aCollins, Francis, S1 aGloyn, Anna, L1 aGyllensten, Ulf1 aHansen, Torben1 aHide, Winston, A1 aHitman, Graham, A1 aHofman, Albert1 aHunter, David, J1 aHveem, Kristian1 aLaakso, Markku1 aMorris, Andrew, D1 aPalmer, Colin, N A1 aRudan, Igor1 aSijbrands, Eric1 aStein, Lincoln, D1 aTuomilehto, Jaakko1 aUitterlinden, Andre1 aWalker, Mark1 aWatanabe, Richard, M1 aAbecasis, Goncalo, R1 aBoehm, Bernhard, O1 aCampbell, Harry1 aDaly, Mark, J1 aHattersley, Andrew, T1 aPedersen, Oluf1 aBarroso, Inês1 aGroop, Leif1 aSladek, Rob1 aThorsteinsdottir, Unnur1 aWilson, James, F1 aIllig, Thomas1 aFroguel, Philippe1 aDuijn, Cornelia, M1 aStefansson, Kari1 aAltshuler, David1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aSoranzo, Nicole1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aMägi, Reedik1 aRandall, Joshua1 aElliott, Paul1 aRybin, Denis1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aSong, Kijoung1 aGoel, Anuj1 aLajunen, Taina1 aDoney, Alex1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aTimpson, Nicholas, J1 aZabena, Carina1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aAriyurek, Yavuz1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBergmann, Sven1 aBochud, Murielle1 aBonnefond, Amélie1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGrundy, Scott1 aGwilliam, Rhian1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHillman, David, R1 aHingorani, Aroon, D1 aHui, Jennie1 aHung, Joe1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aMahley, Robert1 aMangino, Massimo1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, Braxton, D1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNeville, Matthew, J1 aOrrù, Marco1 aPakyz, Ruth1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurðsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTönjes, Anke1 aUitterlinden, André, G1 aDijk, Ko Willems1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWard, Kim, L1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aSilander, Kaisa1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aSerrano-Ríos, Manuel1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPramstaller, Peter Paul1 aWright, Alan, F1 aStumvoll, Michael1 aHamsten, Anders1 aBuchanan, Thomas, A1 aValle, Timo, T1 aRotter, Jerome, I1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aPeltonen, Leena1 aMooser, Vincent1 aSladek, Robert1 aMusunuru, Kiran1 aSmith, Albert, V1 aEdmondson, Andrew, C1 aStylianou, Ioannis, M1 aKoseki, Masahiro1 aPirruccello, James, P1 aChasman, Daniel, I1 aJohansen, Christopher, T1 aFouchier, Sigrid, W1 aPeloso, Gina, M1 aBarbalic, Maja1 aRicketts, Sally, L1 aBis, Joshua, C1 aFeitosa, Mary, F1 aOrho-Melander, Marju1 aMelander, Olle1 aLi, Xiaohui1 aLi, Mingyao1 aCho, Yoon Shin1 aGo, Min Jin1 aKim, Young, Jin1 aLee, Jong-Young1 aPark, Taesung1 aKim, Kyunga1 aSim, Xueling1 aOng, Rick Twee-Hee1 aCroteau-Chonka, Damien, C1 aLange, Leslie, A1 aSmith, Joshua, D1 aZiegler, Andreas1 aZhang, Weihua1 aZee, Robert, Y L1 aWhitfield, John, B1 aThompson, John, R1 aSurakka, Ida1 aSpector, Tim, D1 aSmit, Johannes, H1 aSinisalo, Juha1 aScott, James1 aSaharinen, Juha1 aSabatti, Chiara1 aRose, Lynda, M1 aRoberts, Robert1 aRieder, Mark1 aParker, Alex, N1 aParé, Guillaume1 aO'Donnell, Christopher, J1 aNieminen, Markku, S1 aNickerson, Deborah, A1 aMontgomery, Grant, W1 aMcArdle, Wendy1 aMasson, David1 aMartin, Nicholas, G1 aMarroni, Fabio1 aLucas, Gavin1 aLuben, Robert1 aLokki, Marja-Liisa1 aLettre, Guillaume1 aLauner, Lenore, J1 aLakatta, Edward, G1 aLaaksonen, Reijo1 aKyvik, Kirsten, O1 aKönig, Inke, R1 aKhaw, Kay-Tee1 aKaplan, Lee, M1 aJohansson, Asa1 aJanssens, Cecile, J W1 aIgl, Wilmar1 aHovingh, Kees1 aHengstenberg, Christian1 aHavulinna, Aki, S1 aHastie, Nicholas, D1 aHarris, Tamara, B1 aHaritunians, Talin1 aHall, Alistair, S1 aGroop, Leif, C1 aGonzalez, Elena1 aFreimer, Nelson, B1 aErdmann, Jeanette1 aEjebe, Kenechi, G1 aDöring, Angela1 aDominiczak, Anna, F1 aDemissie, Serkalem1 aDeloukas, Panagiotis1 ade Faire, Ulf1 aCrawford, Gabriel1 aChen, Yii-der, I1 aCaulfield, Mark, J1 aBoekholdt, Matthijs1 aAssimes, Themistocles, L1 aQuertermous, Thomas1 aSeielstad, Mark1 aWong, Tien, Y1 aTai, E-Shyong1 aFeranil, Alan, B1 aKuzawa, Christopher, W1 aTaylor, Herman, A1 aGabriel, Stacey, B1 aHolm, Hilma1 aGudnason, Vilmundur1 aKrauss, Ronald, M1 aOrdovas, Jose, M1 aMunroe, Patricia, B1 aKooner, Jaspal, S1 aTall, Alan, R1 aHegele, Robert, A1 aKastelein, John, J P1 aSchadt, Eric, E1 aStrachan, David, P1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aKathiresan, Sekar1 aDIAGRAM+ Consortium1 aMAGIC Consortium1 aGLGC Investigators1 aMuTHER Consortium1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal B Pgen Consortium1 aProcardis Consortium1 aMAGIC investigators1 aGLGC Consortium uhttps://chs-nhlbi.org/node/137803175nas a2200409 4500008004100000022001400041245011900055210006900174260001600243300001100259490000700270520196300277653002502240653001102265653002302276653000802299653001102307653003802318653003402356653001302390653001102403653001602414653002602430653002902456100002402485700001602509700002302525700002302548700002102571700002002592700002802612700002202640700002002662700002202682700002502704856003602729 2012 eng d a1552-578300aVariation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.0 aVariation in the lysyl oxidase LOX gene is associated with kerat c2012 Jun 28 a4152-70 v533 aPURPOSE: Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.
METHODS: Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.
RESULTS: Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3×10(-3) and 7×10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7×10(-3) and 7.7×10(-4), respectively. Meta P values of 4.0×10(-5) and 4.0×10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.
CONCLUSIONS: Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.
10aCase-Control Studies10aCornea10aCorneal Topography10aDNA10aFamily10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aKeratoconus10aPolymorphism, Genetic10aProtein-Lysine 6-Oxidase1 aBykhovskaya, Yelena1 aLi, Xiaohui1 aEpifantseva, Irina1 aHaritunians, Talin1 aSiscovick, David1 aAldave, Anthony1 aSzczotka-Flynn, Loretta1 aIyengar, Sudha, K1 aTaylor, Kent, D1 aRotter, Jerome, I1 aRabinowitz, Yaron, S uhttps://chs-nhlbi.org/node/154303514nas a2200673 4500008004100000022001400041245014600055210006900201260001500270300001100285490000800296520155600304653001001860653002201870653002101892653003801913653001601951653004001967653001102007653003802018653002502056653003402081653000902115653003202124653001102156653002802167653000902195653002202204653001602226653002202242653002602264653001802290653002102308653001802329653001402347100001602361700002202377700002202399700002302421700002002444700001802464700002902482700002102511700002202532700001702554700002302571700002102594700002302615700001902638700002002657700001902677700001402696700001502710700002002725700001902745700002002764700002002784856003602804 2013 eng d a1476-625600aAssociation of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study.0 aAssociation of functional polymorphism rs2231142 Q141K in the AB c2013 May 1 a923-320 v1773 aA loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.
10aAdult10aAfrican Americans10aAge Distribution10aATP-Binding Cassette Transporters10aComorbidity10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenetics, Population10aGenome-Wide Association Study10aGout10aHormone Replacement Therapy10aHumans10aIndians, North American10aMale10aMexican Americans10aMiddle Aged10aNeoplasm Proteins10aPolymorphism, Genetic10aPostmenopause10aSex Distribution10aUnited States10aUric Acid1 aZhang, Lili1 aSpencer, Kylee, L1 aVoruganti, Saroja1 aJorgensen, Neal, W1 aFornage, Myriam1 aBest, Lyle, G1 aBrown-Gentry, Kristin, D1 aCole, Shelley, A1 aCrawford, Dana, C1 aDeelman, Ewa1 aFranceschini, Nora1 aGaffo, Angelo, L1 aGlenn, Kimberly, R1 aHeiss, Gerardo1 aJenny, Nancy, S1 aKöttgen, Anna1 aLi, Qiong1 aLiu, Kiang1 aMatise, Tara, C1 aNorth, Kari, E1 aUmans, Jason, G1 aKao, Linda, W H uhttps://chs-nhlbi.org/node/682703504nas a2200505 4500008004100000022001400041245021500055210006900270260001300339300000900352490000600361520189100367653003902258653002002297653004002317653001102357653003402368653001102402653000902413653001602422653003502438653003602473653002402509653003002533653001702563653001502580100001302595700001902608700002002627700001702647700002202664700001802686700002202704700002202726700003002748700003002778700002202808700001402830700002302844700002802867700002002895700002102915710002602936856003602962 2013 eng d a1942-326800aAssociation of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies.0 aAssociation of genomewide variation with highly sensitive cardia c2013 Feb a82-80 v63 aBACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.
METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).
CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.
10aAfrican Continental Ancestry Group10aAtherosclerosis10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNuclear Receptor Coactivator 210aPolymorphism, Single Nucleotide10aProspective Studies10aResidence Characteristics10aRisk Factors10aTroponin T1 aYu, Bing1 aBarbalic, Maja1 aBrautbar, Ariel1 aNambi, Vijay1 aHoogeveen, Ron, C1 aTang, Weihong1 aMosley, Thomas, H1 aRotter, Jerome, I1 adeFilippi, Christopher, R1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aRice, Ken1 aHeckbert, Susan, R1 aBallantyne, Christie, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/585700896nas a2200289 4500008004100000022001400041245012600055210006900181260001300250300001000263490000700273653001000280653001900290653002500309653003400334653001800368653001100386653001400397653003300411653002600444653003000470653001100500653001800511100002000529700002100549856003600570 2013 eng d a1531-548700aThe Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium as a model of collaborative science.0 aCohorts for Heart and Aging Research in Genomic Epidemiology CHA c2013 May a346-80 v2410aAging10aCohort Studies10aCooperative Behavior10aGenome-Wide Association Study10aHeart Failure10aHumans10aIncidence10aMulticenter Studies as Topic10aMyocardial Infarction10aResearch Support as Topic10aStroke10aUnited States1 aPsaty, Bruce, M1 aSitlani, Colleen uhttps://chs-nhlbi.org/node/603004753nas a2201057 4500008004100000022001400041245017100055210006900226260001300295300001000308490000700318520203200325653001002357653002202367653000902389653002502398653001602423653002402439653001102463653002202474653003402496653001302530653001502543653001102558653000902569653002702578653001602605653003602621653000902657653001802666100001102684700001602695700001602711700001602727700001602743700001702759700001702776700001802793700001002811700002102821700001602842700001402858700002102872700001402893700001602907700001802923700001902941700001302960700001502973700001202988700001903000700001803019700001603037700001603053700001403069700001803083700001303101700001603114700001503130700001903145700001103164700001703175700001803192700001303210700001703223700001703240700001703257700001403274700001603288700001703304700001503321700001803336700001703354700001903371700001603390700002003406700001803426700001703444700002003461700001703481700001803498700001903516700002103535700001703556700001603573700001303589700002003602700001903622700001803641856003603659 2013 eng d a1556-387100aCommon genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.0 aCommon genetic variation near the connexin43 gene is associated c2013 Mar a401-80 v103 aBACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.
OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.
METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)).
RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.
CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.
10aAdult10aAfrican Americans10aAged10aArrhythmias, Cardiac10aConnexin 4310aElectrocardiography10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHeart Rate10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRest10aUnited States1 aDeo, R1 aNalls, M, A1 aAvery, C, L1 aSmith, J, G1 aEvans, D, S1 aKeller, M, F1 aButler, A, M1 aBuxbaum, S, G1 aLi, G1 aQuibrera, Miguel1 aSmith, E, N1 aTanaka, T1 aAkylbekova, E, L1 aAlonso, A1 aArking, D E1 aBenjamin, E J1 aBerenson, G, S1 aBis, J C1 aChen, L, Y1 aChen, W1 aCummings, S, R1 aEllinor, P, T1 aEvans, M, K1 aFerrucci, L1 aFox, E, R1 aHeckbert, S R1 aHeiss, G1 aHsueh, W, C1 aKerr, K, F1 aLimacher, M, C1 aLiu, Y1 aLubitz, S, A1 aMagnani, J, W1 aMehra, R1 aMarcus, G, M1 aMurray, S, S1 aNewman, A, B1 aNjajou, O1 aNorth, K, E1 aPaltoo, D, N1 aPsaty, B M1 aRedline, S, S1 aReiner, A, P1 aRobinson, J, G1 aRotter, J I1 aSamdarshi, T, E1 aSchnabel, R B1 aSchork, N, J1 aSingleton, A, B1 aSiscovick, D1 aSoliman, E, Z1 aSotoodehnia, N1 aSrinivasan, S, R1 aTaylor, H, A1 aTrevisan, M1 aZhang, Z1 aZonderman, A, B1 aNewton-Cheh, C1 aWhitsel, E, A uhttps://chs-nhlbi.org/node/606307440nas a2202173 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520143200253653002301685653004001708653001901748653002201767653003401789653001101823653001101834653003701845653001401882653003601896653003301932100001801965700002701983700001902010700002602029700002202055700002302077700002302100700002202123700002202145700002002167700002002187700001802207700001802225700001902243700001202262700001802274700002002292700001602312700002502328700002402353700001902377700001802396700002002414700002102434700002602455700002302481700002002504700001202524700002002536700002702556700001702583700002502600700001902625700001802644700001902662700002102681700002702702700002102729700002102750700002202771700001602793700002202809700001802831700001902849700002102868700002002889700001902909700002302928700002002951700002202971700002202993700001903015700002403034700002503058700002103083700002003104700001703124700001403141700001903155700001903174700002303193700002003216700002503236700002303261700002303284700002103307700001803328700002003346700002203366700001603388700002203404700001803426700002103444700002403465700001603489700001903505700001903524700002003543700002003563700002203583700002003605700001903625700001903644700001903663700001803682700002103700700002003721700002003741700001703761700001903778700001803797700002203815700001803837700001903855700002803874700002603902700002403928700001903952700001703971700002203988700002204010700001904032700002504051700002204076700001904098700002004117700001904137700002204156700002204178700001904200700001604219700002304235700002504258700001804283700001404301700002404315700001704339700002104356700002404377700001704401700001704418700001904435700001904454700002404473700002004497700002104517700001804538700002104556700001904577700001904596700002904615700002404644700002104668700002404689700002304713700001804736700002204754700002004776700002304796700002004819700002404839700001704863700002004880700001604900700002004916700002104936700001804957700002604975700001905001700002105020700002505041700002205066700002005088700002105108700001805129700002405147700002105171700001505192700002305207856003605230 2013 eng d a1533-345000aCommon variants in Mendelian kidney disease genes and their association with renal function.0 aCommon variants in Mendelian kidney disease genes and their asso c2013 Dec a2105-170 v243 aMany common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aHumans10aKidney10aMendelian Randomization Analysis10aPhenotype10aPolymorphism, Single Nucleotide10aRenal Insufficiency, Chronic1 aParsa, Afshin1 aFuchsberger, Christian1 aKöttgen, Anna1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 ade Andrade, Mariza1 aChasman, Daniel, I1 aTeumer, Alexander1 aEndlich, Karlhans1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aKim, Young, J1 aTaliun, Daniel1 aLi, Man1 aFeitosa, Mary1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aGlazer, Nicole1 aIsaacs, Aaron1 aRao, Madhumathi1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aCouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aHofer, Edith1 aHu, Frank1 aDemirkan, Ayse1 aOostra, Ben, A1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aGiulianini, Franco1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aZgaga, Lina1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aStengel, Bénédicte1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMitchell, Paul1 aCiullo, Marina1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline1 aHayward, Caroline1 aRidker, Paul, M1 aBochud, Murielle1 aHeid, Iris, M1 aSiscovick, David, S1 aFox, Caroline, S1 aKao, Linda1 aBöger, Carsten, A uhttps://chs-nhlbi.org/node/628810661nas a2203397 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2013 eng d a1546-171800aDiscovery and refinement of loci associated with lipid levels.0 aDiscovery and refinement of loci associated with lipid levels c2013 Nov a1274-12830 v453 aLevels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
10aAfrican Continental Ancestry Group10aAsian Continental Ancestry Group10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLipids10aTriglycerides1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDo, Ron1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 aKesäniemi, Antero1 aKivimaki, Mika1 aKooner, Jaspal, S1 aKoudstaal, Peter, J1 aKrauss, Ronald, M1 aKuh, Diana1 aKuusisto, Johanna1 aKyvik, Kirsten, O1 aLaakso, Markku1 aLakka, Timo, A1 aLind, Lars1 aLindgren, Cecilia, M1 aMartin, Nicholas, G1 aMärz, Winfried1 aMcCarthy, Mark, I1 aMcKenzie, Colin, A1 aMeneton, Pierre1 aMetspalu, Andres1 aMoilanen, Leena1 aMorris, Andrew, D1 aMunroe, Patricia, B1 aNjølstad, Inger1 aPedersen, Nancy, L1 aPower, Chris1 aPramstaller, Peter, P1 aPrice, Jackie, F1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRauramaa, Rainer1 aSaleheen, Danish1 aSalomaa, Veikko1 aSanghera, Dharambir, K1 aSaramies, Jouko1 aSchwarz, Peter, E H1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aSiegbahn, Agneta1 aSpector, Tim, D1 aStefansson, Kari1 aStrachan, David, P1 aTayo, Bamidele, O1 aTremoli, Elena1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aDuijn, Cornelia, M1 aVollenweider, Peter1 aWallentin, Lars1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWolffenbuttel, Bruce, H R1 aOrdovas, Jose, M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aKathiresan, Sekar1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aGlobal Lipids Genetics Consortium uhttps://chs-nhlbi.org/node/615404096nas a2200901 4500008004100000022001400041245007000055210006900125260001500194300001100209490000700220520164400227653001001871653002201881653000901903653002201912653002001934653001101954653001701965653003801982653001802020653003402038653001302072653001102085653002702096653000902123653001602132653001202148653003602160653001602196100001502212700002502227700001502252700002302267700001902290700001902309700002802328700002102356700002102377700002002398700001702418700002102435700002102456700002502477700002002502700001702522700001602539700002002555700002502575700002102600700001602621700002102637700001602658700001902674700001802693700001902711700001702730700002602747700002002773700002202793700002102815700002002836700002402856700001502880700002002895700001602915700003002931700002202961700002102983700002403004700002003028700002303048700002203071700002703093700001903120700001903139856003603158 2013 eng d a1537-660500aFine Mapping and Identification of BMI Loci in African Americans.0 aFine Mapping and Identification of BMI Loci in African Americans c2013 Oct 3 a661-710 v933 aGenome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.
10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aBody Mass Index10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aYoung Adult1 aGong, Jian1 aSchumacher, Fredrick1 aLim, Unhee1 aHindorff, Lucia, A1 aHaessler, Jeff1 aBuyske, Steven1 aCarlson, Christopher, S1 aRosse, Stephanie1 aBůzková, Petra1 aFornage, Myriam1 aGross, Myron1 aPankratz, Nathan1 aPankow, James, S1 aSchreiner, Pamela, J1 aCooper, Richard1 aEhret, Georg1 aGu, Charles1 aHouston, Denise1 aIrvin, Marguerite, R1 aJackson, Rebecca1 aKuller, Lew1 aHenderson, Brian1 aCheng, Iona1 aWilkens, Lynne1 aLeppert, Mark1 aLewis, Cora, E1 aLi, Rongling1 aNguyen, Khanh-Dung, H1 aGoodloe, Robert1 aFarber-Eger, Eric1 aBoston, Jonathan1 aDilks, Holli, H1 aRitchie, Marylyn, D1 aFowke, Jay1 aPooler, Loreall1 aGraff, Misa1 aFernandez-Rhodes, Lindsay1 aCochrane, Barbara1 aBoerwinkle, Eric1 aKooperberg, Charles1 aMatise, Tara, C1 aLe Marchand, Loïc1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aNorth, Kari, E1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/662603887nas a2200601 4500008004100000022001400041245013100055210006900186260001300255300001300268490000700281520205500288653002202343653002002365653002002385653003002405653004002435653001902475653003802494653002202532653003402554653002302588653001102611653002802622653001102650653001702661653002702678653003602705100002802741700002002769700001902789700002702808700002502835700001902860700002802879700001902907700002302926700002402949700002102973700002202994700002203016700002203038700002103060700001803081700001603099700001903115700002303134700002203157700002303179700002703202710002003229856003603249 2013 eng d a1545-788500aGeneralization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.0 aGeneralization and dilution of association results from European c2013 Sep ae10016610 v113 aThe vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
10aAfrican Americans10aAsian Americans10aBody Mass Index10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHispanic Americans10aHumans10aIndians, North American10aLipids10aMetagenomics10aOceanic Ancestry Group10aPolymorphism, Single Nucleotide1 aCarlson, Christopher, S1 aMatise, Tara, C1 aNorth, Kari, E1 aHaiman, Christopher, A1 aFesinmeyer, Megan, D1 aBuyske, Steven1 aSchumacher, Fredrick, R1 aPeters, Ulrike1 aFranceschini, Nora1 aRitchie, Marylyn, D1 aDuggan, David, J1 aSpencer, Kylee, L1 aDumitrescu, Logan1 aEaton, Charles, B1 aThomas, Fridtjof1 aYoung, Alicia1 aCarty, Cara1 aHeiss, Gerardo1 aLe Marchand, Loïc1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aKooperberg, Charles, L1 aPAGE Consortium uhttps://chs-nhlbi.org/node/628903265nas a2200469 4500008004100000022001400041245013900055210006900194260001600263300001300279490000700292520188400299653001002183653000902193653002002202653001102222653002302233653000802256653001102264653003802275653003402313653001302347653001102360653001602371653000902387653002502396653001602421653003602437653003402473100001602507700002402523700002802547700002302575700002102598700002302619700002802642700002202670700002202692700002002714700002502734856003602759 2013 eng d a1552-578300aGenetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus.0 aGenetic association of COL5A1 variants in keratoconus patients s c2013 Apr 12 a2696-7040 v543 aPURPOSE: Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.
METHODS: A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case-control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families.
RESULTS: Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10(-3) and 7.4 × 10(-3)). SNP rs1536482 was replicated in the second case-control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10(-4) (odds ratio [OR] = 1.30) and 2.9 × 10(-3) (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10(-3)).
CONCLUSIONS: SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.
10aAdult10aAged10aCollagen Type V10aCornea10aCorneal Topography10aDNA10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aKeratoconus10aMale10aMicroscopy, Acoustic10aMiddle Aged10aPolymorphism, Single Nucleotide10aTomography, Optical Coherence1 aLi, Xiaohui1 aBykhovskaya, Yelena1 aCanedo, Ana, Laura Caia1 aHaritunians, Talin1 aSiscovick, David1 aAldave, Anthony, J1 aSzczotka-Flynn, Loretta1 aIyengar, Sudha, K1 aRotter, Jerome, I1 aTaylor, Kent, D1 aRabinowitz, Yaron, S uhttps://chs-nhlbi.org/node/607604387nas a2201021 4500008004100000022001400041245005800055210005700113260000900170300001100179490000600190520154700196653000901743653002201752653001501774653003101789653004001820653001101860653001701871653003401888653001301922653001101935653000901946653003101955653002101986653001602007653002002023653002002043100001702063700002302080700001802103700002502121700001602146700002202162700001402184700002602198700002102224700001902245700001802264700002402282700002202306700001902328700002202347700002002369700002702389700001902416700002602435700002802461700002302489700001902512700002402531700002202555700002302577700002202600700001602622700001902638700002002657700002702677700002002704700002202724700002102746700002402767700001202791700002302803700002202826700001702848700002002865700002002885700002402905700002502929700001402954700002002968700002102988700002703009700002103036700002303057700002203080700002203102700001903124700002403143700002803167700002403195700001903219700001803238710004503256710002803301856003603329 2013 eng d a1932-620300aGenetic loci for retinal arteriolar microcirculation.0 aGenetic loci for retinal arteriolar microcirculation c2013 ae658040 v83 aNarrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
10aAged10aAged, 80 and over10aArterioles10aChromosomes, Human, Pair 510aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMEF2 Transcription Factors10aMicrocirculation10aMiddle Aged10aModels, Genetic10aRetinal Vessels1 aSim, Xueling1 aJensen, Richard, A1 aIkram, Kamran1 aCotch, Mary, Frances1 aLi, Xiaohui1 aMacgregor, Stuart1 aXie, Jing1 aSmith, Albert, Vernon1 aBoerwinkle, Eric1 aMitchell, Paul1 aKlein, Ronald1 aKlein, Barbara, E K1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 ade Jong, Paulus, T V M1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aJonasson, Fridbert1 aLauner, Lenore, J1 aAttia, John1 aBaird, Paul, N1 aHarrap, Stephen1 aHolliday, Elizabeth, G1 aInouye, Michael1 aRochtchina, Elena1 aScott, Rodney, J1 aViswanathan, Ananth1 aLi, Guo1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aKuo, Jane, Z1 aTaylor, Kent, D1 aHewitt, Alex, W1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aSun, Cong1 aYoung, Terri, L1 aMackey, David, A1 avan Zuydam, Natalie, R1 aDoney, Alex, S F1 aPalmer, Colin, N A1 aMorris, Andrew, D1 aRotter, Jerome, I1 aTai, Shyong, E1 aGudnason, Vilmundur1 aVingerling, Johannes, R1 aSiscovick, David, S1 aWang, Jie, Jin1 aWong, Tien, Y1 aWellcome Trust Case Control Consortium 21 aGlobal BPgen Consortium uhttps://chs-nhlbi.org/node/602703914nas a2200673 4500008004100000022001400041245016900055210006900224260001300293300001100306490000700317520191200324653001202236653002002248653001802268653001902286653001702305653003802322653003402360653001102394653002702405653001702432653001202449653001402461653003602475653001702511100002502528700001902553700002402572700001502596700002302611700002202634700002002656700002102676700002002697700002102717700003002738700001402768700001802782700001702800700002802817700002202845700002102867700002102888700002002909700002102929700002502950700002302975700002502998700002403023700002403047700002203071700002303093700001903116700002703135700002303162700001903185856003603204 2013 eng d a1930-739X00aGenetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study.0 aGenetic risk factors for BMI and obesity in an ethnically divers c2013 Apr a835-460 v213 aOBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.
DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI.
RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.
CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.
10aAlleles10aBody Mass Index10aEthnic Groups10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMetagenomics10aObesity10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors1 aFesinmeyer, Megan, D1 aNorth, Kari, E1 aRitchie, Marylyn, D1 aLim, Unhee1 aFranceschini, Nora1 aWilkens, Lynne, R1 aGross, Myron, D1 aBůzková, Petra1 aGlenn, Kimberly1 aQuibrera, Miguel1 aFernandez-Rhodes, Lindsay1 aLi, Qiong1 aFowke, Jay, H1 aLi, Rongling1 aCarlson, Christopher, S1 aPrentice, Ross, L1 aKuller, Lewis, H1 aManson, JoAnn, E1 aMatise, Tara, C1 aCole, Shelley, A1 aChen, Christina, T L1 aHoward, Barbara, V1 aKolonel, Laurence, N1 aHenderson, Brian, E1 aMonroe, Kristine, R1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aBuyske, Steven1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/663103932nas a2200769 4500008004100000022001400041245020400055210006900259260001600328300000700344490000700351520160000358653004101958653001001999653002202009653000902031653001202040653003702052653001802089653003002107653004002137653001102177653001902188653001702207653003402224653001302258653002302271653001102294653002802305653001202333653000902345653001602354653003602370653004202406100002502448700002002473700001902493700002802512700002102540700002302561700002202584700002002606700002202626700003102648700002302679700002102702700002502723700001502748700002102763700002402784700002102808700002002829700002602849700001702875700001502892700002202907700002302929700002302952700001902975700002002994700002203014700002303036700002703059700001903086700002103105856003603126 2013 eng d a1471-235000aGenetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.0 aGenetic variants associated with fasting glucose and insulin con c2013 Sep 25 a980 v143 aBACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.
METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.
RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.
CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.
10aAdaptor Proteins, Signal Transducing10aAdult10aAfrican Americans10aAged10aAlleles10aAsian Continental Ancestry Group10aBlood Glucose10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aGenomics10aHispanic Americans10aHumans10aIndians, North American10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factor 7-Like 2 Protein1 aFesinmeyer, Megan, D1 aMeigs, James, B1 aNorth, Kari, E1 aSchumacher, Fredrick, R1 aBůzková, Petra1 aFranceschini, Nora1 aHaessler, Jeffrey1 aGoodloe, Robert1 aSpencer, Kylee, L1 aVoruganti, Venkata, Saroja1 aHoward, Barbara, V1 aJackson, Rebecca1 aKolonel, Laurence, N1 aLiu, Simin1 aManson, JoAnn, E1 aMonroe, Kristine, R1 aMukamal, Kenneth1 aDilks, Holli, H1 aPendergrass, Sarah, A1 aNato, Andrew1 aWan, Peggy1 aWilkens, Lynne, R1 aLe Marchand, Loïc1 aAmbite, Jose, Luis1 aBuyske, Steven1 aFlorez, Jose, C1 aCrawford, Dana, C1 aHindorff, Lucia, A1 aHaiman, Christopher, A1 aPeters, Ulrike1 aPankow, James, S uhttps://chs-nhlbi.org/node/629004091nas a2200793 4500008004100000022001400041245011400055210006900169260001600238300001200254490000700266520179600273653001002069653002202079653000902101653002502110653002402135653002802159653004002187653001102227653004402238653003202282653002202314653003402336653001302370653001102383653000902394653001602403653001502419653003602434653001602470100002502486700002002511700001802531700001902549700001902568700002002587700001802607700002202625700002102647700002002668700002602688700002102714700001802735700002402753700002102777700002102798700003002819700002202849700002002871700001802891700002202909700002402931700002202955700002102977700002202998700002103020700002103041700002103062700002203083700002403105700002003129700002003149700002403169700002203193700002003215710002603235856003603261 2013 eng d a1460-208300aGenome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia.0 aGenomewide and genecentric analyses of circulating myeloperoxida c2013 Aug 15 a3381-930 v223 aIncreased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
10aAdult10aAfrican Americans10aAged10aCase-Control Studies10aComplement Factor H10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aGene Expression Regulation, Enzymologic10aGenetic Association Studies10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPeroxidase10aPolymorphism, Single Nucleotide10aYoung Adult1 aReiner, Alexander, P1 aHartiala, Jaana1 aZeller, Tanja1 aBis, Joshua, C1 aDupuis, Josée1 aFornage, Myriam1 aBaumert, Jens1 aKleber, Marcus, E1 aWild, Philipp, S1 aBaldus, Stephan1 aBielinski, Suzette, J1 aFontes, João, D1 aIllig, Thomas1 aKeating, Brendan, J1 aLange, Leslie, A1 aOjeda, Francisco1 aMüller-Nurasyid, Martina1 aMunzel, Thomas, F1 aPsaty, Bruce, M1 aRice, Kenneth1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aTang, W, H Wilson1 aThorand, Barbara1 aErdmann, Jeanette1 aJacobs, David, R1 aWilson, James, G1 aKoenig, Wolfgang1 aTracy, Russell, P1 aBlankenberg, Stefan1 aMärz, Winfried1 aGross, Myron, D1 aBenjamin, Emelia, J1 aHazen, Stanley, L1 aAllayee, Hooman1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/628209406nas a2203037 4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520104700257653002501304653004001329653001901369653001701388653003401405653001201439653000901451653001101460653001301471653003601484653002401520653001401544100001901558700001801577700002201595700002201617700001801639700002501657700002001682700002201702700002601724700001901750700001601769700002001785700002301805700002101828700002101849700001501870700002301885700002601908700002101934700002101955700002001976700001201996700002202008700002202030700002202052700001602074700001902090700001902109700002102128700001402149700002202163700002002185700001502205700001702220700002202237700002102259700001902280700001902299700002102318700001902339700002502358700001902383700001902402700002202421700001902443700002002462700001702482700002102499700001902520700002202539700002202561700002002583700001802603700002302621700002702644700001802671700002002689700001702709700002002726700002202746700002102768700002902789700002202818700002202840700002102862700002302883700002102906700001802927700002002945700002302965700002402988700002503012700001903037700002103056700002203077700002403099700002203123700002103145700001503166700001703181700001803198700002203216700002003238700002403258700002003282700002003302700002103322700001703343700001803360700002103378700002103399700002203420700001603442700002103458700001903479700002403498700002503522700001803547700001603565700001903581700002103600700002103621700002703642700001403669700002103683700002503704700002303729700001803752700002503770700002103795700002003816700001603836700002403852700001803876700002603894700002203920700001703942700001703959700002403976700002104000700002204021700001804043700002804061700002304089700001904112700002304131700002204154700001704176700001904193700002204212700001804234700001904252700001704271700002104288700002404309700001904333700001504352700001704367700001904384700002604403700002804429700001904457700002804476700002104504700002204525700002504547700002004572700002304592700001904615700001904634700002504653700002404678700002104702700002204723700001604745700001904761700002004780700001804800700002004818700001704838700002004855700002004875700001904895700002804914700002704942700002204969700002204991700001905013700002505032700002205057700001805079700002005097700001605117700001605133700001805149700002105167700002005188700001505208700001905223700001705242700002905259700001905288700002405307700001805331700002205349700002305371700002005394700002105414700002405435700001905459700002005478700001605498700002505514700002105539700002005560700002305580700002305603700002005626700002205646700001805668700003005686700002205716700002005738700002605758700002005784700002005804700002005824700001805844700001805862700003005880700001805910700001905928700002305947700001805970700002005988700002006008700002106028700002306049700002006072700002006092700001906112700002106131700002006152700002106172700002206193710002706215710002606242710002306268710002006291710002106311856003606332 2013 eng d a1546-171800aGenome-wide association analyses identify 18 new loci associated with serum urate concentrations.0 aGenomewide association analyses identify 18 new loci associated c2013 Feb a145-540 v453 aElevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
10aAnalysis of Variance10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aGlucose10aGout10aHumans10aInhibins10aPolymorphism, Single Nucleotide10aSignal Transduction10aUric Acid1 aKöttgen, Anna1 aAlbrecht, Eva1 aTeumer, Alexander1 aVitart, Veronique1 aKrumsiek, Jan1 aHundertmark, Claudia1 aPistis, Giorgio1 aRuggiero, Daniela1 aO'Seaghdha, Conall, M1 aHaller, Toomas1 aYang, Qiong1 aTanaka, Toshiko1 aJohnson, Andrew, D1 aKutalik, Zoltán1 aSmith, Albert, V1 aShi, Julia1 aStruchalin, Maksim1 aMiddelberg, Rita, P S1 aBrown, Morris, J1 aGaffo, Angelo, L1 aPirastu, Nicola1 aLi, Guo1 aHayward, Caroline1 aZemunik, Tatijana1 aHuffman, Jennifer1 aYengo, Loic1 aZhao, Jing Hua1 aDemirkan, Ayse1 aFeitosa, Mary, F1 aLiu, Xuan1 aMalerba, Giovanni1 aLopez, Lorna, M1 aHarst, Pim1 aLi, Xinzhong1 aKleber, Marcus, E1 aHicks, Andrew, A1 aNolte, Ilja, M1 aJohansson, Asa1 aMurgia, Federico1 aWild, Sarah, H1 aBakker, Stephan, J L1 aPeden, John, F1 aDehghan, Abbas1 aSteri, Maristella1 aTenesa, Albert1 aLagou, Vasiliki1 aSalo, Perttu1 aMangino, Massimo1 aRose, Lynda, M1 aLehtimäki, Terho1 aWoodward, Owen, M1 aOkada, Yukinori1 aTin, Adrienne1 aMüller, Christian1 aOldmeadow, Christopher1 aPutku, Margus1 aCzamara, Darina1 aKraft, Peter1 aFrogheri, Laura1 aThun, Gian, Andri1 aGrotevendt, Anne1 aGislason, Gauti, Kjartan1 aHarris, Tamara, B1 aLauner, Lenore, J1 aMcArdle, Patrick1 aShuldiner, Alan, R1 aBoerwinkle, Eric1 aCoresh, Josef1 aSchmidt, Helena1 aSchallert, Michael1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aKubo, Michiaki1 aNakamura, Yusuke1 aTanaka, Toshihiro1 aMunroe, Patricia, B1 aSamani, Nilesh, J1 aJacobs, David, R1 aLiu, Kiang1 aD'Adamo, Pio1 aUlivi, Sheila1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aVollenweider, Peter1 aWaeber, Gérard1 aCampbell, Susan1 aDevuyst, Olivier1 aNavarro, Pau1 aKolcic, Ivana1 aHastie, Nicholas1 aBalkau, Beverley1 aFroguel, Philippe1 aEsko, Tõnu1 aSalumets, Andres1 aKhaw, Kay, Tee1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aIsaacs, Aaron1 aKraja, Aldi1 aZhang, Qunyuan1 aWild, Philipp, S1 aScott, Rodney, J1 aHolliday, Elizabeth, G1 aOrg, Elin1 aViigimaa, Margus1 aBandinelli, Stefania1 aMetter, Jeffrey, E1 aLupo, Antonio1 aTrabetti, Elisabetta1 aSorice, Rossella1 aDöring, Angela1 aLattka, Eva1 aStrauch, Konstantin1 aTheis, Fabian1 aWaldenberger, Melanie1 aWichmann, H-Erich1 aDavies, Gail1 aGow, Alan, J1 aBruinenberg, Marcel1 aStolk, Ronald, P1 aKooner, Jaspal, S1 aZhang, Weihua1 aWinkelmann, Bernhard, R1 aBoehm, Bernhard, O1 aLucae, Susanne1 aPenninx, Brenda, W1 aSmit, Johannes, H1 aCurhan, Gary1 aMudgal, Poorva1 aPlenge, Robert, M1 aPortas, Laura1 aPersico, Ivana1 aKirin, Mirna1 aWilson, James, F1 aLeach, Irene, Mateo1 aGilst, Wiek, H1 aGoel, Anuj1 aOngen, Halit1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aImboden, Medea1 avon Eckardstein, Arnold1 aCucca, Francesco1 aNagaraja, Ramaiah1 aPiras, Maria, Grazia1 aNauck, Matthias1 aSchurmann, Claudia1 aBudde, Kathrin1 aErnst, Florian1 aFarrington, Susan, M1 aTheodoratou, Evropi1 aProkopenko, Inga1 aStumvoll, Michael1 aJula, Antti1 aPerola, Markus1 aSalomaa, Veikko1 aShin, So-Youn1 aSpector, Tim, D1 aSala, Cinzia1 aRidker, Paul, M1 aKähönen, Mika1 aViikari, Jorma1 aHengstenberg, Christian1 aNelson, Christopher, P1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aSingleton, Andrew, B1 aKamatani, Naoyuki1 aZeller, Tanja1 aBurnier, Michel1 aAttia, John1 aLaan, Maris1 aKlopp, Norman1 aHillege, Hans, L1 aKloiber, Stefan1 aChoi, Hyon1 aPirastu, Mario1 aTore, Silvia1 aProbst-Hensch, Nicole, M1 aVölzke, Henry1 aGudnason, Vilmundur1 aParsa, Afshin1 aSchmidt, Reinhold1 aWhitfield, John, B1 aFornage, Myriam1 aGasparini, Paolo1 aSiscovick, David, S1 aPolasek, Ozren1 aCampbell, Harry1 aRudan, Igor1 aBouatia-Naji, Nabila1 aMetspalu, Andres1 aLoos, Ruth, J F1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aFerrucci, Luigi1 aGambaro, Giovanni1 aDeary, Ian, J1 aWolffenbuttel, Bruce, H R1 aChambers, John, C1 aMärz, Winfried1 aPramstaller, Peter, P1 aSnieder, Harold1 aGyllensten, Ulf1 aWright, Alan, F1 aNavis, Gerjan1 aWatkins, Hugh1 aWitteman, Jacqueline, C M1 aSanna, Serena1 aSchipf, Sabine1 aDunlop, Malcolm, G1 aTönjes, Anke1 aRipatti, Samuli1 aSoranzo, Nicole1 aToniolo, Daniela1 aChasman, Daniel, I1 aRaitakari, Olli1 aKao, Linda, W H1 aCiullo, Marina1 aFox, Caroline, S1 aCaulfield, Mark1 aBochud, Murielle1 aGieger, Christian1 aLifeLines Cohort Study1 aCARDIoGRAM consortium1 aDIAGRAM Consortium1 aICBP Consortium1 aMAGIC Consortium uhttps://chs-nhlbi.org/node/607506047nas a2201393 4500008004100000022001400041245010400055210006900159260000900228300001300237490000600250520209200256653001402348653003902362653002602401653004002427653001102467653001702478653003402495653001102529653000902540653001202549653003602561653002002597100001802617700001902635700002002654700001802674700002302692700001902715700002402734700002102758700002202779700001502801700002802816700002502844700001602869700002202885700002202907700002302929700001802952700001202970700002802982700001803010700001503028700002403043700002403067700002803091700001903119700001703138700002503155700001603180700002203196700001903218700002003237700002303257700002203280700002803302700001703330700002003347700002303367700001503390700001703405700002003422700002103442700001803463700002203481700002303503700002303526700003103549700002203580700002003602700001703622700002803639700001403667700002403681700002403705700002203729700002103751700001803772700001403790700003203804700002503836700002403861700001703885700002403902700002103926700002103947700002803968700002203996700002004018700002104038700002104059700002704080700002204107700002304129700002104152700002404173700001704197700002404214700002304238700002204261700002104283700002504304700002304329700002204352700001904374700002204393700002104415700002804436700002304464700001804487700002204505700002504527700002504552700001904577700002104596856003604617 2013 eng d a1553-740400aGenome-wide association of body fat distribution in African ancestry populations suggests new loci.0 aGenomewide association of body fat distribution in African ances c2013 ae10036810 v93 aCentral obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
10aAdiposity10aAfrican Continental Ancestry Group10aBody Fat Distribution10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aObesity10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aLiu, Ching-Ti1 aMonda, Keri, L1 aTaylor, Kira, C1 aLange, Leslie1 aDemerath, Ellen, W1 aPalmas, Walter1 aWojczynski, Mary, K1 aEllis, Jaclyn, C1 aVitolins, Mara, Z1 aLiu, Simin1 aPapanicolaou, George, J1 aIrvin, Marguerite, R1 aXue, Luting1 aGriffin, Paula, J1 aNalls, Michael, A1 aAdeyemo, Adebowale1 aLiu, Jiankang1 aLi, Guo1 aRuiz-Narvaez, Edward, A1 aChen, Wei-Min1 aChen, Fang1 aHenderson, Brian, E1 aMillikan, Robert, C1 aAmbrosone, Christine, B1 aStrom, Sara, S1 aGuo, Xiuqing1 aAndrews, Jeanette, S1 aSun, Yan, V1 aMosley, Thomas, H1 aYanek, Lisa, R1 aShriner, Daniel1 aHaritunians, Talin1 aRotter, Jerome, I1 aSpeliotes, Elizabeth, K1 aSmith, Megan1 aRosenberg, Lynn1 aMychaleckyj, Josyf1 aNayak, Uma1 aSpruill, Ida1 aGarvey, Timothy1 aPettaway, Curtis1 aNyante, Sarah1 aBandera, Elisa, V1 aBritton, Angela, F1 aZonderman, Alan, B1 aRasmussen-Torvik, Laura, J1 aChen, Yii-Der Ida1 aDing, Jingzhong1 aLohman, Kurt1 aKritchevsky, Stephen, B1 aZhao, Wei1 aPeyser, Patricia, A1 aKardia, Sharon, L R1 aKabagambe, Edmond1 aBroeckel, Ulrich1 aChen, Guanjie1 aZhou, Jie1 aWassertheil-Smoller, Sylvia1 aNeuhouser, Marian, L1 aRampersaud, Evadnie1 aPsaty, Bruce1 aKooperberg, Charles1 aManson, JoAnn, E1 aKuller, Lewis, H1 aOchs-Balcom, Heather, M1 aJohnson, Karen, C1 aSucheston, Lara1 aOrdovas, Jose, M1 aPalmer, Julie, R1 aHaiman, Christopher, A1 aMcKnight, Barbara1 aHoward, Barbara, V1 aBecker, Diane, M1 aBielak, Lawrence, F1 aLiu, Yongmei1 aAllison, Matthew, A1 aGrant, Struan, F A1 aBurke, Gregory, L1 aPatel, Sanjay, R1 aSchreiner, Pamela, J1 aBorecki, Ingrid, B1 aEvans, Michele, K1 aTaylor, Herman1 aSale, Michèle, M1 aHoward, Virginia1 aCarlson, Christopher, S1 aRotimi, Charles, N1 aCushman, Mary1 aHarris, Tamara, B1 aReiner, Alexander, P1 aCupples, Adrienne, L1 aNorth, Kari, E1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/628704061nas a2200781 4500008004100000022001400041245015900055210006900214260001300283300001200296490000700308520179500315653000902110653001002119653002502129653001902154653001102173653003402184653001102218653000902229653002702238653001602265653003602281653002402317653001702341653002702358100001802385700002202403700002302425700001802448700002902466700001202495700002102507700002202528700002102550700002302571700002402594700002002618700001702638700001802655700001602673700002502689700001902714700002302733700002802756700001802784700002102802700001802823700001902841700002602860700002202886700002102908700002802929700002202957700001902979700002102998700001903019700002203038700002103060700002203081700003203103700001803135700002603153700002003179700002103199700002303220856003603243 2013 eng d a1098-227200aA genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.0 agenomewide association study for venous thromboembolism the exte c2013 Jul a512-5210 v373 aVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
10aAged10aAging10aCase-Control Studies10aCohort Studies10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aVenous Thromboembolism1 aTang, Weihong1 aTeichert, Martina1 aChasman, Daniel, I1 aHeit, John, A1 aMorange, Pierre-Emmanuel1 aLi, Guo1 aPankratz, Nathan1 aLeebeek, Frank, W1 aParé, Guillaume1 ade Andrade, Mariza1 aTzourio, Christophe1 aPsaty, Bruce, M1 aBasu, Saonli1 aRuiter, Rikje1 aRose, Lynda1 aArmasu, Sebastian, M1 aLumley, Thomas1 aHeckbert, Susan, R1 aUitterlinden, André, G1 aLathrop, Mark1 aRice, Kenneth, M1 aCushman, Mary1 aHofman, Albert1 aLambert, Jean-Charles1 aGlazer, Nicole, L1 aPankow, James, S1 aWitteman, Jacqueline, C1 aAmouyel, Philippe1 aBis, Joshua, C1 aBovill, Edwin, G1 aKong, Xiaoxiao1 aTracy, Russell, P1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aTrégouët, David-Alexandre1 aLoth, Daan, W1 aStricker, Bruno, H Ch1 aRidker, Paul, M1 aFolsom, Aaron, R1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/602904169nas a2200709 4500008004100000022001400041245026000055210006900315260001300384300001100397490000600408520202600414653001002440653000902450653003102459653001902490653002102509653003002530653003302560653001102593653001702604653003402621653001302655653001102668653002702679653001602706653000902722653001602731653001502747653001802762653003602780653001802816100001802834700002402852700002102876700001702897700002002914700001902934700002502953700001802978700002102996700002203017700002303039700001903062700002003081700002203101700002103123700002103144700002703165700001803192700002503210700002103235700002303256700002103279700001703300700002103317700002003338700002003358700002003378700002503398856003603423 2013 eng d a1942-326800aGenome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu0 aGenomewide association study identifies novel loci associated wi c2013 Apr a171-830 v63 aBACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.
10aAdult10aAged10aChromosomes, Human, Pair 210aCohort Studies10aCoronary Disease10aDiabetes Mellitus, Type 210aFatty Acids, Monounsaturated10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aLinkage Disequilibrium10aLipogenesis10aMale10aMiddle Aged10aOleic Acid10aPalmitic Acid10aPolymorphism, Single Nucleotide10aStearic Acids1 aH Y Wu, Jason1 aLemaitre, Rozenn, N1 aManichaikul, Ani1 aGuan, Weihua1 aTanaka, Toshiko1 aFoy, Millennia1 aKabagambe, Edmond, K1 aDjoussé, Luc1 aSiscovick, David1 aFretts, Amanda, M1 aJohnson, Catherine1 aKing, Irena, B1 aPsaty, Bruce, M1 aMcKnight, Barbara1 aRich, Stephen, S1 aChen, Yii-der, I1 aNettleton, Jennifer, A1 aTang, Weihong1 aBandinelli, Stefania1 aJacobs, David, R1 aBrowning, Brian, L1 aLaurie, Cathy, C1 aGu, Xiangjun1 aTsai, Michael, Y1 aSteffen, Lyn, M1 aFerrucci, Luigi1 aFornage, Myriam1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/588004246nas a2200769 4500008004100000022001400041245015300055210006900208260001300277300001000290490000600300520206100306653002202367653000902389653001902398653001302417653002102430653004002451653001102491653003402502653001302536653001002549653001102559653000902570653001602579653001402595653003602609653001202645100001802657700002302675700001902698700001902717700001302736700002402749700002302773700002102796700002202817700001902839700002002858700002102878700002302899700002502922700002202947700002302969700001602992700002103008700001903029700001303048700001803061700002503079700002003104700002903124700002103153700002403174700002203198700002403220700001903244700001803263700002203281700002203303700002203325700002003347700002303367700002303390700002703413856003603440 2013 eng d a1942-326800aGenome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study.0 aGenomewide association study of cardiac structure and systolic f c2013 Feb a37-460 v63 aBACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.
METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.
CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
10aAfrican Americans10aAged10aCohort Studies10aDiastole10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aMusani, Solomon, K1 aBarbalic, Maja1 aLin, Honghuang1 aYu, Bing1 aOgunyankin, Kofo, O1 aSmith, Nicholas, L1 aKutlar, Abdullah1 aGlazer, Nicole, L1 aPost, Wendy, S1 aPaltoo, Dina, N1 aDries, Daniel, L1 aFarlow, Deborah, N1 aDuarte, Christine, W1 aKardia, Sharon, L1 aMeyers, Kristin, J1 aSun, Yan, V1 aArnett, Donna, K1 aPatki, Amit, A1 aSha, Jin1 aCui, Xiangqui1 aSamdarshi, Tandaw, E1 aPenman, Alan, D1 aBibbins-Domingo, Kirsten1 aBůzková, Petra1 aBenjamin, Emelia, J1 aBluemke, David, A1 aMorrison, Alanna, C1 aHeiss, Gerardo1 aCarr, Jeffrey1 aTracy, Russell, P1 aMosley, Thomas, H1 aTaylor, Herman, A1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aCappola, Thomas, P1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/663205039nas a2201297 4500008004100000022001400041245006000055210005600115260001600171300001100187490000700198520149400205653000901699653002201708653003101730653001501761653001101776653003801787653003401825653001101859653000901870653001601879653003601895100001501931700001901946700001601965700002501981700002202006700002502028700001602053700001802069700001802087700002002105700001702125700002302142700002202165700002202187700001602209700002302225700001202248700002502260700002402285700002202309700002002331700002302351700002002374700001702394700002402411700002202435700001902457700001702476700001902493700002102512700002202533700001702555700001802572700002002590700002202610700002202632700001902654700002302673700002002696700002002716700002002736700002402756700001902780700001802799700001902817700002602836700002102862700001702883700002002900700002302920700001802943700002102961700002402982700001703006700001903023700001903042700002003061700002303081700002103104700001703125700001803142700002003160700001903180700002303199700002503222700002103247700002303268700002803291700001903319700002103338700002003359700002303379700002103402700001903423700002303442700002403465700002303489700002003512700002303532700001903555700002203574700002403596700002203620700002003642700002203662700002103684856003603705 2013 eng d a1873-240200aA genome-wide association study of depressive symptoms.0 agenomewide association study of depressive symptoms c2013 Apr 01 a667-780 v733 aBACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
10aAged10aAged, 80 and over10aChromosomes, Human, Pair 510aDepression10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aHek, Karin1 aDemirkan, Ayse1 aLahti, Jari1 aTerracciano, Antonio1 aTeumer, Alexander1 aCornelis, Marilyn, C1 aAmin, Najaf1 aBakshis, Erin1 aBaumert, Jens1 aDing, Jingzhong1 aLiu, Yongmei1 aMarciante, Kristin1 aMeirelles, Osorio1 aNalls, Michael, A1 aSun, Yan, V1 aVogelzangs, Nicole1 aYu, Lei1 aBandinelli, Stefania1 aBenjamin, Emelia, J1 aBennett, David, A1 aBoomsma, Dorret1 aCannas, Alessandra1 aCoker, Laura, H1 ade Geus, Eco1 aDe Jager, Philip, L1 aDiez-Roux, Ana, V1 aPurcell, Shaun1 aHu, Frank, B1 aRimma, Eric, B1 aHunter, David, J1 aJensen, Majken, K1 aCurhan, Gary1 aRice, Kenneth1 aPenman, Alan, D1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aEmeny, Rebecca1 aEriksson, Johan, G1 aEvans, Denis, A1 aFerrucci, Luigi1 aFornage, Myriam1 aGudnason, Vilmundur1 aHofman, Albert1 aIllig, Thomas1 aKardia, Sharon1 aKelly-Hayes, Margaret1 aKoenen, Karestan1 aKraft, Peter1 aKuningas, Maris1 aMassaro, Joseph, M1 aMelzer, David1 aMulas, Antonella1 aMulder, Cornelis, L1 aMurray, Anna1 aOostra, Ben, A1 aPalotie, Aarno1 aPenninx, Brenda1 aPetersmann, Astrid1 aPilling, Luke, C1 aPsaty, Bruce1 aRawal, Rajesh1 aReiman, Eric, M1 aSchulz, Andrea1 aShulman, Joshua, M1 aSingleton, Andrew, B1 aSmith, Albert, V1 aSutin, Angelina, R1 aUitterlinden, André, G1 aVölzke, Henry1 aWiden, Elisabeth1 aYaffe, Kristine1 aZonderman, Alan, B1 aCucca, Francesco1 aHarris, Tamara1 aLadwig, Karl-Heinz1 aLlewellyn, David, J1 aRäikkönen, Katri1 aTanaka, Toshiko1 aDuijn, Cornelia, M1 aGrabe, Hans, J1 aLauner, Lenore, J1 aLunetta, Kathryn, L1 aMosley, Thomas, H1 aNewman, Anne, B1 aTiemeier, Henning1 aMurabito, Joanne uhttps://chs-nhlbi.org/node/607004181nas a2201057 4500008004100000022001400041245010300055210006900158260001600227300001200243490000700255520120000262653002501462653001101487653001901498653003401517653001101551653002501562653003601587653003401623653002801657653000901685100002101694700001801715700001601733700002301749700002001772700002301792700001601815700002101831700002101852700001901873700002601892700001901918700001901937700002301956700001901979700001801998700001902016700001902035700002102054700001802075700002002093700002502113700002102138700002202159700002402181700001902205700001902224700001902243700001702262700001902279700002102298700001202319700002202331700002302353700001702376700001802393700002002411700002002431700002602451700001702477700002102494700002302515700002102538700002002559700002402579700002302603700002002626700002402646700001702670700002102687700002402708700002102732700002502753700002402778700002002802700001602822700002002838700002102858700002502879700002802904700002002932700002802952700002102980700002403001700002103025700001703046710002403063856003603087 2013 eng d a1460-208300aA genome-wide association study of early menopause and the combined impact of identified variants.0 agenomewide association study of early menopause and the combined c2013 Apr 01 a1465-720 v223 aEarly menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
10aCase-Control Studies10aFemale10aGene Frequency10aGenome-Wide Association Study10aHumans10aMenopause, Premature10aPolymorphism, Single Nucleotide10aPrimary Ovarian Insufficiency10aQuantitative Trait Loci10aRisk1 aPerry, John, R B1 aCorre, Tanguy1 aEsko, Tõnu1 aChasman, Daniel, I1 aFischer, Krista1 aFranceschini, Nora1 aHe, Chunyan1 aKutalik, Zoltán1 aMangino, Massimo1 aRose, Lynda, M1 aSmith, Albert, Vernon1 aStolk, Lisette1 aSulem, Patrick1 aWeedon, Michael, N1 aZhuang, Wei, V1 aArnold, Alice1 aAshworth, Alan1 aBergmann, Sven1 aBuring, Julie, E1 aBurri, Andrea1 aChen, Constance1 aCornelis, Marilyn, C1 aCouper, David, J1 aGoodarzi, Mark, O1 aGudnason, Vilmundur1 aHarris, Tamara1 aHofman, Albert1 aJones, Michael1 aKraft, Peter1 aLauner, Lenore1 aLaven, Joop, S E1 aLi, Guo1 aMcKnight, Barbara1 aMasciullo, Corrado1 aMilani, Lili1 aOrr, Nicholas1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aSala, Cinzia1 aSalumets, Andres1 aSchoemaker, Minouk1 aTraglia, Michela1 aWaeber, Gérard1 aChanock, Stephen, J1 aDemerath, Ellen, W1 aGarcia, Melissa1 aHankinson, Susan, E1 aHu, Frank, B1 aHunter, David, J1 aLunetta, Kathryn, L1 aMetspalu, Andres1 aMontgomery, Grant, W1 aMurabito, Joanne, M1 aNewman, Anne, B1 aOng, Ken, K1 aSpector, Tim, D1 aStefansson, Kari1 aSwerdlow, Anthony, J1 aThorsteinsdottir, Unnur1 avan Dam, Rob, M1 aUitterlinden, André, G1 aVisser, Jenny, A1 aVollenweider, Peter1 aToniolo, Daniela1 aMurray, Anna1 aReproGen Consortium uhttps://chs-nhlbi.org/node/615304413nas a2200889 4500008004100000022001400041245008200055210006900137260000900206300001100215490000600226520194300232653000902175653002202184653001102206653003402217653001302251653002502264653001102289653001702300653000902317653003602326653002302362653002102385100002302406700001702429700001602446700002502462700001802487700002702505700002402532700002202556700002302578700002402601700002202625700002602647700002102673700001702694700002002711700001702731700001902748700001902767700001602786700001802802700002202820700001902842700002202861700002002883700001702903700001902920700002702939700002602966700002802992700001803020700001903038700002003057700001703077700002003094700001903114700001403133700002203147700003003169700001903199700002203218700001703240700002303257700002403280700001803304700002403322700002203346700001503368700002503383700001803408710003903426710002203465856003603487 2013 eng d a1932-620300aGenome-wide association study of retinopathy in individuals without diabetes.0 aGenomewide association study of retinopathy in individuals witho c2013 ae542320 v83 aBACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.
RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.
CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
10aAged10aAged, 80 and over10aFemale10aGenome-Wide Association Study10aGenotype10aHistone Deacetylases10aHumans10aHypertension10aMale10aPolymorphism, Single Nucleotide10aRepressor Proteins10aRetinal Diseases1 aJensen, Richard, A1 aSim, Xueling1 aLi, Xiaohui1 aCotch, Mary, Frances1 aIkram, Kamran1 aHolliday, Elizabeth, G1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore, J1 aSmith, Albert, Vernon1 aBoerwinkle, Eric1 aCheung, Ning1 aHewitt, Alex, W1 aLiew, Gerald1 aMitchell, Paul1 aWang, Jie, Jin1 aAttia, John1 aScott, Rodney1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aTaylor, Kent1 aHofman, Albert1 ade Jong, Paulus, T V M1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aTay, Wan-Ting1 aTeo, Yik, Ying1 aSeielstad, Mark1 aLiu, Jianjun1 aCheng, Ching-Yu1 aSaw, Seang-Mei1 aAung, Tin1 aGanesh, Santhi, K1 aO'Donnell, Christopher, J1 aNalls, Mike, A1 aWiggins, Kerri, L1 aKuo, Jane, Z1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aKlein, Ronald1 aSiscovick, David, S1 aRotter, Jerome, I1 aTai, Shong1 aVingerling, Johannes1 aWong, Tien, Y1 aBlue Mountains Eye Study GWAS Team1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/607212626nas a2204177 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2013 eng d a1546-171800aGenome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.0 aGenomewide metaanalysis identifies 11 new loci for anthropometri c2013 May a501-120 v453 aApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
10aAnthropometry10aBody Height10aBody Mass Index10aCase-Control Studies10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMeta-Analysis as Topic10aObesity10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aWaist-Hip Ratio1 aBerndt, Sonja, I1 aGustafsson, Stefan1 aMägi, Reedik1 aGanna, Andrea1 aWheeler, Eleanor1 aFeitosa, Mary, F1 aJustice, Anne, E1 aMonda, Keri, L1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aEsko, Tõnu1 aFall, Tove1 aFerreira, Teresa1 aGentilini, Davide1 aJackson, Anne, U1 aLuan, Jian'an1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWiller, Cristen, J1 aWinkler, Thomas, W1 aWood, Andrew, R1 aWorkalemahu, Tsegaselassie1 aHu, Yi-Juan1 aLee, Sang, Hong1 aLiang, Liming1 aLin, Dan-Yu1 aMin, Josine, L1 aNeale, Benjamin, M1 aThorleifsson, Gudmar1 aYang, Jian1 aAlbrecht, Eva1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aHeijer, Martin, den1 aEklund, Niina1 aFischer, Krista1 aGoel, Anuj1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aJarick, Ivonne1 aJohansson, Asa1 aJohnson, Toby1 aKanoni, Stavroula1 aKleber, Marcus, E1 aKönig, Inke, R1 aKristiansson, Kati1 aKutalik, Zoltán1 aLamina, Claudia1 aLecoeur, Cécile1 aLi, Guo1 aMangino, Massimo1 aMcArdle, Wendy, L1 aMedina-Gómez, Carolina1 aMüller-Nurasyid, Martina1 aNgwa, Julius, S1 aNolte, Ilja, M1 aPaternoster, Lavinia1 aPechlivanis, Sonali1 aPerola, Markus1 aPeters, Marjolein, J1 aPreuss, Michael1 aRose, Lynda, M1 aShi, Jianxin1 aShungin, Dmitry1 aSmith, Albert, Vernon1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTeumer, Alexander1 aTrip, Mieke, D1 aTyrer, Jonathan1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aWaite, Lindsay, L1 aZhao, Jing Hua1 aAbsher, Devin1 aAsselbergs, Folkert, W1 aAtalay, Mustafa1 aAttwood, Antony, P1 aBalmforth, Anthony, J1 aBasart, Hanneke1 aBeilby, John1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBruinenberg, Marcel1 aCampbell, Harry1 aChasman, Daniel, I1 aChines, Peter, S1 aCollins, Francis, S1 aConnell, John, M1 aCookson, William, O1 ade Faire, Ulf1 ade Vegt, Femmie1 aDei, Mariano1 aDimitriou, Maria1 aEdkins, Sarah1 aEstrada, Karol1 aEvans, David, M1 aFarrall, Martin1 aFerrario, Marco, M1 aFerrieres, Jean1 aFranke, Lude1 aFrau, Francesca1 aGejman, Pablo, V1 aGrallert, Harald1 aGrönberg, Henrik1 aGudnason, Vilmundur1 aHall, Alistair, S1 aHall, Per1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHeath, Andrew, C1 aHebebrand, Johannes1 aHomuth, Georg1 aHu, Frank, B1 aHunt, Sarah, E1 aHyppönen, Elina1 aIribarren, Carlos1 aJacobs, Kevin, B1 aJansson, John-Olov1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKee, Frank1 aKhaw, Kay-Tee1 aKivimaki, Mika1 aKoenig, Wolfgang1 aKraja, Aldi, T1 aKumari, Meena1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaitinen, Jaana, H1 aLakka, Timo, A1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLind, Lars1 aLindström, Jaana1 aLiu, Jianjun1 aLiuzzi, Antonio1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aMadden, Pamela, A1 aMagnusson, Patrik, K1 aManunta, Paolo1 aMarek, Diana1 aMärz, Winfried1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMihailov, Evelin1 aMilani, Lili1 aMontgomery, Grant, W1 aMooser, Vincent1 aMühleisen, Thomas, W1 aMunroe, Patricia, B1 aMusk, Arthur, W1 aNarisu, Narisu1 aNavis, Gerjan1 aNicholson, George1 aNohr, Ellen, A1 aOng, Ken, K1 aOostra, Ben, A1 aPalmer, Colin, N A1 aPalotie, Aarno1 aPeden, John, F1 aPedersen, Nancy1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aProkopenko, Inga1 aPütter, Carolin1 aRadhakrishnan, Aparna1 aRaitakari, Olli1 aRendon, Augusto1 aRivadeneira, Fernando1 aRudan, Igor1 aSaaristo, Timo, E1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSanna, Serena1 aSaramies, Jouko1 aSchipf, Sabine1 aSchreiber, Stefan1 aSchunkert, Heribert1 aShin, So-Youn1 aSignorini, Stefano1 aSinisalo, Juha1 aSkrobek, Boris1 aSoranzo, Nicole1 aStančáková, Alena1 aStark, Klaus1 aStephens, Jonathan, C1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStumvoll, Michael1 aSwift, Amy, J1 aTheodoraki, Eirini, V1 aThorand, Barbara1 aTrégouët, David-Alexandre1 aTremoli, Elena1 avan der Klauw, Melanie, M1 avan Meurs, Joyce, B J1 aVermeulen, Sita, H1 aViikari, Jorma1 aVirtamo, Jarmo1 aVitart, Veronique1 aWaeber, Gérard1 aWang, Zhaoming1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWinkelmann, Bernhard, R1 aWitteman, Jacqueline, C M1 aWolffenbuttel, Bruce, H R1 aWong, Andrew1 aWright, Alan, F1 aZillikens, Carola, M1 aAmouyel, Philippe1 aBoehm, Bernhard, O1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCupples, Adrienne, L1 aCusi, Daniele1 aDedoussis, George, V1 aErdmann, Jeanette1 aEriksson, Johan, G1 aFranks, Paul, W1 aFroguel, Philippe1 aGieger, Christian1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHingorani, Aroon1 aHinney, Anke1 aHofman, Albert1 aHovingh, Kees, G1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aJöckel, Karl-Heinz1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKiemeney, Lambertus, A1 aKuh, Diana1 aLaakso, Markku1 aLehtimäki, Terho1 aLevinson, Douglas, F1 aMartin, Nicholas, G1 aMetspalu, Andres1 aMorris, Andrew, D1 aNieminen, Markku, S1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aOuwehand, Willem, H1 aPalmer, Lyle, J1 aPenninx, Brenda1 aPower, Chris1 aProvince, Michael, A1 aPsaty, Bruce, M1 aQi, Lu1 aRauramaa, Rainer1 aRidker, Paul, M1 aRipatti, Samuli1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSnieder, Harold1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aTönjes, Anke1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aHarst, Pim1 aVollenweider, Peter1 aWallaschofski, Henri1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWichmann, H-Erich1 aWilson, James, F1 aAbecasis, Goncalo, R1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunian, Talin1 aHeid, Iris, M1 aHunter, David1 aKaplan, Robert, C1 aKarpe, Fredrik1 aMoffatt, Miriam, F1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPawitan, Yudi1 aSchadt, Eric, E1 aSchlessinger, David1 aSteinthorsdottir, Valgerdur1 aStrachan, David, P1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aVisscher, Peter, M1 aDi Blasio, Anna, Maria1 aHirschhorn, Joel, N1 aLindgren, Cecilia, M1 aMorris, Andrew, P1 aMeyre, David1 aScherag, Andre1 aMcCarthy, Mark, I1 aSpeliotes, Elizabeth, K1 aNorth, Kari, E1 aLoos, Ruth, J F1 aIngelsson, Erik uhttps://chs-nhlbi.org/node/615205845nas a2201189 4500008004100000022001400041245012300055210006900178260001300247300001300260490000700273520235900280653001202639653002002651653002002671653002602691653001702717653002102734653001802755653004002773653003002813653002202843653003302865653003802898653003402936653001302970653001102983653001502994653001203009653003603021653002403057653002803081653003103109100002003140700002003160700002603180700002503206700002403231700002803255700002303283700002203306700002403328700001803352700001903370700002003389700002103409700001903430700001903449700001103468700002303479700002903502700002503531700002103556700002403577700001803601700002003619700002103639700002303660700002503683700002203708700002303730700001903753700001403772700002503786700001903811700002003830700002103850700001903871700001703890700002803907700001903935700002103954700002103975700002003996700002404016700002104040700002804061700001704089700003104106700002004137700002104157700002004178700002004198700002504218700002204243700002404265700002104289700002304310700002004333700002804353700002204381700002004403700002504423700002204448700002504470700003004495700002004525700002204545700002504567700002704592856003604619 2013 eng d a1938-320700aGenome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake.0 aGenomewide metaanalysis of observational studies shows common ge c2013 Jun a1395-4020 v973 aBACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).
CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
10aAlleles10aAtherosclerosis10aBody Mass Index10aDietary Carbohydrates10aDietary Fats10aDietary Proteins10aEnergy Intake10aEuropean Continental Ancestry Group10aFibroblast Growth Factors10aFollow-Up Studies10aGene-Environment Interaction10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLife Style10aObesity10aPolymorphism, Single Nucleotide10aProspective Studies10aQuantitative Trait Loci10aSurveys and Questionnaires1 aTanaka, Toshiko1 aNgwa, Julius, S1 avan Rooij, Frank, J A1 aZillikens, Carola, M1 aWojczynski, Mary, K1 aFrazier-Wood, Alexis, C1 aHouston, Denise, K1 aKanoni, Stavroula1 aLemaitre, Rozenn, N1 aLuan, Jian'an1 aMikkilä, Vera1 aRenstrom, Frida1 aSonestedt, Emily1 aZhao, Jing Hua1 aChu, Audrey, Y1 aQi, Lu1 aChasman, Daniel, I1 aOtto, Marcia, C de Olive1 aDhurandhar, Emily, J1 aFeitosa, Mary, F1 aJohansson, Ingegerd1 aKhaw, Kay-Tee1 aLohman, Kurt, K1 aManichaikul, Ani1 aMcKeown, Nicola, M1 aMozaffarian, Dariush1 aSingleton, Andrew1 aStirrups, Kathleen1 aViikari, Jorma1 aYe, Zheng1 aBandinelli, Stefania1 aBarroso, Inês1 aDeloukas, Panos1 aForouhi, Nita, G1 aHofman, Albert1 aLiu, Yongmei1 aLyytikäinen, Leo-Pekka1 aNorth, Kari, E1 aDimitriou, Maria1 aHallmans, Göran1 aKähönen, Mika1 aLangenberg, Claudia1 aOrdovas, Jose, M1 aUitterlinden, André, G1 aHu, Frank, B1 aKalafati, Ioanna-Panagiota1 aRaitakari, Olli1 aFranco, Oscar, H1 aJohnson, Andrew1 aEmilsson, Valur1 aSchrack, Jennifer, A1 aSemba, Richard, D1 aSiscovick, David, S1 aArnett, Donna, K1 aBorecki, Ingrid, B1 aFranks, Paul, W1 aKritchevsky, Stephen, B1 aLehtimäki, Terho1 aLoos, Ruth, J F1 aOrho-Melander, Marju1 aRotter, Jerome, I1 aWareham, Nicholas, J1 aWitteman, Jacqueline, C M1 aFerrucci, Luigi1 aDedoussis, George1 aCupples, Adrienne, L1 aNettleton, Jennifer, A uhttps://chs-nhlbi.org/node/616304041nas a2200805 4500008004100000022001400041245010600055210006900161260001300230300001000243490000800253520176400261653001002025653001302035653003202048653003202080653001902112653001102131653003402142653003802176653001102214653002702225653000902252653000902261653002202270653001602292653003602308653004302344100002102387700002002408700002202428700001602450700001802466700001902484700001602503700002102519700001802540700001702558700002402575700002302599700002002622700001202642700001802654700002302672700001902695700002402714700002102738700001902759700001902778700002202797700002202819700001802841700003202859700002402891700002302915700002002938700002002958700002102978700001502999700001903014700002003033700001803053700002003071700002103091700002303112700002003135700002003155700002403175856003603199 2013 eng d a1432-120300aGenome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.0 aGenomewide study identifies two loci associated with lung functi c2013 Jan a79-900 v1323 aAccelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
10aAdult10aAnkyrins10aChromosomes, Human, Pair 1010aChromosomes, Human, Pair 1410aCohort Studies10aFemale10aGenome-Wide Association Study10aHepatocyte Nuclear Factor 3-alpha10aHumans10aLinkage Disequilibrium10aLung10aMale10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aPulmonary Disease, Chronic Obstructive1 aHansel, Nadia, N1 aRuczinski, Ingo1 aRafaels, Nicholas1 aSin, Don, D1 aDaley, Denise1 aMalinina, Alla1 aHuang, Lili1 aSandford, Andrew1 aMurray, Tanda1 aKim, Yoonhee1 aVergara, Candelaria1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aLi, Guo1 aElliott, Mark1 aAminuddin, Farzian1 aDupuis, Josée1 aO'Connor, George, T1 aDoheny, Kimberly1 aScott, Alan, F1 aBoezen, Marike1 aPostma, Dirkje, S1 aSmolonska, Joanna1 aZanen, Pieter1 aHoesein, Firdaus, A Mohamed1 ade Koning, Harry, J1 aCrystal, Ronald, G1 aTanaka, Toshiko1 aFerrucci, Luigi1 aSilverman, Edwin1 aWan, Emily1 aVestbo, Jorgen1 aLomas, David, A1 aConnett, John1 aWise, Robert, A1 aNeptune, Enid, R1 aMathias, Rasika, A1 aParé, Peter, D1 aBeaty, Terri, H1 aBarnes, Kathleen, C uhttps://chs-nhlbi.org/node/606811009nas a2203553 4500008004100000022001400041245011100055210006900166260001300235300001100248490000700259520106100266653001201327653002501339653001901364653001701383653003401400653002801434653001501462653001101477653003601488653003601524653002801560100002201588700002201610700001601632700002701648700001901675700002001694700001901714700002301733700001601756700002501772700002101797700001801818700001801836700001501854700001901869700001901888700002001907700001601927700001901943700002101962700002301983700002502006700002502031700001802056700001502074700002202089700002402111700001602135700002102151700002102172700001802193700001802211700002302229700002102252700002302273700002202296700002002318700002202338700002502360700002302385700002002408700001702428700002002445700002502465700002202490700001902512700002102531700001802552700002502570700002102595700002202616700002202638700002102660700003102681700001302712700002302725700001602748700001602764700001802780700002502798700001902823700001902842700002502861700002102886700002502907700002002932700001902952700002502971700001802996700002403014700002103038700001603059700001903075700002003094700001803114700001803132700002203150700002003172700002703192700001903219700002203238700002403260700002203284700002803306700002203334700002303356700002103379700001903400700002203419700002803441700002403469700002203493700001903515700002103534700001903555700001603574700002003590700001803610700002303628700002203651700001703673700001803690700001703708700001803725700002303743700002403766700002103790700001703811700002103828700002403849700002103873700002603894700002503920700002403945700002203969700002503991700002204016700002304038700002504061700002404086700003004110700001704140700001604157700002604173700003004199700001604229700002004245700002004265700001904285700001804304700002604322700002004348700002004368700001904388700002504407700001704432700001804449700002104467700002004488700001904508700002004527700002504547700002104572700002004593700002004613700001804633700002604651700002304677700002804700700002404728700002004752700002304772700002004795700001904815700002304834700002104857700003004878700001704908700001704925700002004942700001904962700002304981700002305004700002305027700002305050700001705073700002105090700002205111700002105133700002005154700001905174700002405193700001505217700001505232700002405247700001905271700002305290700002405313700002205337700002205359700002905381700001705410700002305427700002005450700002905470700002505499700002105524700002305545700002105568700002505589700002205614700001705636700001805653700002005671700002005691700001905711700002105730700002505751700001605776700002005792700001905812700001705831700002305848700002105871700002205892700001505914700002705929700001605956700002005972700002705992700003006019700002206049700001706071700002206088700002206110700002606132700002506158700001806183700002406201700001906225700002106244700001106265700002306276700001806299700001906317700002006336700001606356700002006372700002006392700002206412700002306434700001906457700002206476700002106498700002306519700002406542700002806566700002206594700002806616700001906644700001906663700002406682700002006706700002106726700001906747700002106766700002306787700002006810700001706830700002206847700002206869700001806891700002206909700002906931700002406960700002606984700002107010700001907031700002507050700002407075700002107099700002507120700002407145700002007169700002007189700002007209700002207229700002007251710002807271710002607299710002307325710002407348710002207372710002507394856003607419 2013 eng d a1546-171800aIdentification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.0 aIdentification of heart rateassociated loci and their effects on c2013 Jun a621-310 v453 aElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
10aAnimals10aArrhythmias, Cardiac10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHeart Rate10aHumans10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aHoed, Marcel, den1 aEijgelsheim, Mark1 aEsko, Tõnu1 aBrundel, Bianca, J J M1 aPeal, David, S1 aEvans, David, M1 aNolte, Ilja, M1 aSegrè, Ayellet, V1 aHolm, Hilma1 aHandsaker, Robert, E1 aWestra, Harm-Jan1 aJohnson, Toby1 aIsaacs, Aaron1 aYang, Jian1 aLundby, Alicia1 aZhao, Jing Hua1 aKim, Young, Jin1 aGo, Min Jin1 aAlmgren, Peter1 aBochud, Murielle1 aBoucher, Gabrielle1 aCornelis, Marilyn, C1 aGudbjartsson, Daniel1 aHadley, David1 aHarst, Pim1 aHayward, Caroline1 aHeijer, Martin, den1 aIgl, Wilmar1 aJackson, Anne, U1 aKutalik, Zoltán1 aLuan, Jian'an1 aKemp, John, P1 aKristiansson, Kati1 aLadenvall, Claes1 aLorentzon, Mattias1 aMontasser, May, E1 aNjajou, Omer, T1 aO'Reilly, Paul, F1 aPadmanabhan, Sandosh1 aSt Pourcain, Beate1 aRankinen, Tuomo1 aSalo, Perttu1 aTanaka, Toshiko1 aTimpson, Nicholas, J1 aVitart, Veronique1 aWaite, Lindsay1 aWheeler, William1 aZhang, Weihua1 aDraisma, Harmen, H M1 aFeitosa, Mary, F1 aKerr, Kathleen, F1 aLind, Penelope, A1 aMihailov, Evelin1 aOnland-Moret, Charlotte, N1 aSong, Ci1 aWeedon, Michael, N1 aXie, Weijia1 aYengo, Loic1 aAbsher, Devin1 aAlbert, Christine, M1 aAlonso, Alvaro1 aArking, Dan, E1 ade Bakker, Paul, I W1 aBalkau, Beverley1 aBarlassina, Cristina1 aBenaglio, Paola1 aBis, Joshua, C1 aBouatia-Naji, Nabila1 aBrage, Søren1 aChanock, Stephen, J1 aChines, Peter, S1 aChung, Mina1 aDarbar, Dawood1 aDina, Christian1 aDörr, Marcus1 aElliott, Paul1 aFelix, Stephan, B1 aFischer, Krista1 aFuchsberger, Christian1 aGeus, Eco, J C1 aGoyette, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aHofman, Albert1 aHolewijn, Suzanne1 aHoogstra-Berends, Femke1 aHottenga, Jouke-Jan1 aJensen, Majken, K1 aJohansson, Asa1 aJunttila, Juhani1 aKääb, Stefan1 aKanon, Bart1 aKetkar, Shamika1 aKhaw, Kay-Tee1 aKnowles, Joshua, W1 aKooner, Angrad, S1 aKors, Jan, A1 aKumari, Meena1 aMilani, Lili1 aLaiho, Päivi1 aLakatta, Edward, G1 aLangenberg, Claudia1 aLeusink, Maarten1 aLiu, Yongmei1 aLuben, Robert, N1 aLunetta, Kathryn, L1 aLynch, Stacey, N1 aMarkus, Marcello, R P1 aMarques-Vidal, Pedro1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcCarroll, Steven, A1 aMedland, Sarah, E1 aMiller, Kathryn, A1 aMontgomery, Grant, W1 aMorrison, Alanna, C1 aMüller-Nurasyid, Martina1 aNavarro, Pau1 aNelis, Mari1 aO'Connell, Jeffrey, R1 aO'Donnell, Christopher, J1 aOng, Ken, K1 aNewman, Anne, B1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aRao, Dabeeru, C1 aRing, Susan, M1 aRossin, Elizabeth, J1 aRudan, Diana1 aSanna, Serena1 aScott, Robert, A1 aSehmi, Jaban, S1 aSharp, Stephen1 aShin, Jordan, T1 aSingleton, Andrew, B1 aSmith, Albert, V1 aSoranzo, Nicole1 aSpector, Tim, D1 aStewart, Chip1 aStringham, Heather, M1 aTarasov, Kirill, V1 aUitterlinden, André, G1 aVandenput, Liesbeth1 aHwang, Shih-Jen1 aWhitfield, John, B1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aWong, Andrew1 aWong, Quenna1 aJamshidi, Yalda1 aZitting, Paavo1 aBoer, Jolanda, M A1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aEkelund, Ulf1 aForouhi, Nita, G1 aFroguel, Philippe1 aHingorani, Aroon1 aIngelsson, Erik1 aKivimaki, Mika1 aKronmal, Richard, A1 aKuh, Diana1 aLind, Lars1 aMartin, Nicholas, G1 aOostra, Ben, A1 aPedersen, Nancy, L1 aQuertermous, Thomas1 aRotter, Jerome, I1 aSchouw, Yvonne, T1 aVerschuren, W, M Monique1 aWalker, Mark1 aAlbanes, Demetrius1 aArnar, David, O1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBoehnke, Michael1 ade Boer, Rudolf, A1 aBouchard, Claude1 aCaulfield, W, L Mark1 aChambers, John, C1 aCurhan, Gary1 aCusi, Daniele1 aEriksson, Johan1 aFerrucci, Luigi1 aGilst, Wiek, H1 aGlorioso, Nicola1 ade Graaf, Jacqueline1 aGroop, Leif1 aGyllensten, Ulf1 aHsueh, Wen-Chi1 aHu, Frank, B1 aHuikuri, Heikki, V1 aHunter, David, J1 aIribarren, Carlos1 aIsomaa, Bo1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKiemeney, Lambertus, A1 avan der Klauw, Melanie, M1 aKooner, Jaspal, S1 aKraft, Peter1 aIacoviello, Licia1 aLehtimäki, Terho1 aLokki, Marja-Liisa, L1 aMitchell, Braxton, D1 aNavis, Gerjan1 aNieminen, Markku, S1 aOhlsson, Claes1 aPoulter, Neil, R1 aQi, Lu1 aRaitakari, Olli, T1 aRimm, Eric, B1 aRioux, John, D1 aRizzi, Federica1 aRudan, Igor1 aSalomaa, Veikko1 aSever, Peter, S1 aShields, Denis, C1 aShuldiner, Alan, R1 aSinisalo, Juha1 aStanton, Alice, V1 aStolk, Ronald, P1 aStrachan, David, P1 aTardif, Jean-Claude1 aThorsteinsdottir, Unnur1 aTuomilehto, Jaako1 avan Veldhuisen, Dirk, J1 aVirtamo, Jarmo1 aViikari, Jorma1 aVollenweider, Peter1 aWaeber, Gérard1 aWiden, Elisabeth1 aCho, Yoon Shin1 aOlsen, Jesper, V1 aVisscher, Peter, M1 aWiller, Cristen1 aFranke, Lude1 aErdmann, Jeanette1 aThompson, John, R1 aPfeufer, Arne1 aSotoodehnia, Nona1 aNewton-Cheh, Christopher1 aEllinor, Patrick, T1 aStricker, Bruno, H Ch1 aMetspalu, Andres1 aPerola, Markus1 aBeckmann, Jacques, S1 aSmith, George Davey1 aStefansson, Kari1 aWareham, Nicholas, J1 aMunroe, Patricia, B1 aSibon, Ody, C M1 aMilan, David, J1 aSnieder, Harold1 aSamani, Nilesh, J1 aLoos, Ruth, J F1 aGlobal BPgen Consortium1 aCARDIoGRAM consortium1 aPR GWAS Consortium1 aQRS GWAS Consortium1 aQT-IGC consortium1 aCHARGE-AF Consortium uhttps://chs-nhlbi.org/node/801504392nas a2200841 4500008004100000022001400041245013900055210006900194260000900263300001100272490000600283520190900289653002202198653002402220653003802244653003402282653001302316653001102329653003902340653002502379653002602404653003602430653001302466653001702479653002902496100002702525700002102552700002302573700003202596700002302628700001702651700001902668700001402687700001902701700002102720700002102741700002302762700002402785700002402809700001902833700002002852700002002872700002302892700002402915700001902939700001602958700001702974700001902991700002203010700002203032700001903054700002003073700002203093700002203115700002103137700001703158700001703175700001903192700002803211700002403239700001603263700002803279700002603307700001903333700002103352700001803373700002503391700001803416700001603434700001903450710004503469856003603514 2013 eng d a1932-620300aInsights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.0 aInsights into the genetic architecture of early stage agerelated c2013 ae538300 v83 aGenetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
10aApolipoproteins E10aComplement Factor H10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aKruppel-Like Transcription Factors10aMacular Degeneration10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aProteins10aRisk Factors10aZinc Finger Protein Gli31 aHolliday, Elizabeth, G1 aSmith, Albert, V1 aCornes, Belinda, K1 aBuitendijk, Gabriëlle, H S1 aJensen, Richard, A1 aSim, Xueling1 aAspelund, Thor1 aAung, Tin1 aBaird, Paul, N1 aBoerwinkle, Eric1 aCheng, Ching, Yu1 aDuijn, Cornelia, M1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aHarris, Tamara1 aHewitt, Alex, W1 aInouye, Michael1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore1 aLi, Xiaohui1 aLiew, Gerald1 aLumley, Thomas1 aMcElduff, Patrick1 aMcKnight, Barbara1 aMitchell, Paul1 aPsaty, Bruce, M1 aRochtchina, Elena1 aRotter, Jerome, I1 aScott, Rodney, J1 aTay, Wanting1 aTaylor, Kent1 aTeo, Yik, Ying1 aUitterlinden, André, G1 aViswanathan, Ananth1 aXie, Sophia1 aVingerling, Johannes, R1 aKlaver, Caroline, C W1 aTai, Shyong, E1 aSiscovick, David1 aKlein, Ronald1 aCotch, Mary, Frances1 aWong, Tien, Y1 aAttia, John1 aWang, Jie, Jin1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/587503673nas a2200601 4500008004100000022001400041245015800055210006900213260000900282300000700291490000700298520191500305653001102220653002602231653001802257653003402275653001102309653001102320653000902331653003602340653002202376100002002398700001902418700002202437700002102459700002102480700002002501700002402521700002202545700002102567700002102588700002202609700002402631700001902655700002302674700002202697700002102719700002102740700001602761700002202777700002602799700002102825700002302846700002402869700002302893700002402916700002202940700001902962700001902981700002003000710001503020856003603035 2013 eng d a1471-215600aInvestigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study.0 aInvestigation of genebysex interactions for lipid traits in dive c2013 a330 v143 aBACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.
RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.
CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.
10aFemale10aGenetic Heterogeneity10aGenome, Human10aGenome-Wide Association Study10aHumans10aLipids10aMale10aPolymorphism, Single Nucleotide10aPopulation Groups1 aTaylor, Kira, C1 aCarty, Cara, L1 aDumitrescu, Logan1 aBůzková, Petra1 aCole, Shelley, A1 aHindorff, Lucia1 aSchumacher, Fred, R1 aWilkens, Lynne, R1 aShohet, Ralph, V1 aQuibrera, Miguel1 aJohnson, Karen, C1 aHenderson, Brian, E1 aHaessler, Jeff1 aFranceschini, Nora1 aEaton, Charles, B1 aDuggan, David, J1 aCochran, Barbara1 aCheng, Iona1 aCarlson, Chris, S1 aBrown-Gentry, Kristin1 aAnderson, Garnet1 aAmbite, Jose, Luis1 aHaiman, Christopher1 aLe Marchand, Loïc1 aKooperberg, Charles1 aCrawford, Dana, C1 aBuyske, Steven1 aNorth, Kari, E1 aFornage, Myriam1 aPAGE Study uhttps://chs-nhlbi.org/node/662705259nas a2201129 4500008004100000022001400041245007400055210006900129260001300198300001000211490000700221520208800228653002702316653001502343653001002358653000902368653002202377653002202399653001902421653001902440653001102459653001102470653001702481653003802498653002202536653003402558653001102592653000902603653001602612653003602628653001102664653001602675100002702691700002202718700001902740700002502759700002002784700002002804700002102824700001702845700002102862700002502883700001902908700002002927700002002947700001902967700001802986700001803004700002003022700001903042700002003061700002203081700002403103700002003127700002403147700002003171700001903191700002803210700002303238700002203261700002703283700002803310700002503338700002103363700002003384700002103404700002603425700001703451700002103468700002503489700002003514700001903534700002003553700001903573700002203592700001603614700002703630700002103657700002003678700001903698700002003717700002103737700001603758700001903774700002203793700001603815700001903831700002003850700002003870700002003890710002703910710004503937710005103982710001504033710004504048856003604093 2013 eng d a1531-824900aIschemic stroke is associated with the ABO locus: the EuroCLOT study.0 aIschemic stroke is associated with the ABO locus the EuroCLOT st c2013 Jan a16-310 v733 aOBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).
RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).
INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
10aABO Blood-Group System10aAdolescent10aAdult10aAged10aAged, 80 and over10aBlood Coagulation10aBrain Ischemia10aCohort Studies10aEurope10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aStroke10aYoung Adult1 aWilliams, Frances, M K1 aCarter, Angela, M1 aHysi, Pirro, G1 aSurdulescu, Gabriela1 aHodgkiss, Dylan1 aSoranzo, Nicole1 aTraylor, Matthew1 aBevan, Steve1 aDichgans, Martin1 aRothwell, Peter, M W1 aSudlow, Cathie1 aFarrall, Martin1 aSilander, Kaisa1 aKaunisto, Mari1 aWagner, Peter1 aSaarela, Olli1 aKuulasmaa, Kari1 aVirtamo, Jarmo1 aSalomaa, Veikko1 aAmouyel, Philippe1 aArveiler, Dominique1 aFerrieres, Jean1 aWiklund, Per-Gunnar1 aIkram, Arfan, M1 aHofman, Albert1 aBoncoraglio, Giorgio, B1 aParati, Eugenio, A1 aHelgadottir, Anna1 aGretarsdottir, Solveig1 aThorsteinsdottir, Unnur1 aThorleifsson, Gudmar1 aStefansson, Kari1 aSeshadri, Sudha1 aDeStefano, Anita1 aGschwendtner, Andreas1 aPsaty, Bruce1 aLongstreth, Will1 aMitchell, Braxton, D1 aCheng, Yu-Ching1 aClarke, Robert1 aFerrario, Marco1 aBis, Joshua, C1 aLevi, Christopher1 aAttia, John1 aHolliday, Elizabeth, G1 aScott, Rodney, J1 aFornage, Myriam1 aSharma, Pankaj1 aFurie, Karen, L1 aRosand, Jonathan1 aNalls, Mike1 aMeschia, James1 aMosely, Thomas, H1 aEvans, Alun1 aPalotie, Aarno1 aMarkus, Hugh, S1 aGrant, Peter, J1 aSpector, Tim, D1 aEuroCLOT Investigators1 aWellcome Trust Case Control Consortium 21 aMOnica Risk, Genetics, Archiving and Monograph1 aMetaStroke1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/610809008nas a2202809 4500008004100000022001400041245010800055210006900163260001300232300001000245490000700255520108900262653002201351653002001373653002501393653001901418653001701437653003801454653003401492653001101526653002701537653001201564653003601576100001901612700001801631700002001649700002001669700002101689700002101710700001901731700002601750700002401776700002401800700001801824700002201842700002501864700001801889700001201907700001701919700001701936700001801953700002201971700001601993700002402009700001902033700002402052700002202076700002502098700002202123700002102145700002002166700002102186700001602207700002202223700002202245700001802267700001802285700001802303700001502321700002102336700002802357700002402385700002002409700003202429700002002461700002202481700002102503700001302524700002302537700002902560700002002589700001702609700002302626700001902649700002202668700002402690700002302714700002202737700002302759700002302782700002402805700002202829700001702851700002402868700001802892700002102910700002102931700002302952700002202975700001702997700001803014700001603032700002103048700002103069700001703090700002403107700002603131700002003157700002603177700001803203700002803221700001503249700002003264700002203284700001603306700002003322700002903342700002203371700001803393700002503411700002203436700002703458700002303485700002903508700002103537700002803558700002603586700002203612700002503634700003103659700002803690700002203718700002003740700002103760700002303781700002103804700001903825700003203844700002803876700002303904700002003927700001903947700002203966700002403988700002704012700002804039700001904067700002104086700002304107700001904130700002204149700001504171700001904186700002104205700002104226700001904247700001804266700002304284700001904307700001404326700001904340700001404359700002304373700002104396700002604417700002204443700002004465700001904485700002004504700002804524700001704552700002104569700001804590700002104608700002104629700002204650700002104672700002304693700002404716700002204740700001904762700002404781700002304805700002004828700001804848700002204866700001804888700002004906700002704926700002204953700002304975700001504998700001405013700002005027700001705047700001905064700002005083700002205103700002505125700002405150700002105174700002405195700001905219700002505238700002305263700001505286700002205301700002405323700002205347700002705369700002005396700002105416700001905437700002405456700002405480700002005504700001905524700002305543700002505566700002205591700002505613700002405638700002505662700002305687700001905710700002105729700001905750700001505769700002005784700002305804700002005827700001805847700002305865700002405888700002805912700002405940700002005964700002405984700002006008700001906028700002706047710002106074710002106095710002606116710002006142856003606162 2013 eng d a1546-171800aA meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.0 ametaanalysis identifies new loci associated with body mass index c2013 Jun a690-60 v453 aGenome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
10aAfrican Americans10aBody Mass Index10aCase-Control Studies10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aObesity10aPolymorphism, Single Nucleotide1 aMonda, Keri, L1 aChen, Gary, K1 aTaylor, Kira, C1 aPalmer, Cameron1 aEdwards, Todd, L1 aLange, Leslie, A1 aC Y Ng, Maggie1 aAdeyemo, Adebowale, A1 aAllison, Matthew, A1 aBielak, Lawrence, F1 aChen, Guanjie1 aGraff, Mariaelisa1 aIrvin, Marguerite, R1 aRhie, Suhn, K1 aLi, Guo1 aLiu, Yongmei1 aLiu, Youfang1 aLu, Yingchang1 aNalls, Michael, A1 aSun, Yan, V1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aAldrich, Melinda, C1 aAdemola, Adeyinka1 aAmos, Christopher, I1 aBandera, Elisa, V1 aBock, Cathryn, H1 aBritton, Angela1 aBroeckel, Ulrich1 aCai, Quiyin1 aCaporaso, Neil, E1 aCarlson, Chris, S1 aCarpten, John1 aCasey, Graham1 aChen, Wei-Min1 aChen, Fang1 aChen, Yii-der, I1 aChiang, Charleston, W K1 aCoetzee, Gerhard, A1 aDemerath, Ellen1 aDeming-Halverson, Sandra, L1 aDriver, Ryan, W1 aDubbert, Patricia1 aFeitosa, Mary, F1 aFeng, Ye1 aFreedman, Barry, I1 aGillanders, Elizabeth, M1 aGottesman, Omri1 aGuo, Xiuqing1 aHaritunians, Talin1 aHarris, Tamara1 aHarris, Curtis, C1 aHennis, Anselm, J M1 aHernandez, Dena, G1 aMcNeill, Lorna, H1 aHoward, Timothy, D1 aHoward, Barbara, V1 aHoward, Virginia, J1 aJohnson, Karen, C1 aKang, Sun, J1 aKeating, Brendan, J1 aKolb, Suzanne1 aKuller, Lewis, H1 aKutlar, Abdullah1 aLangefeld, Carl, D1 aLettre, Guillaume1 aLohman, Kurt1 aLotay, Vaneet1 aLyon, Helen1 aManson, JoAnn, E1 aMaixner, William1 aMeng, Yan, A1 aMonroe, Kristine, R1 aMorhason-Bello, Imran1 aMurphy, Adam, B1 aMychaleckyj, Josyf, C1 aNadukuru, Raj1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aWu, Suh-Yuh1 aLeske, Cristina1 aNeslund-Dudas, Christine1 aNeuhouser, Marian1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgunniyi, Adesola1 aOgundiran, Temidayo, O1 aOjengbede, Oladosu1 aOlopade, Olufunmilayo, I1 aPalmer, Julie, R1 aRuiz-Narvaez, Edward, A1 aPalmer, Nicholette, D1 aPress, Michael, F1 aRampersaud, Evandine1 aRasmussen-Torvik, Laura, J1 aRodriguez-Gil, Jorge, L1 aSalako, Babatunde1 aSchadt, Eric, E1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSiscovick, David1 aSmith, Shad, B1 aWassertheil-Smoller, Sylvia1 aSpeliotes, Elizabeth, K1 aSpitz, Margaret, R1 aSucheston, Lara1 aTaylor, Herman1 aTayo, Bamidele, O1 aTucker, Margaret, A1 aVan Den Berg, David, J1 aEdwards, Digna, R Velez1 aWang, Zhaoming1 aWiencke, John, K1 aWinkler, Thomas, W1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYang, James, J1 aLevin, Albert, M1 aYoung, Taylor, R1 aZakai, Neil, A1 aCushman, Mary1 aZanetti, Krista, A1 aZhao, Jing Hua1 aZhao, Wei1 aZheng, Yonglan1 aZhou, Jie1 aZiegler, Regina, G1 aZmuda, Joseph, M1 aFernandes, Jyotika, K1 aGilkeson, Gary, S1 aKamen, Diane, L1 aHunt, Kelly, J1 aSpruill, Ida, J1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aArnett, Donna, K1 aAtwood, Larry1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBorecki, Ingrid, B1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBurke, Gregory1 aChanock, Stephen, J1 aCooper, Richard, S1 aDing, Jingzhong1 aDuggan, David1 aEvans, Michele, K1 aFox, Caroline1 aGarvey, Timothy1 aBradfield, Jonathan, P1 aHakonarson, Hakon1 aGrant, Struan, F A1 aHsing, Ann1 aChu, Lisa1 aHu, Jennifer, J1 aHuo, Dezheng1 aIngles, Sue, A1 aJohn, Esther, M1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKardia, Sharon, L R1 aKittles, Rick, A1 aGoodman, Phyllis, J1 aKlein, Eric, A1 aKolonel, Laurence, N1 aLe Marchand, Loïc1 aLiu, Simin1 aMcKnight, Barbara1 aMillikan, Robert, C1 aMosley, Thomas, H1 aPadhukasahasram, Badri1 aWilliams, Keoki1 aPatel, Sanjay, R1 aPeters, Ulrike1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRotimi, Charles, N1 aRybicki, Benjamin, A1 aSale, Michèle, M1 aSchreiner, Pamela, J1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aStanford, Janet, L1 aStrom, Sara, S1 aThun, Michael, J1 aVitolins, Mara1 aZheng, Wei1 aMoore, Jason, H1 aWilliams, Scott, M1 aKetkar, Shamika1 aZhu, Xiaofeng1 aZonderman, Alan, B1 aKooperberg, Charles1 aPapanicolaou, George, J1 aHenderson, Brian, E1 aReiner, Alex, P1 aHirschhorn, Joel, N1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aNABEC Consortium1 aUKBEC Consortium1 aBioBank Japan Project1 aAGEN Consortium uhttps://chs-nhlbi.org/node/607806851nas a2202401 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2013 eng d a1546-171800aMeta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.0 aMetaanalysis of 74046 individuals identifies 11 new susceptibili c2013 Dec a1452-80 v453 aEleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
10aAge of Onset10aAged10aAged, 80 and over10aAlzheimer Disease10aCase-Control Studies10aCohort Studies10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aLambert, J, C1 aIbrahim-Verbaas, C, A1 aHarold, D1 aNaj, A, C1 aSims, R1 aBellenguez, C1 aDeStafano, A, L1 aBis, J C1 aBeecham, G, W1 aGrenier-Boley, B1 aRusso, G1 aThorton-Wells, T, A1 aJones, N1 aSmith, A V1 aChouraki, V1 aThomas, C1 aIkram, M, A1 aZelenika, D1 aVardarajan, B, N1 aKamatani, Y1 aLin, C, F1 aGerrish, A1 aSchmidt, H1 aKunkle, B1 aDunstan, M, L1 aRuiz, A1 aBihoreau, M, T1 aChoi, S, H1 aReitz, C1 aPasquier, F1 aCruchaga, C1 aCraig, D1 aAmin, N1 aBerr, C1 aLopez, O, L1 aDe Jager, P, L1 aDeramecourt, V1 aJohnston, J, A1 aEvans, D1 aLovestone, S1 aLetenneur, L1 aMorón, F, J1 aRubinsztein, D, C1 aEiriksdottir, G1 aSleegers, K1 aGoate, A, M1 aFiévet, N1 aHuentelman, M, W1 aGill, M1 aBrown, K1 aKamboh, M, I1 aKeller, L1 aBarberger-Gateau, P1 aMcGuiness, B1 aLarson, E, B1 aGreen, R1 aMyers, A, J1 aDufouil, C1 aTodd, S1 aWallon, D1 aLove, S1 aRogaeva, E1 aGallacher, J1 aSt George-Hyslop, P1 aClarimon, J1 aLleo, A1 aBayer, A1 aTsuang, D, W1 aYu, L1 aTsolaki, M1 aBossù, P1 aSpalletta, G1 aProitsi, P1 aCollinge, J1 aSorbi, S1 aSanchez-Garcia, F1 aFox, N, C1 aHardy, J1 aNaranjo, M, C Deniz1 aBosco, P1 aClarke, R1 aBrayne, C1 aGalimberti, D1 aMancuso, M1 aMatthews, F1 aMoebus, S1 aMecocci, P1 aDel Zompo, M1 aMaier, W1 aHampel, H1 aPilotto, A1 aBullido, M1 aPanza, F1 aCaffarra, P1 aNacmias, B1 aGilbert, J, R1 aMayhaus, M1 aLannefelt, L1 aHakonarson, H1 aPichler, S1 aCarrasquillo, M, M1 aIngelsson, M1 aBeekly, D1 aAlvarez, V1 aZou, F1 aValladares, O1 aYounkin, S, G1 aCoto, E1 aHamilton-Nelson, K, L1 aGu, W1 aRazquin, C1 aPastor, P1 aMateo, I1 aOwen, M, J1 aFaber, K, M1 aJonsson, P, V1 aCombarros, O1 aO'Donovan, M, C1 aCantwell, L, B1 aSoininen, H1 aBlacker, D1 aMead, S1 aMosley, T, H1 aBennett, D, A1 aHarris, T B1 aFratiglioni, L1 aHolmes, C1 ade Bruijn, R, F1 aPassmore, P1 aMontine, T, J1 aBettens, K1 aRotter, J I1 aBrice, A1 aMorgan, K1 aForoud, T, M1 aKukull, W, A1 aHannequin, D1 aPowell, J, F1 aNalls, M, A1 aRitchie, K1 aLunetta, K, L1 aKauwe, J, S1 aBoerwinkle, E1 aRiemenschneider, M1 aBoada, M1 aHiltuenen, M1 aMartin, E, R1 aSchmidt, R1 aRujescu, D1 aWang, L, S1 aDartigues, J, F1 aMayeux, R1 aTzourio, C1 aHofman, A1 aNöthen, M, M1 aGraff, C1 aPsaty, B M1 aJones, L1 aHaines, J, L1 aHolmans, P, A1 aLathrop, M1 aPericak-Vance, M, A1 aLauner, L J1 aFarrer, L, A1 aDuijn, C M1 aVan Broeckhoven, C1 aMoskvina, V1 aSeshadri, S1 aWilliams, J1 aSchellenberg, G, D1 aAmouyel, P1 aEuropean Alzheimer's Disease Initiative (EADI)1 aGenetic and Environmental Risk in Alzheimer's Disease1 aAlzheimer's Disease Genetic Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology uhttps://chs-nhlbi.org/node/615605590nas a2201609 4500008004100000022001400041245011100055210006900166260000900235300001300244490000600257520112100263653001201384653001901396653001701415653001201432653004001444653003101484653003401515653001601549653001101565653001101576653000901587653003601596100002601632700001801658700001601676700001701692700002001709700002601729700001901755700002301774700002201797700002101819700002101840700001901861700001801880700002401898700001201922700002001934700001801954700002001972700002201992700001702014700002002031700002502051700001902076700002102095700001802116700002502134700002202159700002002181700002202201700002402223700002202247700001902269700002202288700001902310700002002329700002102349700002102370700002402391700002202415700002402437700002002461700001902481700002402500700002202524700002002546700002202566700001802588700001802606700001702624700002102641700001902662700002002681700002202701700002502723700002002748700002502768700002102793700002202814700002402836700002302860700002202883700002302905700001702928700001902945700002202964700002302986700002803009700001503037700002103052700001903073700002003092700002203112700002103134700001903155700002803174700002603202700001703228700002003245700001903265700002303284700001803307700002103325700001803346700002303364700002403387700002103411700002003432700001903452700002203471700002003493700001503513700002003528700002103548700001603569700002103585700001903606700001803625700001903643700002003662700001703682700002203699700002203721700003003743700002003773700002003793700002503813700001903838700002103857700002103878710002403899710002103923856003603944 2013 eng d a1553-740400aMeta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.0 aMetaanalysis of genomewide association studies identifies six ne c2013 ae10037960 v93 aCalcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
10aAnimals10aBone and Bones10aBone Density10aCalcium10aEuropean Continental Ancestry Group10aGene Expression Regulation10aGenome-Wide Association Study10aHomeostasis10aHumans10aKidney10aMice10aPolymorphism, Single Nucleotide1 aO'Seaghdha, Conall, M1 aWu, Hongsheng1 aYang, Qiong1 aKapur, Karen1 aGuessous, Idris1 aZuber, Annie, Mercier1 aKöttgen, Anna1 aStoudmann, Candice1 aTeumer, Alexander1 aKutalik, Zoltán1 aMangino, Massimo1 aDehghan, Abbas1 aZhang, Weihua1 aEiriksdottir, Gudny1 aLi, Guo1 aTanaka, Toshiko1 aPortas, Laura1 aLopez, Lorna, M1 aHayward, Caroline1 aLohman, Kurt1 aMatsuda, Koichi1 aPadmanabhan, Sandosh1 aFirsov, Dmitri1 aSorice, Rossella1 aUlivi, Sheila1 aBrockhaus, Catharina1 aKleber, Marcus, E1 aMahajan, Anubha1 aErnst, Florian, D1 aGudnason, Vilmundur1 aLauner, Lenore, J1 aMace, Aurelien1 aBoerwinckle, Eric1 aArking, Dan, E1 aTanikawa, Chizu1 aNakamura, Yusuke1 aBrown, Morris, J1 aGaspoz, Jean-Michel1 aTheler, Jean-Marc1 aSiscovick, David, S1 aPsaty, Bruce, M1 aBergmann, Sven1 aVollenweider, Peter1 aVitart, Veronique1 aWright, Alan, F1 aZemunik, Tatijana1 aBoban, Mladen1 aKolcic, Ivana1 aNavarro, Pau1 aBrown, Edward, M1 aEstrada, Karol1 aDing, Jingzhong1 aHarris, Tamara, B1 aBandinelli, Stefania1 aHernandez, Dena1 aSingleton, Andrew, B1 aGirotto, Giorgia1 aRuggiero, Daniela1 ad'Adamo, Adamo, Pio1 aRobino, Antonietta1 aMeitinger, Thomas1 aMeisinger, Christa1 aDavies, Gail1 aStarr, John, M1 aChambers, John, C1 aBoehm, Bernhard, O1 aWinkelmann, Bernhard, R1 aHuang, Jie1 aMurgia, Federico1 aWild, Sarah, H1 aCampbell, Harry1 aMorris, Andrew, P1 aFranco, Oscar, H1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aVölker, Uwe1 aHannemann, Anke1 aBiffar, Reiner1 aHoffmann, Wolfgang1 aShin, So-Youn1 aLescuyer, Pierre1 aHenry, Hughes1 aSchurmann, Claudia1 aMunroe, Patricia, B1 aGasparini, Paolo1 aPirastu, Nicola1 aCiullo, Marina1 aGieger, Christian1 aMärz, Winfried1 aLind, Lars1 aSpector, Tim, D1 aSmith, Albert, V1 aRudan, Igor1 aWilson, James, F1 aPolasek, Ozren1 aDeary, Ian, J1 aPirastu, Mario1 aFerrucci, Luigi1 aLiu, Yongmei1 aKestenbaum, Bryan1 aKooner, Jaspal, S1 aWitteman, Jacqueline, C M1 aNauck, Matthias1 aKao, Linda, W H1 aWallaschofski, Henri1 aBonny, Olivier1 aFox, Caroline, S1 aBochud, Murielle1 aSUNLIGHT Consortium1 aGEFOS Consortium uhttps://chs-nhlbi.org/node/629105839nas a2201429 4500008004100000022001400041245013600055210006900191260000900260300001300269490000600282520178500288653001102073653003402084653001102118653002002129653001902149653000902168653001402177653002602191653003602217653002402253653002402277653001802301653001602319653001402335100002002349700001802369700002002387700002402407700002102431700002102452700002002473700001802493700002402511700002302535700001602558700001602574700002002590700001902610700002602629700002002655700002002675700001802695700002502713700002002738700002302758700002202781700002402803700002302827700002502850700001702875700002802892700001402920700001602934700002502950700002102975700002002996700002603016700001803042700001903060700003603079700002303115700001903138700002603157700001503183700002303198700002203221700002103243700002503264700002203289700002703311700001903338700001803357700002003375700002003395700002303415700002003438700002603458700001703484700001903501700001903520700002503539700002003564700001903584700002003603700002303623700002003646700003003666700002203696700002203718700002303740700001903763700001903782700002603801700002103827700001803848700002103866700001803887700002303905700002003928700002103948700001903969700002703988700002604015700002404041700002304065700002304088700002804111700001804139700002004157700003004177700002304207700002204230700002004252700002104272700002104293700001804314700002204332700001904354856003604373 2013 eng d a1553-740400aA meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.0 ametaanalysis of thyroidrelated traits reveals novel loci and gen c2013 ae10032660 v93 aThyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
10aFemale10aGenome-Wide Association Study10aHumans10aHyperthyroidism10aHypothyroidism10aMale10aPhenotype10aPolymorphism, Genetic10aPolymorphism, Single Nucleotide10aSex Characteristics10aSignal Transduction10aThyroid Gland10aThyrotropin10aThyroxine1 aPorcu, Eleonora1 aMedici, Marco1 aPistis, Giorgio1 aVolpato, Claudia, B1 aWilson, Scott, G1 aCappola, Anne, R1 aBos, Steffan, D1 aDeelen, Joris1 aHeijer, Martin, den1 aFreathy, Rachel, M1 aLahti, Jari1 aLiu, Chunyu1 aLopez, Lorna, M1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aTanaka, Toshiko1 aTrompet, Stella1 aArnold, Alice1 aBandinelli, Stefania1 aBeekman, Marian1 aBöhringer, Stefan1 aBrown, Suzanne, J1 aBuckley, Brendan, M1 aCamaschella, Clara1 ade Craen, Anton, J M1 aDavies, Gail1 ade Visser, Marieke, C H1 aFord, Ian1 aForsen, Tom1 aFrayling, Timothy, M1 aFugazzola, Laura1 aGögele, Martin1 aHattersley, Andrew, T1 aHermus, Ad, R1 aHofman, Albert1 aHouwing-Duistermaat, Jeanine, J1 aJensen, Richard, A1 aKajantie, Eero1 aKloppenburg, Margreet1 aLim, Ee, M1 aMasciullo, Corrado1 aMariotti, Stefano1 aMinelli, Cosetta1 aMitchell, Braxton, D1 aNagaraja, Ramaiah1 aNetea-Maier, Romana, T1 aPalotie, Aarno1 aPersani, Luca1 aPiras, Maria, G1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRichards, Brent1 aRivadeneira, Fernando1 aSala, Cinzia1 aSabra, Mona, M1 aSattar, Naveed1 aShields, Beverley, M1 aSoranzo, Nicole1 aStarr, John, M1 aStott, David, J1 aSweep, Fred, C G J1 aUsala, Gianluca1 avan der Klauw, Melanie, M1 avan Heemst, Diana1 avan Mullem, Alies1 aVermeulen, Sita, H1 aVisser, Edward1 aWalsh, John, P1 aWestendorp, Rudi, G J1 aWiden, Elisabeth1 aZhai, Guangju1 aCucca, Francesco1 aDeary, Ian, J1 aEriksson, Johan, G1 aFerrucci, Luigi1 aFox, Caroline, S1 aJukema, Wouter1 aKiemeney, Lambertus, A1 aPramstaller, Peter, P1 aSchlessinger, David1 aShuldiner, Alan, R1 aSlagboom, Eline, P1 aUitterlinden, André, G1 aVaidya, Bijay1 aVisser, Theo, J1 aWolffenbuttel, Bruce, H R1 aMeulenbelt, Ingrid1 aRotter, Jerome, I1 aSpector, Tim, D1 aHicks, Andrew, A1 aToniolo, Daniela1 aSanna, Serena1 aPeeters, Robin, P1 aNaitza, Silvia uhttps://chs-nhlbi.org/node/587708187nas a2202209 4500008004100000022001400041245023300055210006900288260001600357300001200373490000800385520188600393653001502279653001002294653003902304653000902343653002202352653002802374653002802402653004002430653001102470653001502481653001702496653003802513653003402551653002302585653001102608653000902619653001602628653002602644653003602670653001702706653001102723653002702734653001602761100002502777700001502802700002002817700001902837700001902856700002302875700002202898700002002920700002102940700001702961700002402978700002003002700002303022700001803045700001903063700001703082700002303099700001803122700002003140700001603160700002003176700001903196700002803215700002103243700001703264700002503281700002203306700001903328700001703347700002003364700001603384700002003400700001803420700001903438700001903457700002003476700001603496700002003512700001503532700002203547700002103569700002103590700002503611700002303636700002103659700001903680700002003699700001703719700001703736700001703753700002103770700002203791700001903813700002703832700002003859700002403879700002503903700002103928700002003949700002603969700002803995700002104023700001904044700002204063700002304085700002304108700001304131700002504144700002304169700002204192700001904214700002004233700002204253700002004275700002004295700002204315700001804337700002104355700001804376700001904394700001904413700001504432700002704447700001704474700001904491700002204510700002304532700001804555700002404573700002004597700001904617700002404636700001604660700002004676700002204696700002004718700002404738700001804762700002104780700002104801700001904822700002804841700002204869700002004891700002204911700001704933700002104950700002304971700002404994700002305018700002205041700002105063700002205084700001705106700002705123700002205150700002405172700002205196700002405218700002905242700002005271700002305291700001805314700001805332700002005350700003005370700001905400700002205419700002205441700002105463700002105484700001905505700001805524700002005542700002005562700001805582700002205600700002505622700002305647700002005670700002005690700001805710700002305728700002005751700003005771710001905801710002205820710005405842710001905896710002605915856003605941 2013 eng d a1524-453900aMultiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.0 aMultiethnic metaanalysis of genomewide association studies in 10 c2013 Sep 17 a1310-240 v1283 aBACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.
METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.
CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aCardiovascular Diseases10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHispanic Americans10aHumans10aMale10aMiddle Aged10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke10aVenous Thromboembolism10aYoung Adult1 aSabater-Lleal, Maria1 aHuang, Jie1 aChasman, Daniel1 aNaitza, Silvia1 aDehghan, Abbas1 aJohnson, Andrew, D1 aTeumer, Alexander1 aReiner, Alex, P1 aFolkersen, Lasse1 aBasu, Saonli1 aRudnicka, Alicja, R1 aTrompet, Stella1 aMälarstig, Anders1 aBaumert, Jens1 aBis, Joshua, C1 aGuo, Xiuqing1 aHottenga, Jouke, J1 aShin, So-Youn1 aLopez, Lorna, M1 aLahti, Jari1 aTanaka, Toshiko1 aYanek, Lisa, R1 aOudot-Mellakh, Tiphaine1 aWilson, James, F1 aNavarro, Pau1 aHuffman, Jennifer, E1 aZemunik, Tatijana1 aRedline, Susan1 aMehra, Reena1 aPulanic, Drazen1 aRudan, Igor1 aWright, Alan, F1 aKolcic, Ivana1 aPolasek, Ozren1 aWild, Sarah, H1 aCampbell, Harry1 aCurb, David1 aWallace, Robert1 aLiu, Simin1 aEaton, Charles, B1 aBecker, Diane, M1 aBecker, Lewis, C1 aBandinelli, Stefania1 aRäikkönen, Katri1 aWiden, Elisabeth1 aPalotie, Aarno1 aFornage, Myriam1 aGreen, David1 aGross, Myron1 aDavies, Gail1 aHarris, Sarah, E1 aLiewald, David, C1 aStarr, John, M1 aWilliams, Frances, M K1 aGrant, Peter, J1 aSpector, Timothy, D1 aStrawbridge, Rona, J1 aSilveira, Angela1 aSennblad, Bengt1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aFranco, Oscar, H1 aHofman, Albert1 avan Dongen, Jenny1 aWillemsen, Gonneke1 aBoomsma, Dorret, I1 aYao, Jie1 aJenny, Nancy, Swords1 aHaritunians, Talin1 aMcKnight, Barbara1 aLumley, Thomas1 aTaylor, Kent, D1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aPeters, Annette1 aGieger, Christian1 aIllig, Thomas1 aGrotevendt, Anne1 aHomuth, Georg1 aVölzke, Henry1 aKocher, Thomas1 aGoel, Anuj1 aFranzosi, Maria Grazia1 aSeedorf, Udo1 aClarke, Robert1 aSteri, Maristella1 aTarasov, Kirill, V1 aSanna, Serena1 aSchlessinger, David1 aStott, David, J1 aSattar, Naveed1 aBuckley, Brendan, M1 aRumley, Ann1 aLowe, Gordon, D1 aMcArdle, Wendy, L1 aChen, Ming-Huei1 aTofler, Geoffrey, H1 aSong, Jaejoon1 aBoerwinkle, Eric1 aFolsom, Aaron, R1 aRose, Lynda, M1 aFranco-Cereceda, Anders1 aTeichert, Martina1 aIkram, Arfan, M1 aMosley, Thomas, H1 aBevan, Steve1 aDichgans, Martin1 aRothwell, Peter, M1 aSudlow, Cathie, L M1 aHopewell, Jemma, C1 aChambers, John, C1 aSaleheen, Danish1 aKooner, Jaspal, S1 aDanesh, John1 aNelson, Christopher, P1 aErdmann, Jeanette1 aReilly, Muredach, P1 aKathiresan, Sekar1 aSchunkert, Heribert1 aMorange, Pierre-Emmanuel1 aFerrucci, Luigi1 aEriksson, Johan, G1 aJacobs, David1 aDeary, Ian, J1 aSoranzo, Nicole1 aWitteman, Jacqueline, C M1 aGeus, Eco, J C1 aTracy, Russell, P1 aHayward, Caroline1 aKoenig, Wolfgang1 aCucca, Francesco1 aJukema, Wouter1 aEriksson, Per1 aSeshadri, Sudha1 aMarkus, Hugh, S1 aWatkins, Hugh1 aSamani, Nilesh, J1 aWallaschofski, Henri1 aSmith, Nicholas, L1 aTregouet, David1 aRidker, Paul, M1 aTang, Weihong1 aStrachan, David, P1 aHamsten, Anders1 aO'Donnell, Christopher, J1 aVTE Consortium1 aSTROKE Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2)1 aC4D Consortium1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/615502686nas a2200697 4500008004100000022001400041245012800055210006900183260001300252300001200265490000800277520066900285653002100954653002100975653001900996653001801015653001101033653001901044653003301063653002501096653003401121653001101155653002101166653000901187653003601196653001501232653001201247653001801259653001601277100002201293700001901315700002301334700002301357700002101380700002101401700002801422700002201450700002301472700002101495700001901516700002101535700002401556700001601580700002201596700002201618700002201640700002601662700002301688700002101711700002101732700002301753700002201776700002301798700002701821700001901848700002401867700001901891700002001910700002201930856003601952 2013 eng d a1432-120300aNo evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population.0 aNo evidence of interaction between known lipidassociated genetic c2013 Dec a1427-310 v1323 aGenome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.
10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aEthnic Groups10aFemale10aGene Frequency10aGene-Environment Interaction10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aMale10aPolymorphism, Single Nucleotide10aPrevalence10aSmoking10aTriglycerides10aYoung Adult1 aDumitrescu, Logan1 aCarty, Cara, L1 aFranceschini, Nora1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBůzková, Petra1 aSchumacher, Fredrick, R1 aEaton, Charles, B1 aGoodloe, Robert, J1 aDuggan, David, J1 aHaessler, Jeff1 aCochran, Barbara1 aHenderson, Brian, E1 aCheng, Iona1 aJohnson, Karen, C1 aCarlson, Chris, S1 aLove, Shelly-Anne1 aBrown-Gentry, Kristin1 aNato, Alejandro, Q1 aQuibrera, Miguel1 aShohet, Ralph, V1 aAmbite, Jose, Luis1 aWilkens, Lynne, R1 aLe Marchand, Loïc1 aHaiman, Christopher, A1 aBuyske, Steven1 aKooperberg, Charles1 aNorth, Kari, E1 aFornage, Myriam1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/629203380nas a2200673 4500008004100000022001400041245020100055210006900256260001300325300001100338490000700349520133800356653001001694653000901704653004001713653001101753653003201764653003401796653001101830653001101841653000901852653001601861653003601877653002801913653003401941653001701975100002201992700001902014700002302033700002302056700002102079700002102100700002802121700002202149700002302171700002102194700001902215700002102234700002402255700001602279700002202295700002202317700002102339700002602360700002302386700002102409700002102430700002102451700002302472700002202495700002202517700002702539700001902566700002402585700001902609700002002628700002202648856003602670 2013 eng d a1469-180900aPost-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study.0 aPostgenomewide association study challenges for lipid traits des c2013 Sep a416-250 v773 aNumerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.
10aAdult10aAged10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aGenome-Wide Association Study10aHumans10aLipids10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRisk Factors1 aDumitrescu, Logan1 aCarty, Cara, L1 aFranceschini, Nora1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBůzková, Petra1 aSchumacher, Fredrick, R1 aEaton, Charles, B1 aGoodloe, Robert, J1 aDuggan, David, J1 aHaessler, Jeff1 aCochran, Barbara1 aHenderson, Brian, E1 aCheng, Iona1 aJohnson, Karen, C1 aCarlson, Chris, S1 aLove, Shelly-Ann1 aBrown-Gentry, Kristin1 aNato, Alejandro, Q1 aQuibrera, Miguel1 aAnderson, Garnet1 aShohet, Ralph, V1 aAmbite, Jose, Luis1 aWilkens, Lynne, R1 aLe Marchand, Loic1 aHaiman, Christopher, A1 aBuyske, Steven1 aKooperberg, Charles1 aNorth, Kari, E1 aFornage, Myriam1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/611105044nas a2200541 4500008004100000022001400041245015700055210006900212260001300281300001300294490000700307520354200314653001603856653002803872653001103900653003403911653001303945653001103958653001303969653001403982653003603996100001604032700001804048700001904066700002404085700001804109700001404127700001304141700002004154700001304174700001804187700002004205700001504225700001204240700001704252700001704269700001904286700002304305700001504328700001704343700001904360700001704379700001704396700002004413700001404433700001904447856003604466 2013 eng d a1460-235000aReplication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.0 aReplication of genetic loci for ages at menarche and menopause i c2013 Jun a1695-7060 v283 aSTUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?
SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.
WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.
STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.
MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.
MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.
LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.
WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.
10aAge Factors10aCross-Sectional Studies10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aMenarche10aMenopause10aPolymorphism, Single Nucleotide1 aCarty, C, L1 aSpencer, K, L1 aSetiawan, V, W1 aFernandez-Rhodes, L1 aMalinowski, J1 aBuyske, S1 aYoung, A1 aJorgensen, N, W1 aCheng, I1 aCarlson, C, S1 aBrown-Gentry, K1 aGoodloe, R1 aPark, A1 aParikh, N, I1 aHenderson, B1 aLe Marchand, L1 aWactawski-Wende, J1 aFornage, M1 aMatise, T, C1 aHindorff, L, A1 aArnold, A, M1 aHaiman, C, A1 aFranceschini, N1 aPeters, U1 aCrawford, D, C uhttps://chs-nhlbi.org/node/610611004nas a2203505 4500008004100000022001400041245014700055210006900202260001300271300001300284490000600297520115200303653001801455653001601473653002001489653001601509653003001525653001101555653001701566653001801583653003401601653001101635653000901646653003601655653002401691653002401715653002001739100002301759700002301782700002101805700002101826700002101847700001901868700002801887700001601915700001801931700001601949700003101965700002101996700003002017700001802047700001502065700002102080700002302101700001902124700002002143700001902163700002202182700002002204700001802224700003202242700002502274700003002299700002302329700001902352700001902371700002202390700002202412700001902434700001802453700001902471700002202490700002302512700002302535700002202558700002402580700002102604700002202625700002202647700002602669700002302695700002202718700002302740700002402763700002202787700002202809700001202831700002502843700001802868700002802886700002402914700001802938700002502956700001902981700001603000700001903016700001903035700002503054700002503079700002603104700001903130700002003149700001703169700002403186700002003210700002303230700001603253700002003269700002203289700002803311700002103339700002403360700002003384700002303404700001803427700002203445700002103467700001903488700002603507700002203533700002803555700002003583700002803603700002703631700002003658700002303678700002003701700002103721700002403742700002003766700001503786700002803801700002603829700001903855700002803874700001903902700002503921700002403946700002703970700002003997700001404017700002004031700002204051700001904073700001804092700001804110700002104128700002004149700002204169700001604191700002204207700002204229700002604251700002604277700001704303700002004320700002304340700001904363700002304382700002004405700002304425700001904448700001804467700002304485700002504508700001904533700001904552700002004571700003004591700003504621700002104656700001704677700002104694700001904715700002504734700002404759700001804783700001504801700002404816700002204840700002504862700001504887700002304902700002004925700001904945700002204964700002004986700001805006700002205024700002005046700002105066700002105087700001705108700002105125700002005146700001605166700002105182700001905203700002505222700002405247700002305271700001905294700002205313700001805335700002005353700002005373700001905393700002105412700002405433700001805457700002005475700002105495700002005516700002505536700002105561700002105582700002405603700001805627700001605645700002105661700003705682700002205719700001805741700002005759700002105779700002005800700002605820700002305846700001905869700002005888700002305908700002405931700002005955700001905975700002005994700002406014700002506038700001906063700002106082700002106103700001806124700002106142700003006163700002006193700002306213700002206236700002006258700002806278700002206306700001906328700002406347700002206371700002006393700001906413700002306432700001506455700001706470700001506487700001806502700001906520700002706539700002306566700002206589700002106611700002206632700002206654700002306676700002506699700002106724700001906745700001806764700001906782700002106801700001906822700001806841700002906859700001906888700002106907700002306928700002006951700002106971700002206992700001907014700002307033700001807056700002007074700001907094700002107113700002607134700002407160700002307184700002107207700002307228700002507251700002207276700002407298700001107322700002007333700002507353700001907378700001807397710002307415710002407438856003607462 2013 eng d a1553-740400aSex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.0 aSexstratified genomewide association studies including 270000 in c2013 Jun ae10035000 v93 aGiven the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
10aAnthropometry10aBody Height10aBody Mass Index10aBody Weight10aBody Weights and Measures10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist Circumference10aWaist-Hip Ratio1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aKutalik, Zoltán1 aBerndt, Sonja, I1 aJackson, Anne, U1 aMonda, Keri, L1 aKilpeläinen, Tuomas, O1 aEsko, Tõnu1 aMägi, Reedik1 aLi, Shengxu1 aWorkalemahu, Tsegaselassie1 aFeitosa, Mary, F1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aFall, Tove1 aFerreira, Teresa1 aGustafsson, Stefan1 aLocke, Adam, E1 aMathieson, Iain1 aScherag, Andre1 aVedantam, Sailaja1 aWood, Andrew, R1 aLiang, Liming1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aDermitzakis, Emmanouil, T1 aDimas, Antigone, S1 aKarpe, Fredrik1 aMin, Josine, L1 aNicholson, George1 aClegg, Deborah, J1 aPerson, Thomas1 aKrohn, Jon, P1 aBauer, Sabrina1 aBuechler, Christa1 aEisinger, Kristina1 aBonnefond, Amélie1 aFroguel, Philippe1 aHottenga, Jouke-Jan1 aProkopenko, Inga1 aWaite, Lindsay, L1 aHarris, Tamara, B1 aSmith, Albert, Vernon1 aShuldiner, Alan, R1 aMcArdle, Wendy, L1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aGrönberg, Henrik1 aChen, Yii-Der Ida1 aLi, Guo1 aBeckmann, Jacques, S1 aJohnson, Toby1 aThorsteinsdottir, Unnur1 aTeder-Laving, Maris1 aKhaw, Kay-Tee1 aWareham, Nicholas, J1 aZhao, Jing Hua1 aAmin, Najaf1 aOostra, Ben, A1 aKraja, Aldi, T1 aProvince, Michael, A1 aCupples, Adrienne, L1 aHeard-Costa, Nancy, L1 aKaprio, Jaakko1 aRipatti, Samuli1 aSurakka, Ida1 aCollins, Francis, S1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aJula, Antti1 aSalomaa, Veikko1 aErdmann, Jeanette1 aHengstenberg, Christian1 aLoley, Christina1 aSchunkert, Heribert1 aLamina, Claudia1 aWichmann, Erich, H1 aAlbrecht, Eva1 aGieger, Christian1 aHicks, Andrew, A1 aJohansson, Asa1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aSpeliotes, Elizabeth, K1 aPenninx, Brenda1 aHartikainen, Anna-Liisa1 aJarvelin, Marjo-Riitta1 aGyllensten, Ulf1 aBoomsma, Dorret, I1 aCampbell, Harry1 aWilson, James, F1 aChanock, Stephen, J1 aFarrall, Martin1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aRivadeneira, Fernando1 aEstrada, Karol1 aUitterlinden, André, G1 aHofman, Albert1 aZillikens, Carola, M1 aHeijer, Martin, den1 aKiemeney, Lambertus, A1 aMaschio, Andrea1 aHall, Per1 aTyrer, Jonathan1 aTeumer, Alexander1 aVölzke, Henry1 aKovacs, Peter1 aTönjes, Anke1 aMangino, Massimo1 aSpector, Tim, D1 aHayward, Caroline1 aRudan, Igor1 aHall, Alistair, S1 aSamani, Nilesh, J1 aAttwood, Antony, Paul1 aSambrook, Jennifer, G1 aHung, Joseph1 aPalmer, Lyle, J1 aLokki, Marja-Liisa1 aSinisalo, Juha1 aBoucher, Gabrielle1 aHuikuri, Heikki1 aLorentzon, Mattias1 aOhlsson, Claes1 aEklund, Niina1 aEriksson, Johan, G1 aBarlassina, Cristina1 aRivolta, Carlo1 aNolte, Ilja, M1 aSnieder, Harold1 avan der Klauw, Melanie, M1 avan Vliet-Ostaptchouk, Jana, V1 aGejman, Pablo, V1 aShi, Jianxin1 aJacobs, Kevin, B1 aWang, Zhaoming1 aBakker, Stephan, J L1 aLeach, Irene, Mateo1 aNavis, Gerjan1 aHarst, Pim1 aMartin, Nicholas, G1 aMedland, Sarah, E1 aMontgomery, Grant, W1 aYang, Jian1 aChasman, Daniel, I1 aRidker, Paul, M1 aRose, Lynda, M1 aLehtimäki, Terho1 aRaitakari, Olli1 aAbsher, Devin1 aIribarren, Carlos1 aBasart, Hanneke1 aHovingh, Kees, G1 aHyppönen, Elina1 aPower, Chris1 aAnderson, Denise1 aBeilby, John, P1 aHui, Jennie1 aJolley, Jennifer1 aSager, Hendrik1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aKristiansson, Kati1 aPerola, Markus1 aLindström, Jaana1 aSwift, Amy, J1 aUusitupa, Matti1 aAtalay, Mustafa1 aLakka, Timo, A1 aRauramaa, Rainer1 aBolton, Jennifer, L1 aFowkes, Gerry1 aFraser, Ross, M1 aPrice, Jackie, F1 aFischer, Krista1 aKov, Kaarel, Krjutå1 aMetspalu, Andres1 aMihailov, Evelin1 aLangenberg, Claudia1 aLuan, Jian'an1 aOng, Ken, K1 aChines, Peter, S1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aEdkins, Sarah1 aFranks, Paul, W1 aHallmans, Göran1 aShungin, Dmitry1 aMorris, Andrew, David1 aPalmer, Colin, N A1 aErbel, Raimund1 aMoebus, Susanne1 aNöthen, Markus, M1 aPechlivanis, Sonali1 aHveem, Kristian1 aNarisu, Narisu1 aHamsten, Anders1 aHumphries, Steve, E1 aStrawbridge, Rona, J1 aTremoli, Elena1 aGrallert, Harald1 aThorand, Barbara1 aIllig, Thomas1 aKoenig, Wolfgang1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aBoehm, Bernhard, O1 aKleber, Marcus, E1 aMärz, Winfried1 aWinkelmann, Bernhard, R1 aKuusisto, Johanna1 aLaakso, Markku1 aArveiler, Dominique1 aCesana, Giancarlo1 aKuulasmaa, Kari1 aVirtamo, Jarmo1 aYarnell, John, W G1 aKuh, Diana1 aWong, Andrew1 aLind, Lars1 ade Faire, Ulf1 aGigante, Bruna1 aMagnusson, Patrik, K E1 aPedersen, Nancy, L1 aDedoussis, George1 aDimitriou, Maria1 aKolovou, Genovefa1 aKanoni, Stavroula1 aStirrups, Kathleen1 aBonnycastle, Lori, L1 aNjølstad, Inger1 aWilsgaard, Tom1 aGanna, Andrea1 aRehnberg, Emil1 aHingorani, Aroon1 aKivimaki, Mika1 aKumari, Meena1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David1 aIngelsson, Erik1 aKaplan, Robert1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aStrachan, David, P1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAbecasis, Goncalo, R1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aQi, Lu1 aLoos, Ruth, J F1 aLindgren, Cecilia, M1 aNorth, Kari, E1 aHeid, Iris, M1 aDIAGRAM Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/602803680nas a2200625 4500008004100000022001400041245012100055210006900176260001300245300001100258490000700269520186000276653002202136653001602158653000902174653001502183653002802198653003102226653004002257653001102297653003802308653003402346653001502380653002402395653001102419653001402430653002702444653001802471653003302489653002002522653000902542653002202551653002602573653001402599653003602613653003302649653001402682653003202696653002402728653002002752653001702772653001702789653001802806100002002824700002002844700002002864700002302884700001802907700001202925700002002937700002102957700001802978700002202996856003603018 2013 eng d a1524-463600aSoluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults.0 aSoluble CD14 genomewide association analysis and relationship to c2013 Jan a158-640 v333 aOBJECTIVE: CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.
METHODS AND RESULTS: We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the CD14 locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of PIGC, which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults.
CONCLUSIONS: CD14 independently predicts risk mortality in older adults.
10aAfrican Americans10aAge Factors10aAged10aBiomarkers10aCardiovascular Diseases10aChromosomes, Human, Pair 510aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHaplotypes10aHexosyltransferases10aHumans10aIncidence10aInflammation Mediators10aLinear Models10aLipopolysaccharide Receptors10aLogistic Models10aMale10aMembrane Proteins10aMultivariate Analysis10aPhenotype10aPolymorphism, Single Nucleotide10aPrincipal Component Analysis10aPrognosis10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aRisk Factors10aTime Factors10aUnited States1 aReiner, Alex, P1 aLange, Ethan, M1 aJenny, Nancy, S1 aChaves, Paulo, H M1 aEllis, Jaclyn1 aLi, Jin1 aWalston, Jeremy1 aLange, Leslie, A1 aCushman, Mary1 aTracy, Russell, P uhttps://chs-nhlbi.org/node/156402198nas a2200289 4500008004100000022001400041245012100055210006900176260001300245300001100258490000700269520133900276653001901615653002401634653002201658653003401680653001101714653001801725653002001743653003601763100001601799700001001815700001701825700001301842700001701855856003601872 2013 eng d a1098-227200aStrategy to control type I error increases power to identify genetic variation using the full biological trajectory.0 aStrategy to control type I error increases power to identify gen c2013 Jul a419-300 v373 aGenome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.
10aCohort Studies10aComputer Simulation10aGenetic Variation10aGenome-Wide Association Study10aHumans10aLinear Models10aModels, Genetic10aPolymorphism, Single Nucleotide1 aBenke, K, S1 aWu, Y1 aFallin, D, M1 aMaher, B1 aPalmer, L, J uhttps://chs-nhlbi.org/node/621804247nas a2200757 4500008004100000022001400041245023300055210006900288260000900357300001300366490000600379520199400385653004102379653001002420653002202430653000902452653002202461653001202483653002002495653002302515653003402538653004002572653001102612653003802623653003402661653001102695653002702706653000902733653001702742653001602759653001202775653001302787100001902800700001902819700002402838700001802862700001902880700001502899700002502914700002402939700001902963700002502982700001503007700001603022700002103038700001903059700001703078700001603095700001703111700002603128700002003154700001903174700001803193700002503211700001603236700002003252700002103272700002103293700002003314700002303334700002303357700002203380700002703402700002403429856003603453 2013 eng d a1553-740400aA systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.0 asystematic mapping approach of 16q122FTO and BMI in more than 20 c2013 ae10031710 v93 aGenetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.
10aAdaptor Proteins, Signal Transducing10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aAlleles10aBody Mass Index10aChromosome Mapping10aContinental Population Groups10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMale10aMetagenomics10aMiddle Aged10aObesity10aProteins1 aPeters, Ulrike1 aNorth, Kari, E1 aSethupathy, Praveen1 aBuyske, Steve1 aHaessler, Jeff1 aJiao, Shuo1 aFesinmeyer, Megan, D1 aJackson, Rebecca, D1 aKuller, Lew, H1 aRajkovic, Aleksandar1 aLim, Unhee1 aCheng, Iona1 aSchumacher, Fred1 aWilkens, Lynne1 aLi, Rongling1 aMonda, Keri1 aEhret, Georg1 aNguyen, Khanh-Dung, H1 aCooper, Richard1 aLewis, Cora, E1 aLeppert, Mark1 aIrvin, Marguerite, R1 aGu, Charles1 aHouston, Denise1 aBůzková, Petra1 aRitchie, Marylyn1 aMatise, Tara, C1 aLe Marchand, Loïc1 aHindorff, Lucia, A1 aCrawford, Dana, C1 aHaiman, Christopher, A1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/662805266nas a2201201 4500008004100000022001400041245015400055210006900209260001300278300001300291490000600304520181500310653002202125653002202147653002102169653002102190653004002211653003402251653001102285653002202296653002202318653002702340653002602367653001802393100001302411700002202424700002102446700002102467700001902488700001802507700002102525700002102546700002502567700001902592700001602611700002102627700003002648700002202678700002202700700002302722700001702745700002402762700002302786700001402809700002002823700002202843700001802865700002302883700001202906700002202918700002802940700002502968700001902993700002603012700002103038700002503059700002003084700001703104700001803121700002003139700001903159700001903178700002103197700002003218700002803238700002103266700002603287700002403313700001803337700002103355700001703376700001703393700002003410700002003430700002303450700002603473700002203499700001903521700001903540700001403559700002103573700002003594700002003614700002103634700001903655700002403674700002103698700002203719700002003741700002303761700002003784700002003804700002103824700002703845700002103872700002403893700002903917700002203946700002003968700001903988700002104007856003604028 2013 eng d a1553-740400aTrans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.0 aTransethnic finemapping of lipid loci identifies populationspeci c2013 Mar ae10033790 v93 aGenome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
10aAfrican Americans10aApolipoproteins A10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aGenome-Wide Association Study10aHumans10aLipoproteins, HDL10aLipoproteins, LDL10aProprotein Convertases10aSerine Endopeptidases10aTriglycerides1 aWu, Ying1 aWaite, Lindsay, L1 aJackson, Anne, U1 aSheu, Wayne, H-H1 aBuyske, Steven1 aAbsher, Devin1 aArnett, Donna, K1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aCarty, Cara, L1 aCheng, Iona1 aCochran, Barbara1 aCroteau-Chonka, Damien, C1 aDumitrescu, Logan1 aEaton, Charles, B1 aFranceschini, Nora1 aGuo, Xiuqing1 aHenderson, Brian, E1 aHindorff, Lucia, A1 aKim, Eric1 aKinnunen, Leena1 aKomulainen, Pirjo1 aLee, Wen-Jane1 aLe Marchand, Loïc1 aLin, Yi1 aLindström, Jaana1 aLingaas-Holmen, Oddgeir1 aMitchell, Sabrina, L1 aNarisu, Narisu1 aRobinson, Jennifer, G1 aSchumacher, Fred1 aStančáková, Alena1 aSundvall, Jouko1 aSung, Yun-Ju1 aSwift, Amy, J1 aWang, Wen-Chang1 aWilkens, Lynne1 aWilsgaard, Tom1 aYoung, Alicia, M1 aAdair, Linda, S1 aBallantyne, Christie, M1 aBůzková, Petra1 aChakravarti, Aravinda1 aCollins, Francis, S1 aDuggan, David1 aFeranil, Alan, B1 aHo, Low-Tone1 aHung, Yi-Jen1 aHunt, Steven, C1 aHveem, Kristian1 aJuang, Jyh-Ming, J1 aKesäniemi, Antero, Y1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo, A1 aLee, I-Te1 aLeppert, Mark, F1 aMatise, Tara, C1 aMoilanen, Leena1 aNjølstad, Inger1 aPeters, Ulrike1 aQuertermous, Thomas1 aRauramaa, Rainer1 aRotter, Jerome, I1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aWang, Tzung-Dau1 aBoehnke, Michael1 aHaiman, Christopher, A1 aChen, Yii-der, I1 aKooperberg, Charles1 aAssimes, Themistocles, L1 aCrawford, Dana, C1 aHsiung, Chao, A1 aNorth, Kari, E1 aMohlke, Karen, L uhttps://chs-nhlbi.org/node/662902102nas a2200469 4500008004100000022001400041245008200055210006900137260001300206300001200219490000700231520073300238653002100971653002600992653002301018653002201041653001801063653003401081653001301115653001701128653001101145653002401156100002401180700001901204700002301223700001801246700001201264700001801276700001701294700001301311700001801324700001901342700001601361700001901377700003001396700002001426700002501446700001901471700002101490710008501511856003601596 2013 eng d a1546-171800aWhole-genome sequence-based analysis of high-density lipoprotein cholesterol.0 aWholegenome sequencebased analysis of highdensity lipoprotein ch c2013 Aug a899-9010 v453 aWe describe initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol (HDL-C). We report whole-genome sequencing and analysis of 962 individuals from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. From this analysis, we estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions.
10aCholesterol, HDL10aComputational Biology10aDatabases, Genetic10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aGenomics10aHeterozygote10aHumans10aOpen Reading Frames1 aMorrison, Alanna, C1 aVoorman, Arend1 aJohnson, Andrew, D1 aLiu, Xiaoming1 aYu, Jin1 aLi, Alexander1 aMuzny, Donna1 aYu, Fuli1 aRice, Kenneth1 aZhu, Chengsong1 aBis, Joshua1 aHeiss, Gerardo1 aO'Donnell, Christopher, J1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aGibbs, Richard1 aBoerwinkle, Eric1 aCohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium uhttps://chs-nhlbi.org/node/628303479nas a2200553 4500008004100000022001400041245016100055210006900216260001300285300001000298490000600308520190300314653001802217653000902235653002202244653001002266653001902276653001102295653002202306653003402328653001302362653001902375653001102394653000902405653000902414653001602423653003602439653002702475100002502502700001302527700002002540700002102560700001902581700001902600700002202619700002002641700001902661700002302680700001902703700002002722700002302742700001802765700001702783700002302800700002302823700002402846700001902870856003602889 2014 eng d a1942-326800aADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aADAM19 and HTR4 variants and pulmonary function Cohorts for Hear c2014 Jun a350-80 v73 aBACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.
METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.
CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.
10aADAM Proteins10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aLung10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aLondon, Stephanie, J1 aGao, Wei1 aGharib, Sina, A1 aHancock, Dana, B1 aWilk, Jemma, B1 aHouse, John, S1 aGibbs, Richard, A1 aMuzny, Donna, M1 aLumley, Thomas1 aFranceschini, Nora1 aNorth, Kari, E1 aPsaty, Bruce, M1 aKovar, Christie, L1 aCoresh, Josef1 aZhou, Yanhua1 aHeckbert, Susan, R1 aBrody, Jennifer, A1 aMorrison, Alanna, C1 aDupuis, Josée uhttps://chs-nhlbi.org/node/658004045nas a2200733 4500008004100000022001400041245022200055210006900277260001300346300001200359490000600371520185400377653000902231653002202240653001002262653001802272653003202290653001902322653005302341653003002394653001202424653001102436653001902447653002202466653003402488653001302522653004002535653001902575653001102594653001202605653000902617653001602626653003602642653002702678100002302705700002302728700002102751700002402772700001402796700002002810700001602830700001802846700002402864700001902888700002002907700001802927700002202945700002002967700001802987700002203005700001703027700002103044700002103065700002203086700002303108700001803131700002003149700002103169700002203190700002403212700001903236700002003255856003603275 2014 eng d a1942-326800aAssociation of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aAssociation of levels of fasting glucose and insulin with rare v c2014 Jun a374-3820 v73 aBACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.
METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.
CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
10aAged10aAged, 80 and over10aAging10aBlood Glucose10aChromosomes, Human, Pair 1110aCohort Studies10aDeath Domain Receptor Signaling Adaptor Proteins10aDiabetes Mellitus, Type 210aFasting10aFemale10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aGuanine Nucleotide Exchange Factors10aHeart Diseases10aHumans10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aCornes, Belinda, K1 aBrody, Jennifer, A1 aNikpoor, Naghmeh1 aMorrison, Alanna, C1 aChu, Huan1 aAhn, Byung, Soo1 aWang, Shuai1 aDauriz, Marco1 aBarzilay, Joshua, I1 aDupuis, Josée1 aFlorez, Jose, C1 aCoresh, Josef1 aGibbs, Richard, A1 aKao, Linda, W H1 aLiu, Ching-Ti1 aMcKnight, Barbara1 aMuzny, Donna1 aPankow, James, S1 aReid, Jeffrey, G1 aWhite, Charles, C1 aJohnson, Andrew, D1 aWong, Tien, Y1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aSiscovick, David, S1 aSladek, Robert1 aMeigs, James, B uhttps://chs-nhlbi.org/node/655503125nas a2200553 4500008004100000022001400041245011100055210006900166260000900235300001200244490000600256520150100262653002101763653001101784653003401795653001101829653000901840653001601849653003601865100003001901700002901931700002001960700002201980700002102002700002202023700002202045700002402067700001202091700002302103700001902126700002202145700001802167700001902185700001902204700002602223700002802249700002102277700002802298700002402326700002002350700002502370700002702395700002002422700001802442700002802460700002402488700002302512856003602535 2014 eng d a1932-620300aThe challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.0 achallenges of genomewide interaction studies lessons to learn fr c2014 ae1092900 v93 aGenome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.
10aCholesterol, HDL10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 avan Leeuwen, Elisabeth, M1 aSmouter, Françoise, A S1 aKam-Thong, Tony1 aKarbalai, Nazanin1 aSmith, Albert, V1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSitlani, Colleen, M1 aLi, Guo1 aBrody, Jennifer, A1 aBis, Joshua, C1 aWhite, Charles, C1 aJaiswal, Alok1 aOostra, Ben, A1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aBoerwinkle, Eric1 aBallantyne, Christie, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aJarvelin, Marjo-Riitta1 aRipatti, Samuli1 aIsaacs, Aaron1 aMüller-Myhsok, Bertram1 aKarssen, Lennart, C1 aDuijn, Cornelia, M uhttps://chs-nhlbi.org/node/660703835nas a2200949 4500008004100000022001400041245012900055210006900184260001300253300000900266490000700275520126900282653002401551653002801575653005201603653002401655653004001679653003301719653003401752653001101786653001801797653002101815653001801836653002101854653003601875653003401911100001601945700001801961700001601979700001601995700001302011700001802024700001802042700001902060700002102079700001902100700001902119700001602138700001202154700001702166700001602183700001602199700001802215700001502233700001402248700001502262700001402277700001702291700001302308700001502321700001802336700002002354700001702374700001102391700001002402700002102412700001902433700001902452700001602471700001702487700001502504700001202519700002202531700001602553700001502569700001402584700002002598700001902618700001502637700001902652700001602671700001802687700001602705700001502721700002202736700001702758700002302775700001802798700001802816700001502834856003602849 2014 eng d a1473-115000aDrug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.0 aDruggene interactions and the search for missing heritability a c2014 Feb a6-130 v143 aVariability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
10aComputer Simulation10aCross-Sectional Studies10aDrug-Related Side Effects and Adverse Reactions10aElectrocardiography10aEuropean Continental Ancestry Group10aGene-Environment Interaction10aGenome-Wide Association Study10aHumans10aLinear Models10aLong QT Syndrome10aMarkov Chains10aPharmacogenetics10aPolymorphism, Single Nucleotide10aQuantitative Trait, Heritable1 aAvery, C, L1 aSitlani, C, M1 aArking, D E1 aArnett, D K1 aBis, J C1 aBoerwinkle, E1 aBuckley, B, M1 aChen, Y-D, Ida1 ade Craen, A, J M1 aEijgelsheim, M1 aEnquobahrie, D1 aEvans, D, S1 aFord, I1 aGarcia, M, E1 aGudnason, V1 aHarris, T B1 aHeckbert, S R1 aHochner, H1 aHofman, A1 aHsueh, W-C1 aIsaacs, A1 aJukema, J, W1 aKnekt, P1 aKors, J, A1 aKrijthe, B, P1 aKristiansson, K1 aLaaksonen, M1 aLiu, Y1 aLi, X1 aMacfarlane, P, W1 aNewton-Cheh, C1 aNieminen, M, S1 aOostra, B A1 aPeloso, G, M1 aPorthan, K1 aRice, K1 aRivadeneira, F, F1 aRotter, J I1 aSalomaa, V1 aSattar, N1 aSiscovick, D, S1 aSlagboom, P, E1 aSmith, A V1 aSotoodehnia, N1 aStott, D, J1 aStricker, B H1 aStürmer, T1 aTrompet, S1 aUitterlinden, A G1 avan Duijn, C1 aWestendorp, R, G J1 aWitteman, J C1 aWhitsel, E, A1 aPsaty, B M uhttps://chs-nhlbi.org/node/597803970nas a2200877 4500008004100000022001400041245011500055210006900170260001600239300001000255490000700265520145800272653001901730653003401749653001101783653002501794653001401819653003601833653002801869100002201897700002301919700002201942700001701964700002201981700001902003700001702022700002102039700001802060700001502078700001702093700001902110700002002129700002702149700002302176700001802199700002402217700001702241700002002258700002702278700002902305700002202334700001602356700002202372700001502394700002202409700001302431700002002444700002402464700002302488700002202511700001902533700001202552700002102564700002202585700001402607700002102621700002402642700001302666700002802679700002602707700001902733700002302752700002102775700001402796700003002810700002402840700002402864700001902888700002002907700002002927700001702947700002002964700002602984710004603010856003603056 2014 eng d a1537-660500aEffects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations.0 aEffects of longterm averaging of quantitative blood pressure tra c2014 Jul 03 a49-650 v953 aBlood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.
10aBlood Pressure10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aGanesh, Santhi, K1 aChasman, Daniel, I1 aLarson, Martin, G1 aGuo, Xiuqing1 aVerwoert, Germain1 aBis, Joshua, C1 aGu, Xiangjun1 aSmith, Albert, V1 aYang, Min-Lee1 aZhang, Yan1 aEhret, Georg1 aRose, Lynda, M1 aHwang, Shih-Jen1 aPapanicolau, George, J1 aSijbrands, Eric, J1 aRice, Kenneth1 aEiriksdottir, Gudny1 aPihur, Vasyl1 aRidker, Paul, M1 aVasan, Ramachandran, S1 aNewton-Cheh, Christopher1 aRaffel, Leslie, J1 aAmin, Najaf1 aRotter, Jerome, I1 aLiu, Kiang1 aLauner, Lenore, J1 aXu, Ming1 aCaulfield, Mark1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aVaidya, Dhananjay1 aDehghan, Abbas1 aLi, Guo1 aBouchard, Claude1 aHarris, Tamara, B1 aZhang, He1 aBoerwinkle, Eric1 aSiscovick, David, S1 aGao, Wei1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aHofman, Albert1 aWiller, Cristen, J1 aFranco, Oscar, H1 aHuo, Yong1 aWitteman, Jacqueline, C M1 aMunroe, Patricia, B1 aGudnason, Vilmundur1 aPalmas, Walter1 aDuijn, Cornelia1 aFornage, Myriam1 aLevy, Daniel1 aPsaty, Bruce, M1 aChakravarti, Aravinda1 aGlobal Blood Pressure Genetics Consortium uhttps://chs-nhlbi.org/node/656305300nas a2201225 4500008004100000022001400041245016600055210006900221260001600290300001300306490000700319520181200326653001402138653001002152653000902162653002202171653002002193653004002213653001102253653003402264653001102298653000902309653001602318653002402334653002002358653001602378100002202394700001502416700002502431700002302456700002102479700002602500700002502526700002102551700001802572700002302590700002402613700002302637700001902660700001602679700001402695700002902709700001802738700002202756700001402778700002002792700002302812700001802835700002402853700002302877700001902900700003102919700002702950700002602977700001803003700001603021700002003037700002203057700001803079700001603097700001903113700002103132700002103153700002903174700002003203700002103223700002403244700002203268700001503290700002203305700002303327700001803350700002203368700002003390700002103410700002403431700002203455700001903477700002503496700002103521700002103542700002503563700001903588700002103607700002203628700002403650700002203674700001903696700002303715700002103738700002003759700001703779700002203796700002103818700002303839700002103862700001903883700002003902700002103922700002003943710003003963710002103993710002404014856003604038 2014 eng d a1460-208300aGene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.0 aGenecentric metaanalyses for central adiposity traits in up to 5 c2014 May 01 a2498-5100 v233 aWaist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
10aAdiposity10aAdult10aAged10aAged, 80 and over10aBody Mass Index10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aWaist Circumference10aWaist-Hip Ratio10aYoung Adult1 aYoneyama, Sachiko1 aGuo, Yiran1 aLanktree, Matthew, B1 aBarnes, Michael, R1 aElbers, Clara, C1 aKarczewski, Konrad, J1 aPadmanabhan, Sandosh1 aBauer, Florianne1 aBaumert, Jens1 aBeitelshees, Amber1 aBerenson, Gerald, S1 aBoer, Jolanda, M A1 aBurke, Gregory1 aCade, Brian1 aChen, Wei1 aCooper-Dehoff, Rhonda, M1 aGaunt, Tom, R1 aGieger, Christian1 aGong, Yan1 aGorski, Mathias1 aHeard-Costa, Nancy1 aJohnson, Toby1 aLamonte, Michael, J1 aMcDonough, Caitrin1 aMonda, Keri, L1 aOnland-Moret, Charlotte, N1 aNelson, Christopher, P1 aO'Connell, Jeffrey, R1 aOrdovas, Jose1 aPeter, Inga1 aPeters, Annette1 aShaffer, Jonathan1 aShen, Haiqinq1 aSmith, Erin1 aSpeilotes, Liz1 aThomas, Fridtjof1 aThorand, Barbara1 aVerschuren, W, M Monique1 aAnand, Sonia, S1 aDominiczak, Anna1 aDavidson, Karina, W1 aHegele, Robert, A1 aHeid, Iris1 aHofker, Marten, H1 aHuggins, Gordon, S1 aIllig, Thomas1 aJohnson, Julie, A1 aKirkland, Susan1 aKönig, Wolfgang1 aLangaee, Taimour, Y1 aMcCaffery, Jeanne1 aMelander, Olle1 aMitchell, Braxton, D1 aMunroe, Patricia1 aMurray, Sarah, S1 aPapanicolaou, George1 aRedline, Susan1 aReilly, Muredach1 aSamani, Nilesh, J1 aSchork, Nicholas, J1 aSchouw, Yvonne, T1 aShimbo, Daichi1 aShuldiner, Alan, R1 aTobin, Martin, D1 aWijmenga, Cisca1 aYusuf, Salim1 aHakonarson, Hakon1 aLange, Leslie, A1 aDemerath, Ellen, W1 aFox, Caroline, S1 aNorth, Kari, E1 aReiner, Alex, P1 aKeating, Brendan1 aTaylor, Kira, C1 aLook AHEAD Research Group1 aGIANT Consortium1 aCARe IBC Consortium uhttps://chs-nhlbi.org/node/636810059nas a2203157 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2014 eng d a1546-171800aGenetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.0 aGenetic association study of QT interval highlights role for cal c2014 Aug a826-360 v463 aThe QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
10aAdult10aAged10aArrhythmias, Cardiac10aCalcium Signaling10aDeath, Sudden, Cardiac10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHeart Ventricles10aHumans10aLong QT Syndrome10aMale10aMiddle Aged10aMyocardium10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aPulit, Sara, L1 aCrotti, Lia1 aHarst, Pim1 aMunroe, Patricia, B1 aKoopmann, Tamara, T1 aSotoodehnia, Nona1 aRossin, Elizabeth, J1 aMorley, Michael1 aWang, Xinchen1 aJohnson, Andrew, D1 aLundby, Alicia1 aGudbjartsson, Daniel, F1 aNoseworthy, Peter, A1 aEijgelsheim, Mark1 aBradford, Yuki1 aTarasov, Kirill, V1 aDörr, Marcus1 aMüller-Nurasyid, Martina1 aLahtinen, Annukka, M1 aNolte, Ilja, M1 aSmith, Albert, Vernon1 aBis, Joshua, C1 aIsaacs, Aaron1 aNewhouse, Stephen, J1 aEvans, Daniel, S1 aPost, Wendy, S1 aWaggott, Daryl1 aLyytikäinen, Leo-Pekka1 aHicks, Andrew, A1 aEisele, Lewin1 aEllinghaus, David1 aHayward, Caroline1 aNavarro, Pau1 aUlivi, Sheila1 aTanaka, Toshiko1 aTester, David, J1 aChatel, Stéphanie1 aGustafsson, Stefan1 aKumari, Meena1 aMorris, Richard, W1 aNaluai, Åsa, T1 aPadmanabhan, Sandosh1 aKluttig, Alexander1 aStrohmer, Bernhard1 aPanayiotou, Andrie, G1 aTorres, Maria1 aKnoflach, Michael1 aHubacek, Jaroslav, A1 aSlowikowski, Kamil1 aRaychaudhuri, Soumya1 aKumar, Runjun, D1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShuldiner, Alan, R1 aAlonso, Alvaro1 aBader, Joel, S1 aEhret, Georg1 aHuang, Hailiang1 aKao, Linda, W H1 aStrait, James, B1 aMacfarlane, Peter, W1 aBrown, Morris1 aCaulfield, Mark, J1 aSamani, Nilesh, J1 aKronenberg, Florian1 aWilleit, Johann1 aSmith, Gustav1 aGreiser, Karin, H1 aSchwabedissen, Henriette, Meyer Zu1 aWerdan, Karl1 aCarella, Massimo1 aZelante, Leopoldo1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aKolcic, Ivana1 aPolasek, Ozren1 aWright, Alan, F1 aGriffin, Maura1 aDaly, Mark, J1 aArnar, David, O1 aHolm, Hilma1 aThorsteinsdottir, Unnur1 aDenny, Joshua, C1 aRoden, Dan, M1 aZuvich, Rebecca, L1 aEmilsson, Valur1 aPlump, Andrew, S1 aLarson, Martin, G1 aO'Donnell, Christopher, J1 aYin, Xiaoyan1 aBobbo, Marco1 aD'Adamo, Adamo, P1 aIorio, Annamaria1 aSinagra, Gianfranco1 aCarracedo, Angel1 aCummings, Steven, R1 aNalls, Michael, A1 aJula, Antti1 aKontula, Kimmo, K1 aMarjamaa, Annukka1 aOikarinen, Lasse1 aPerola, Markus1 aPorthan, Kimmo1 aErbel, Raimund1 aHoffmann, Per1 aJöckel, Karl-Heinz1 aKälsch, Hagen1 aNöthen, Markus, M1 aHoed, Marcel, den1 aLoos, Ruth, J F1 aThelle, Dag, S1 aGieger, Christian1 aMeitinger, Thomas1 aPerz, Siegfried1 aPeters, Annette1 aPrucha, Hanna1 aSinner, Moritz, F1 aWaldenberger, Melanie1 ade Boer, Rudolf, A1 aFranke, Lude1 avan der Vleuten, Pieter, A1 aBeckmann, Britt, Maria1 aMartens, Eimo1 aBardai, Abdennasser1 aHofman, Nynke1 aWilde, Arthur, A M1 aBehr, Elijah, R1 aDalageorgou, Chrysoula1 aGiudicessi, John, R1 aMedeiros-Domingo, Argelia1 aBarc, Julien1 aKyndt, Florence1 aProbst, Vincent1 aGhidoni, Alice1 aInsolia, Roberto1 aHamilton, Robert, M1 aScherer, Stephen, W1 aBrandimarto, Jeffrey1 aMargulies, Kenneth1 aMoravec, Christine, E1 aM, Fabiola, del Greco1 aFuchsberger, Christian1 aO'Connell, Jeffrey, R1 aLee, Wai, K1 aWatt, Graham, C M1 aCampbell, Harry1 aWild, Sarah, H1 aMokhtari, Nour, E El1 aFrey, Norbert1 aAsselbergs, Folkert, W1 aLeach, Irene, Mateo1 aNavis, Gerjan1 avan den Berg, Maarten, P1 avan Veldhuisen, Dirk, J1 aKellis, Manolis1 aKrijthe, Bouwe, P1 aFranco, Oscar, H1 aHofman, Albert1 aKors, Jan, A1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aKedenko, Lyudmyla1 aLamina, Claudia1 aOostra, Ben, A1 aAbecasis, Goncalo, R1 aLakatta, Edward, G1 aMulas, Antonella1 aOrrù, Marco1 aSchlessinger, David1 aUda, Manuela1 aMarkus, Marcello, R P1 aVölker, Uwe1 aSnieder, Harold1 aSpector, Timothy, D1 aArnlöv, Johan1 aLind, Lars1 aSundström, Johan1 aSyvänen, Ann-Christine1 aKivimaki, Mika1 aKähönen, Mika1 aMononen, Nina1 aRaitakari, Olli, T1 aViikari, Jorma, S1 aAdamkova, Vera1 aKiechl, Stefan1 aBrion, Maria1 aNicolaides, Andrew, N1 aPaulweber, Bernhard1 aHaerting, Johannes1 aDominiczak, Anna, F1 aNyberg, Fredrik1 aWhincup, Peter, H1 aHingorani, Aroon, D1 aSchott, Jean-Jacques1 aBezzina, Connie, R1 aIngelsson, Erik1 aFerrucci, Luigi1 aGasparini, Paolo1 aWilson, James, F1 aRudan, Igor1 aFranke, Andre1 aMühleisen, Thomas, W1 aPramstaller, Peter, P1 aLehtimäki, Terho, J1 aPaterson, Andrew, D1 aParsa, Afshin1 aLiu, Yongmei1 aDuijn, Cornelia, M1 aSiscovick, David, S1 aGudnason, Vilmundur1 aJamshidi, Yalda1 aSalomaa, Veikko1 aFelix, Stephan, B1 aSanna, Serena1 aRitchie, Marylyn, D1 aStricker, Bruno, H1 aStefansson, Kari1 aBoyer, Laurie, A1 aCappola, Thomas, P1 aOlsen, Jesper, V1 aLage, Kasper1 aSchwartz, Peter, J1 aKääb, Stefan1 aChakravarti, Aravinda1 aAckerman, Michael, J1 aPfeufer, Arne1 ade Bakker, Paul, I W1 aNewton-Cheh, Christopher1 aCARe Consortium1 aCOGENT Consortium1 aDCCT/EDIC1 aeMERGE Consortium1 aHRGEN Consortium uhttps://chs-nhlbi.org/node/654403582nas a2200829 4500008004100000022001400041245006100055210006000116260000900176300000800185490000700193520130000200653003401500653001701534653001101551653001401562653003601576653003201612100002501644700002301669700002601692700002401718700001601742700002301758700002001781700001701801700001201818700002401830700002201854700001801876700002101894700002301915700001801938700001801956700002001974700002401994700002402018700002202042700001502064700001902079700002102098700002002119700001702139700002102156700002302177700001402200700002002214700002302234700002202257700001802279700001902297700002402316700002002340700001602360700002702376700002402403700001802427700002102445700001902466700001902485700002402504700002502528700001902553700002502572700001802597700002202615700002202637700001902659700001902678700001902697856003602716 2014 eng d a1471-215600aGenetic diversity is a predictor of mortality in humans.0 aGenetic diversity is a predictor of mortality in humans c2014 a1590 v153 aBACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.
CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
10aGenome-Wide Association Study10aHeterozygote10aHumans10aMortality10aPolymorphism, Single Nucleotide10aProportional Hazards Models1 aBihlmeyer, Nathan, A1 aBrody, Jennifer, A1 aSmith, Albert, Vernon1 aLunetta, Kathryn, L1 aNalls, Mike1 aSmith, Jennifer, A1 aTanaka, Toshiko1 aDavies, Gail1 aYu, Lei1 aMirza, Saira, Saeed1 aTeumer, Alexander1 aCoresh, Josef1 aPankow, James, S1 aFranceschini, Nora1 aScaria, Anish1 aOshima, Junko1 aPsaty, Bruce, M1 aGudnason, Vilmundur1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLi, Hanyue1 aKarasik, David1 aKiel, Douglas, P1 aGarcia, Melissa1 aLiu, Yongmei1 aFaul, Jessica, D1 aKardia, Sharon, Lr1 aZhao, Wei1 aFerrucci, Luigi1 aAllerhand, Michael1 aLiewald, David, C1 aRedmond, Paul1 aStarr, John, M1 aDe Jager, Philip, L1 aEvans, Denis, A1 aDirek, Nese1 aIkram, Mohammed, Arfan1 aUitterlinden, Andre1 aHomuth, Georg1 aLorbeer, Roberto1 aGrabe, Hans, J1 aLauner, Lenore1 aMurabito, Joanne, M1 aSingleton, Andrew, B1 aWeir, David, R1 aBandinelli, Stefania1 aDeary, Ian, J1 aBennett, David, A1 aTiemeier, Henning1 aKocher, Thomas1 aLumley, Thomas1 aArking, Dan, E uhttps://chs-nhlbi.org/node/669008236nas a2202509 4500008004100000022001400041245008500055210006900140260000900209300001100218490000600229520112800235653002201363653002101385653002501406653003401431653002401465653001101489653003601500653003101536100002801567700002401595700001801619700002101637700001901658700001801677700001901695700001701714700002301731700002401754700002401778700002601802700003001828700001701858700001801875700001701893700001901910700002101929700002801950700002101978700003001999700002002029700002102049700002202070700002102092700002002113700002002133700002502153700002302178700002002201700002002221700001802241700002402259700002102283700002302304700001802327700003002345700002202375700002302397700002302420700001902443700002802462700002302490700002302513700001902536700002102555700001602576700002402592700002102616700001702637700001602654700001902670700002002689700002402709700002502733700002302758700001702781700002102798700001902819700002202838700002602860700002402886700002202910700002102932700002202953700002702975700001803002700002103020700001803041700001703059700003003076700002703106700002003133700002103153700002003174700001803194700001803212700001503230700002303245700002003268700002803288700002003316700001803336700001903354700002103373700001203394700001903406700001803425700002603443700001903469700001903488700001803507700003203525700001703557700001603574700003103590700001703621700001903638700001803657700002403675700001903699700002303718700002603741700002403767700002003791700002203811700002103833700002003854700001903874700002103893700002303914700002103937700002403958700002003982700002304002700001904025700002004044700001904064700002204083700002104105700002904126700002204155700001804177700002204195700001804217700002104235700002304256700001804279700002904297700001204326700002204338700001604360700001904376700002104395700002104416700002204437700002204459700002604481700002304507700002104530700002104551700001604572700002204588700002204610700002204632700002304654700001804677700002804695700002004723700002304743700002204766700002204788700001804810700001804828700002304846700002204869700002204891700002004913700002204933700001904955700002404974700002104998700002105019700003005040700001705070700002005087700002005107700002205127700001705149700003005166700002005196700002405216700001905240700002305259700002005282700002005302700002405322700001805346700003105364700002205395700003105417700002305448700002305471700002105494700002005515700002805535700002205563700002005585710004705605710003805652856003605690 2014 eng d a1932-620300aGene-wide analysis detects two new susceptibility genes for Alzheimer's disease.0 aGenewide analysis detects two new susceptibility genes for Alzhe c2014 ae946610 v93 aBACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.
SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
10aAlzheimer Disease10aCarrier Proteins10aCase-Control Studies10aGenome-Wide Association Study10aHeat-Shock Proteins10aHumans10aPolymorphism, Single Nucleotide10aReceptors, Antigen, B-Cell1 aEscott-Price, Valentina1 aBellenguez, Céline1 aSan Wang, Li-1 aChoi, Seung-Hoan1 aHarold, Denise1 aJones, Lesley1 aHolmans, Peter1 aGerrish, Amy1 aVedernikov, Alexey1 aRichards, Alexander1 aDeStefano, Anita, L1 aLambert, Jean-Charles1 aIbrahim-Verbaas, Carla, A1 aNaj, Adam, C1 aSims, Rebecca1 aJun, Gyungah1 aBis, Joshua, C1 aBeecham, Gary, W1 aGrenier-Boley, Benjamin1 aRusso, Giancarlo1 aThornton-Wells, Tricia, A1 aDenning, Nicola1 aSmith, Albert, V1 aChouraki, Vincent1 aThomas, Charlene1 aIkram, Arfan, M1 aZelenika, Diana1 aVardarajan, Badri, N1 aKamatani, Yoichiro1 aLin, Chiao-Feng1 aSchmidt, Helena1 aKunkle, Brian1 aDunstan, Melanie, L1 aVronskaya, Maria1 aJohnson, Andrew, D1 aRuiz, Agustin1 aBihoreau, Marie-Thérèse1 aReitz, Christiane1 aPasquier, Florence1 aHollingworth, Paul1 aHanon, Olivier1 aFitzpatrick, Annette, L1 aBuxbaum, Joseph, D1 aCampion, Dominique1 aCrane, Paul, K1 aBaldwin, Clinton1 aBecker, Tim1 aGudnason, Vilmundur1 aCruchaga, Carlos1 aCraig, David1 aAmin, Najaf1 aBerr, Claudine1 aLopez, Oscar, L1 aDe Jager, Philip, L1 aDeramecourt, Vincent1 aJohnston, Janet, A1 aEvans, Denis1 aLovestone, Simon1 aLetenneur, Luc1 aHernandez, Isabel1 aRubinsztein, David, C1 aEiriksdottir, Gudny1 aSleegers, Kristel1 aGoate, Alison, M1 aFiévet, Nathalie1 aHuentelman, Matthew, J1 aGill, Michael1 aBrown, Kristelle1 aKamboh, Ilyas1 aKeller, Lina1 aBarberger-Gateau, Pascale1 aMcGuinness, Bernadette1 aLarson, Eric, B1 aMyers, Amanda, J1 aDufouil, Carole1 aTodd, Stephen1 aWallon, David1 aLove, Seth1 aRogaeva, Ekaterina1 aGallacher, John1 aSt George-Hyslop, Peter1 aClarimon, Jordi1 aLleo, Alberto1 aBayer, Anthony1 aTsuang, Debby, W1 aYu, Lei1 aTsolaki, Magda1 aBossù, Paola1 aSpalletta, Gianfranco1 aProitsi, Petra1 aCollinge, John1 aSorbi, Sandro1 aGarcia, Florentino, Sanchez1 aFox, Nick, C1 aHardy, John1 aNaranjo, Maria, Candida De1 aBosco, Paolo1 aClarke, Robert1 aBrayne, Carol1 aGalimberti, Daniela1 aScarpini, Elio1 aBonuccelli, Ubaldo1 aMancuso, Michelangelo1 aSiciliano, Gabriele1 aMoebus, Susanne1 aMecocci, Patrizia1 aDel Zompo, Maria1 aMaier, Wolfgang1 aHampel, Harald1 aPilotto, Alberto1 aFrank-García, Ana1 aPanza, Francesco1 aSolfrizzi, Vincenzo1 aCaffarra, Paolo1 aNacmias, Benedetta1 aPerry, William1 aMayhaus, Manuel1 aLannfelt, Lars1 aHakonarson, Hakon1 aPichler, Sabrina1 aCarrasquillo, Minerva, M1 aIngelsson, Martin1 aBeekly, Duane1 aAlvarez, Victoria1 aZou, Fanggeng1 aValladares, Otto1 aYounkin, Steven, G1 aCoto, Eliecer1 aHamilton-Nelson, Kara, L1 aGu, Wei1 aRazquin, Cristina1 aPastor, Pau1 aMateo, Ignacio1 aOwen, Michael, J1 aFaber, Kelley, M1 aJonsson, Palmi, V1 aCombarros, Onofre1 aO'Donovan, Michael, C1 aCantwell, Laura, B1 aSoininen, Hilkka1 aBlacker, Deborah1 aMead, Simon1 aMosley, Thomas, H1 aBennett, David, A1 aHarris, Tamara, B1 aFratiglioni, Laura1 aHolmes, Clive1 ade Bruijn, Renee, F A G1 aPassmore, Peter1 aMontine, Thomas, J1 aBettens, Karolien1 aRotter, Jerome, I1 aBrice, Alexis1 aMorgan, Kevin1 aForoud, Tatiana, M1 aKukull, Walter, A1 aHannequin, Didier1 aPowell, John, F1 aNalls, Michael, A1 aRitchie, Karen1 aLunetta, Kathryn, L1 aKauwe, John, S K1 aBoerwinkle, Eric1 aRiemenschneider, Matthias1 aBoada, Merce1 aHiltunen, Mikko1 aMartin, Eden, R1 aSchmidt, Reinhold1 aRujescu, Dan1 aDartigues, Jean-François1 aMayeux, Richard1 aTzourio, Christophe1 aHofman, Albert1 aNöthen, Markus, M1 aGraff, Caroline1 aPsaty, Bruce, M1 aHaines, Jonathan, L1 aLathrop, Mark1 aPericak-Vance, Margaret, A1 aLauner, Lenore, J1 aVan Broeckhoven, Christine1 aFarrer, Lindsay, A1 aDuijn, Cornelia, M1 aRamirez, Alfredo1 aSeshadri, Sudha1 aSchellenberg, Gerard, D1 aAmouyel, Philippe1 aWilliams, Julie1 aUnited Kingdom Brain Expression Consortium1 aCardiovascular Health Study (CHS) uhttps://chs-nhlbi.org/node/661707147nas a2202257 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2014 eng d a1546-171800aGenome-wide association analysis identifies six new loci associated with forced vital capacity.0 aGenomewide association analysis identifies six new loci associat c2014 Jul a669-770 v463 aForced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
10aCohort Studies10aDatabases, Genetic10aFollow-Up Studies10aForced Expiratory Volume10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLung Diseases10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aPrognosis10aQuantitative Trait Loci10aRespiratory Function Tests10aSpirometry10aVital Capacity1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aWain, Louise, V1 aFranceschini, Nora1 aKoch, Beate1 aPottinger, Tess, D1 aSmith, Albert, Vernon1 aDuan, Qing1 aOldmeadow, Chris1 aLee, Mi, Kyeong1 aStrachan, David, P1 aJames, Alan, L1 aHuffman, Jennifer, E1 aVitart, Veronique1 aRamasamy, Adaikalavan1 aWareham, Nicholas, J1 aKaprio, Jaakko1 aWang, Xin-Qun1 aTrochet, Holly1 aKähönen, Mika1 aFlexeder, Claudia1 aAlbrecht, Eva1 aLopez, Lorna, M1 ade Jong, Kim1 aThyagarajan, Bharat1 aAlves, Alexessander, Couto1 aEnroth, Stefan1 aOmenaas, Ernst1 aJoshi, Peter, K1 aFall, Tove1 aViñuela, Ana1 aLauner, Lenore, J1 aLoehr, Laura, R1 aFornage, Myriam1 aLi, Guo1 aWilk, Jemma, B1 aTang, Wenbo1 aManichaikul, Ani1 aLahousse, Lies1 aHarris, Tamara, B1 aNorth, Kari, E1 aRudnicka, Alicja, R1 aHui, Jennie1 aGu, Xiangjun1 aLumley, Thomas1 aWright, Alan, F1 aHastie, Nicholas, D1 aCampbell, Susan1 aKumar, Rajesh1 aPin, Isabelle1 aScott, Robert, A1 aPietiläinen, Kirsi, H1 aSurakka, Ida1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aSchulz, Holger1 aHeinrich, Joachim1 aDavies, Gail1 aVonk, Judith, M1 aWojczynski, Mary1 aPouta, Anneli1 aJohansson, Asa1 aWild, Sarah, H1 aIngelsson, Erik1 aRivadeneira, Fernando1 aVölzke, Henry1 aHysi, Pirro, G1 aEiriksdottir, Gudny1 aMorrison, Alanna, C1 aRotter, Jerome, I1 aGao, Wei1 aPostma, Dirkje, S1 aWhite, Wendy, B1 aRich, Stephen, S1 aHofman, Albert1 aAspelund, Thor1 aCouper, David1 aSmith, Lewis, J1 aPsaty, Bruce, M1 aLohman, Kurt1 aBurchard, Esteban, G1 aUitterlinden, André, G1 aGarcia, Melissa1 aJoubert, Bonnie, R1 aMcArdle, Wendy, L1 aMusk, Bill1 aHansel, Nadia1 aHeckbert, Susan, R1 aZgaga, Lina1 avan Meurs, Joyce, B J1 aNavarro, Pau1 aRudan, Igor1 aOh, Yeon-Mok1 aRedline, Susan1 aJarvis, Deborah, L1 aZhao, Jing Hua1 aRantanen, Taina1 aO'Connor, George, T1 aRipatti, Samuli1 aScott, Rodney, J1 aKarrasch, Stefan1 aGrallert, Harald1 aGaddis, Nathan, C1 aStarr, John, M1 aWijmenga, Cisca1 aMinster, Ryan, L1 aLederer, David, J1 aPekkanen, Juha1 aGyllensten, Ulf1 aCampbell, Harry1 aMorris, Andrew, P1 aGläser, Sven1 aHammond, Christopher, J1 aBurkart, Kristin, M1 aBeilby, John1 aKritchevsky, Stephen, B1 aGudnason, Vilmundur1 aHancock, Dana, B1 aWilliams, Dale1 aPolasek, Ozren1 aZemunik, Tatijana1 aKolcic, Ivana1 aPetrini, Marcy, F1 aWjst, Matthias1 aKim, Woo, Jin1 aPorteous, David, J1 aScotland, Generation1 aSmith, Blair, H1 aViljanen, Anne1 aHeliövaara, Markku1 aAttia, John, R1 aSayers, Ian1 aHampel, Regina1 aGieger, Christian1 aDeary, Ian, J1 aBoezen, Marike1 aNewman, Anne1 aJarvelin, Marjo-Riitta1 aWilson, James, F1 aLind, Lars1 aStricker, Bruno, H1 aTeumer, Alexander1 aSpector, Timothy, D1 aMelén, Erik1 aPeters, Marjolein, J1 aLange, Leslie, A1 aBarr, Graham1 aBracke, Ken, R1 aVerhamme, Fien, M1 aSung, Joohon1 aHiemstra, Pieter, S1 aCassano, Patricia, A1 aSood, Akshay1 aHayward, Caroline1 aDupuis, Josée1 aHall, Ian, P1 aBrusselle, Guy, G1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/658206414nas a2201585 4500008004100000022001400041245015100055210006900206260001300275300001300288490000700301520179000308653000902098653002002107653002802127653002202155653001102177653001102188653003102199653001902230653001702249653003802266653003402304653001102338653000902349653001602358653002602374653001402400653003602414653002102450653001702471653001102488653001502499653003302514653001702547653001802564653001802582100001502600700002502615700002402640700002402664700002002688700002702708700002502735700003202760700001802792700002302810700002202833700001802855700002102873700001802894700001902912700002302931700001702954700002102971700001602992700002803008700002403036700002003060700002703080700002003107700002603127700002203153700001603175700002403191700002103215700002103236700002003257700002003277700002503297700002503322700002403347700001603371700002203387700002003409700001503429700002003444700002103464700002303485700002803508700002203536700001903558700001903577700001903596700002303615700002203638700002203660700002003682700001403702700001703716700002003733700002203753700001803775700002803793700002303821700001903844700002003863700001803883700001903901700003003920700002103950700001703971700002003988700001904008700002104027700002604048700002204074700002404096700002204120700001904142700002804161700002004189700002104209700002204230700002004252700002004272700002404292700002004316700002004336700001804356700002104374700002904395700002004424700002304444700002204467700001504489700002004504700002704524700002304551700003004574710010804604710002604712710005404738856003604792 2014 eng d a1524-463600aGenome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.0 aGenomewide association study for circulating tissue plasminogen c2014 May a1093-1010 v343 aOBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.
APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.
CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
10aAged10aCells, Cultured10aCoronary Artery Disease10aEndothelial Cells10aEurope10aFemale10aGene Expression Regulation10aGene Silencing10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aR-SNARE Proteins10aRisk Factors10aStroke10aSyntaxin 110aTissue Plasminogen Activator10aTransfection10aUnited States10aUp-Regulation1 aHuang, Jie1 aHuffman, Jennifer, E1 aYamakuchi, Munekazu1 aYamkauchi, Munekazu1 aTrompet, Stella1 aAsselbergs, Folkert, W1 aSabater-Lleal, Maria1 aTrégouët, David-Alexandre1 aChen, Wei-Min1 aSmith, Nicholas, L1 aKleber, Marcus, E1 aShin, So-Youn1 aBecker, Diane, M1 aTang, Weihong1 aDehghan, Abbas1 aJohnson, Andrew, D1 aTruong, Vinh1 aFolkersen, Lasse1 aYang, Qiong1 aOudot-Mellkah, Tiphaine1 aBuckley, Brendan, M1 aMoore, Jason, H1 aWilliams, Frances, M K1 aCampbell, Harry1 aSilbernagel, Günther1 aVitart, Veronique1 aRudan, Igor1 aTofler, Geoffrey, H1 aNavis, Gerjan, J1 aDeStefano, Anita1 aWright, Alan, F1 aChen, Ming-Huei1 ade Craen, Anton, J M1 aWorrall, Bradford, B1 aRudnicka, Alicja, R1 aRumley, Ann1 aBookman, Ebony, B1 aPsaty, Bruce, M1 aChen, Fang1 aKeene, Keith, L1 aFranco, Oscar, H1 aBöhm, Bernhard, O1 aUitterlinden, André, G1 aCarter, Angela, M1 aJukema, Wouter1 aSattar, Naveed1 aBis, Joshua, C1 aIkram, Mohammad, A1 aSale, Michèle, M1 aMcKnight, Barbara1 aFornage, Myriam1 aFord, Ian1 aTaylor, Kent1 aSlagboom, Eline1 aMcArdle, Wendy, L1 aHsu, Fang-Chi1 aFranco-Cereceda, Anders1 aGoodall, Alison, H1 aYanek, Lisa, R1 aFurie, Karen, L1 aCushman, Mary1 aHofman, Albert1 aWitteman, Jacqueline, C M1 aFolsom, Aaron, R1 aBasu, Saonli1 aMatijevic, Nena1 aGilst, Wiek, H1 aWilson, James, F1 aWestendorp, Rudi, G J1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTracy, Russell, P1 aPolasek, Ozren1 aWinkelmann, Bernhard, R1 aGrant, Peter, J1 aHillege, Hans, L1 aCambien, Francois1 aStott, David, J1 aLowe, Gordon, D1 aSpector, Timothy, D1 aMeigs, James, B1 aMärz, Winfried1 aEriksson, Per1 aBecker, Lewis, C1 aMorange, Pierre-Emmanuel1 aSoranzo, Nicole1 aWilliams, Scott, M1 aHayward, Caroline1 aHarst, Pim1 aHamsten, Anders1 aLowenstein, Charles, J1 aStrachan, David, P1 aO'Donnell, Christopher, J1 aCohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium Neurology Working Group1 aCARDIoGRAM consortium1 aCHARGE Consortium Hemostatic Factor Working Group uhttps://chs-nhlbi.org/node/636704635nas a2200913 4500008004100000022001400041245013400055210006900189260001300258300001100271490000600282520207800288653001002366653000902376653002002385653001302405653001802418653001902436653001102455653001702466653003402483653001302517653001702530653001102547653000902558653002102567653001602588653003602604653003202640653001702672653001102689653002602700653001802726100002202744700001902766700001802785700002002803700001602823700002202839700002302861700002202884700002302906700002002929700002702949700002702976700002003003700002003023700002103043700002403064700002003088700002003108700002103128700001703149700001803166700002403184700002203208700002003230700002203250700002103272700002203293700001803315700002303333700002203356700002103378700002403399700002003423700002203443700002303465700002003488700001803508700002403526700002403550700002203574700002003596700002003616700002703636700002203663856003603685 2014 eng d a1942-326800aGenome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.0 aGenomewide association study of Larginine and dimethylarginines c2014 Dec a864-720 v73 aBACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.
METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.
10aAdult10aAged10aAmidohydrolases10aArginine10aBinding Sites10aCohort Studies10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHEK293 Cells10aHumans10aMale10aMediator Complex10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Structure, Tertiary10aRisk Factors10aStroke10aSubstrate Specificity10aTransaminases1 aLüneburg, Nicole1 aLieb, Wolfgang1 aZeller, Tanja1 aChen, Ming-Huei1 aMaas, Renke1 aCarter, Angela, M1 aXanthakis, Vanessa1 aGlazer, Nicole, L1 aSchwedhelm, Edzard1 aSeshadri, Sudha1 aIkram, Mohammad, Arfan1 aLongstreth, William, T1 aFornage, Myriam1 aKönig, Inke, R1 aLoley, Christina1 aOjeda, Francisco, M1 aSchillert, Arne1 aWang, Thomas, J1 aSticht, Heinrich1 aKittel, Anja1 aKönig, Jörg1 aBenjamin, Emelia, J1 aSullivan, Lisa, M1 aBernges, Isabel1 aAnderssohn, Maike1 aZiegler, Andreas1 aGieger, Christian1 aIllig, Thomas1 aMeisinger, Christa1 aWichmann, H-Erich1 aWild, Philipp, S1 aSchunkert, Heribert1 aPsaty, Bruce, M1 aWiggins, Kerri, L1 aHeckbert, Susan, R1 aSmith, Nicholas1 aLackner, Karl1 aLunetta, Kathryn, L1 aBlankenberg, Stefan1 aErdmann, Jeanette1 aMünzel, Thomas1 aGrant, Peter, J1 aVasan, Ramachandran, S1 aBöger, Rainer, H uhttps://chs-nhlbi.org/node/681903759nas a2200649 4500008004100000022001400041245015900055210006900214260001300283300001200296490000600308520187100314653001002185653000902195653002202204653001002226653003202236653003202268653003102300653002702331653002502358653001102383653003402394653001302428653001902441653001102460653000902471653001602480653003602496653002402532653002702556100001702583700002202600700002402622700001802646700002002664700002102684700001902705700002102724700001302745700002702758700001802785700001702803700002502820700001902845700002202864700002002886700002102906700001802927700002202945700002002967700002002987700002503007700002103032700002003053856003603073 2014 eng d a1942-326800aGenome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.0 aGenomewide association study of plasma N6 polyunsaturated fatty c2014 Jun a321-3310 v73 aBACKGROUND: Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.
METHODS AND RESULTS: To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1×10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2×10(-15), 5.0×10(-11), 7.6×10(-65), and 2.4×10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1×10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3×10(-72), 2.6×10(-151), and 6.3×10(-140), respectively).
CONCLUSIONS: Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.
10aAdult10aAged10aAged, 80 and over10aAging10aChromosomes, Human, Pair 1010aChromosomes, Human, Pair 1610aChromosomes, Human, Pair 610aFatty Acid Desaturases10aFatty Acids, Omega-610aFemale10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies10aSequence Analysis, DNA1 aGuan, Weihua1 aSteffen, Brian, T1 aLemaitre, Rozenn, N1 aH Y Wu, Jason1 aTanaka, Toshiko1 aManichaikul, Ani1 aFoy, Millennia1 aRich, Stephen, S1 aWang, Lu1 aNettleton, Jennifer, A1 aTang, Weihong1 aGu, Xiangjun1 aBandinelli, Stafania1 aKing, Irena, B1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aSiscovick, David1 aDjoussé, Luc1 aChen, Yii-Der Ida1 aFerrucci, Luigi1 aFornage, Myriam1 aMozafarrian, Dariush1 aTsai, Michael, Y1 aSteffen, Lyn, M uhttps://chs-nhlbi.org/node/656706926nas a2201669 4500008004100000022001400041245011700055210006900172260001300241300001300254490000700267520222800274653001902502653001702521653003402538653001902572653002202591653001102613653002202624653001702646653002802663653001602691100001802707700002002725700002002745700002202765700002202787700002302809700001802832700001902850700002302869700002302892700001602915700002502931700002802956700002302984700002503007700002003032700001803052700001703070700001803087700002303105700002403128700001703152700001703169700002003186700001903206700002203225700001803247700001903265700002003284700001903304700001903323700002603342700002203368700002403390700001203414700001803426700001803444700002203462700002003484700002403504700002003528700002503548700001503573700001803588700002503606700002603631700001803657700002503675700002303700700002503723700001503748700001703763700002203780700001603802700002503818700002603843700002403869700002003893700002103913700001903934700002203953700001603975700001603991700002104007700001604028700002104044700002504065700001904090700001904109700002504128700002304153700002204176700002304198700001804221700002104239700002804260700001604288700002304304700001904327700001804346700001804364700002304382700002304405700002204428700001904450700001804469700002004487700002004507700001904527700001904546700002404565700002504589700002004614700002404634700002704658700002704685700002404712700003904736700002504775700002304800700002104823700002304844700002404867700002704891700002604918700002804944700001904972700002304991700002405014700002005038700002405058700002105082700001905103700001805122700002105140700001805161700001905179700002205198856003605220 2014 eng d a1553-740400aIdentification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.0 aIdentification of novel genetic Loci associated with thyroid per c2014 Feb ae10041230 v103 aAutoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
10aAutoantibodies10aGenetic Loci10aGenome-Wide Association Study10aGraves Disease10aHashimoto Disease10aHumans10aIodide Peroxidase10aRisk Factors10aThyroiditis, Autoimmune10aThyrotropin1 aMedici, Marco1 aPorcu, Eleonora1 aPistis, Giorgio1 aTeumer, Alexander1 aBrown, Suzanne, J1 aJensen, Richard, A1 aRawal, Rajesh1 aRoef, Greet, L1 aPlantinga, Theo, S1 aVermeulen, Sita, H1 aLahti, Jari1 aSimmonds, Matthew, J1 aHusemoen, Lise, Lotte N1 aFreathy, Rachel, M1 aShields, Beverley, M1 aPietzner, Diana1 aNagy, Rebecca1 aBroer, Linda1 aChaker, Layal1 aKorevaar, Tim, I M1 aPlia, Maria, Grazia1 aSala, Cinzia1 aVölker, Uwe1 aRichards, Brent1 aSweep, Fred, C1 aGieger, Christian1 aCorre, Tanguy1 aKajantie, Eero1 aThuesen, Betina1 aTaes, Youri, E1 aVisser, Edward1 aHattersley, Andrew, T1 aKratzsch, Jürgen1 aHamilton, Alexander1 aLi, Wei1 aHomuth, Georg1 aLobina, Monia1 aMariotti, Stefano1 aSoranzo, Nicole1 aCocca, Massimiliano1 aNauck, Matthias1 aSpielhagen, Christin1 aRoss, Alec1 aArnold, Alice1 avan de Bunt, Martijn1 aLiyanarachchi, Sandya1 aHeier, Margit1 aGrabe, Hans, Jörgen1 aMasciullo, Corrado1 aGalesloot, Tessel, E1 aLim, Ee, M1 aReischl, Eva1 aLeedman, Peter, J1 aLai, Sandra1 aDelitala, Alessandro1 aBremner, Alexandra, P1 aPhilips, David, I W1 aBeilby, John, P1 aMulas, Antonella1 aVocale, Matteo1 aAbecasis, Goncalo1 aForsen, Tom1 aJames, Alan1 aWiden, Elisabeth1 aHui, Jennie1 aProkisch, Holger1 aRietzschel, Ernst, E1 aPalotie, Aarno1 aFeddema, Peter1 aFletcher, Stephen, J1 aSchramm, Katharina1 aRotter, Jerome, I1 aKluttig, Alexander1 aRadke, Dörte1 aTraglia, Michela1 aSurdulescu, Gabriela, L1 aHe, Huiling1 aFranklyn, Jayne, A1 aTiller, Daniel1 aVaidya, Bijay1 aDe Meyer, Tim1 aJørgensen, Torben1 aEriksson, Johan, G1 aO'Leary, Peter, C1 aWichmann, Eric1 aHermus, Ad, R1 aPsaty, Bruce, M1 aIttermann, Till1 aHofman, Albert1 aBosi, Emanuele1 aSchlessinger, David1 aWallaschofski, Henri1 aPirastu, Nicola1 aAulchenko, Yurii, S1 ade la Chapelle, Albert1 aNetea-Maier, Romana, T1 aGough, Stephen, C L1 aSchwabedissen, Henriette, Meyer Zu1 aFrayling, Timothy, M1 aKaufman, Jean-Marc1 aLinneberg, Allan1 aRäikkönen, Katri1 aSmit, Johannes, W A1 aKiemeney, Lambertus, A1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWalsh, John, P1 aMeisinger, Christa1 aHeijer, Martin, den1 aVisser, Theo, J1 aSpector, Timothy, D1 aWilson, Scott, G1 aVölzke, Henry1 aCappola, Anne1 aToniolo, Daniela1 aSanna, Serena1 aNaitza, Silvia1 aPeeters, Robin, P uhttps://chs-nhlbi.org/node/629404043nas a2200769 4500008004100000022001400041245014200055210006900197260001300266300001100279490000800290520183700298653001002135653002202145653000902167653001502176653002302191653002802214653001802242653001102260653001702271653003802288653002502326653003402351653001102385653002702396653001602423653003602439653001702475100001802492700002002510700001202530700001902542700001802561700002302579700002402602700001702626700001802643700002302661700001702684700001802701700002302719700002402742700002102766700001702787700002002804700001902824700001502843700002702858700002302885700002102908700002102929700002802950700002202978700002803000700002003028700002203048700002103070700001903091700002103110700002203131700001903153700002003172700002403192700002103216856003603237 2014 eng d a1432-120300aLarge multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans.0 aLarge multiethnic Candidate Gene Study for Creactive protein lev c2014 Aug a985-950 v1333 aC-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.
10aAdult10aAfrican Americans10aAged10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aCD36 Antigens10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetics, Population10aGenome-Wide Association Study10aHumans10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aEllis, Jaclyn1 aLange, Ethan, M1 aLi, Jin1 aDupuis, Josée1 aBaumert, Jens1 aWalston, Jeremy, D1 aKeating, Brendan, J1 aDurda, Peter1 aFox, Ervin, R1 aPalmer, Cameron, D1 aMeng, Yan, A1 aYoung, Taylor1 aFarlow, Deborah, N1 aSchnabel, Renate, B1 aMarzi, Carola, S1 aLarkin, Emma1 aMartin, Lisa, W1 aBis, Joshua, C1 aAuer, Paul1 aRamachandran, Vasan, S1 aGabriel, Stacey, B1 aWillis, Monte, S1 aPankow, James, S1 aPapanicolaou, George, J1 aRotter, Jerome, I1 aBallantyne, Christie, M1 aGross, Myron, D1 aLettre, Guillaume1 aWilson, James, G1 aPeters, Ulrike1 aKoenig, Wolfgang1 aTracy, Russell, P1 aRedline, Susan1 aReiner, Alex, P1 aBenjamin, Emelia, J1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/655805294nas a2201225 4500008004100000022001400041245011300055210006900168260000900237300001200246490000600258520192600264653001002190653003202200653001102232653003102243653001702274653003402291653001102325653002502336653000902361653001602370100001602386700002102402700001802423700002602441700002302467700001702490700002002507700002102527700002002548700002402568700002302592700002202615700002102637700002202658700002402680700002302704700001802727700002402745700002302769700001702792700002202809700002102831700001902852700001702871700001802888700001902906700001502925700001902940700002302959700001302982700001802995700001703013700002103030700002203051700001903073700001903092700002003111700001603131700002103147700001603168700002803184700001803212700001903230700001203249700001503261700002203276700001703298700001703315700001903332700002203351700001903373700002203392700002403414700001503438700001903453700002003472700002903492700002003521700002603541700002203567700001903589700002003608700001703628700001903645700002303664700002203687700002803709700001903737700001903756700002003775700002103795700001903816700001903835700002303854700002303877700002503900700002003925700002103945700002403966700001703990700002504007856003604032 2014 eng d a1932-620300aLarge-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.0 aLargescale genomewide association studies and metaanalyses of lo c2014 ae1007760 v93 aBACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
10aAdult10aChromosomes, Human, Pair 1110aFemale10aGene Expression Regulation10aGenetic Loci10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aMale10aRespiration1 aTang, Wenbo1 aKowgier, Matthew1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aJoubert, Bonnie, R1 aHodge, Emily1 aGharib, Sina, A1 aSmith, Albert, V1 aRuczinski, Ingo1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aHarris, Tamara, B1 aHansel, Nadia, N1 aLauner, Lenore, J1 aBarnes, Kathleen, C1 aHansen, Joyanna, G1 aAlbrecht, Eva1 aAldrich, Melinda, C1 aAllerhand, Michael1 aBarr, Graham1 aBrusselle, Guy, G1 aCouper, David, J1 aCurjuric, Ivan1 aDavies, Gail1 aDeary, Ian, J1 aDupuis, Josée1 aFall, Tove1 aFoy, Millennia1 aFranceschini, Nora1 aGao, Wei1 aGläser, Sven1 aGu, Xiangjun1 aHancock, Dana, B1 aHeinrich, Joachim1 aHofman, Albert1 aImboden, Medea1 aIngelsson, Erik1 aJames, Alan1 aKarrasch, Stefan1 aKoch, Beate1 aKritchevsky, Stephen, B1 aKumar, Ashish1 aLahousse, Lies1 aLi, Guo1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLohman, Kurt1 aLumley, Thomas1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMusk, Bill1 aNorth, Kari, E1 aPalmer, Lyle, J1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchulz, Holger1 aSmith, Lewis, J1 aSood, Akshay1 aStarr, John, M1 aStrachan, David, P1 aTeumer, Alexander1 aUitterlinden, André, G1 aVölzke, Henry1 aVoorman, Arend1 aWain, Louise, V1 aWells, Martin, T1 aWilk, Jemma, B1 aWilliams, Dale1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aLondon, Stephanie, J1 aFornage, Myriam1 aTobin, Martin, D1 aO'Connor, George, T1 aHall, Ian, P1 aCassano, Patricia, A uhttps://chs-nhlbi.org/node/660404090nas a2200949 4500008004100000022001400041245011600055210006900171260001300240300001100253490000700264520106600271653002501337653001701362653003801379653003401417653001301451653001101464653002201475653003601497653001701533100001901550700002101569700002301590700001801613700002301631700001801654700002401672700001801696700001501714700001701729700002101746700002301767700002201790700002401812700001901836700002301855700001601878700001901894700001901913700001601932700002001948700002501968700003101993700001902024700002002043700002402063700001802087700001802105700001702123700002502140700002602165700002202191700002302213700002102236700001902257700001902276700001802295700002202313700001902335700001902354700001802373700002202391700001902413700001802432700002302450700002002473700002502493710006602518710010002584710001202684710001102696710004502707710004702752710004202799710007502841710005502916710005502971710004103026710003703067856003603104 2014 eng d a1546-171800aLarge-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.0 aLargescale metaanalysis of genomewide association data identifie c2014 Sep a989-930 v463 aWe conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
10aCase-Control Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aParkinson Disease10aPolymorphism, Single Nucleotide10aRisk Factors1 aNalls, Mike, A1 aPankratz, Nathan1 aLill, Christina, M1 aDo, Chuong, B1 aHernandez, Dena, G1 aSaad, Mohamad1 aDeStefano, Anita, L1 aKara, Eleanna1 aBras, Jose1 aSharma, Manu1 aSchulte, Claudia1 aKeller, Margaux, F1 aArepalli, Sampath1 aLetson, Christopher1 aEdsall, Connor1 aStefansson, Hreinn1 aLiu, Xinmin1 aPliner, Hannah1 aLee, Joseph, H1 aCheng, Rong1 aIkram, Arfan, M1 aIoannidis, John, P A1 aHadjigeorgiou, Georgios, M1 aBis, Joshua, C1 aMartinez, Maria1 aPerlmutter, Joel, S1 aGoate, Alison1 aMarder, Karen1 aFiske, Brian1 aSutherland, Margaret1 aXiromerisiou, Georgia1 aMyers, Richard, H1 aClark, Lorraine, N1 aStefansson, Kari1 aHardy, John, A1 aHeutink, Peter1 aChen, Honglei1 aWood, Nicholas, W1 aHoulden, Henry1 aPayami, Haydeh1 aBrice, Alexis1 aScott, William, K1 aGasser, Thomas1 aBertram, Lars1 aEriksson, Nicholas1 aForoud, Tatiana1 aSingleton, Andrew, B1 aInternational Parkinson's Disease Genomics Consortium (IPDGC)1 aParkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI)1 a23andMe1 aGenePD1 aNeuroGenetics Research Consortium (NGRC)1 aHussman Institute of Human Genomics (HIHG)1 aAshkenazi Jewish Dataset Investigator1 aCohorts for Health and Aging Research in Genetic Epidemiology (CHARGE)1 aNorth American Brain Expression Consortium (NABEC)1 aUnited Kingdom Brain Expression Consortium (UKBEC)1 aGreek Parkinson's Disease Consortium1 aAlzheimer Genetic Analysis Group uhttps://chs-nhlbi.org/node/678904120nas a2200841 4500008004100000022001400041245010400055210006900159260001600228300001100244490000700255520154500262653001901807653002401826653003201850653003801882653003401920653001301954653001101967653003601978653000902014653001102023100002302034700002402057700002202081700002102103700001802124700001902142700001902161700001902180700002302199700001902222700002102241700002502262700002202287700001502309700001902324700002002343700001702363700002502380700002002405700001402425700001802439700001902457700002302476700002202499700002702521700002002548700001702568700002702585700002802612700002002640700002502660700002002685700001902705700002302724700001902747700002802766700001902794700002002813700002102833700001902854700002502873700002002898700002102918700002502939700002002964700002102984700002003005700001703025710020003042856003603242 2014 eng d a1526-632X00aMeta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12.0 aMetaanalysis in more than 17900 cases of ischemic stroke reveals c2014 Aug 19 a678-850 v833 aOBJECTIVES: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.
METHODS: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.
RESULTS: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).
CONCLUSION: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
10aBrain Ischemia10aCerebral Hemorrhage10aChromosomes, Human, Pair 1210aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aPolymorphism, Single Nucleotide10aRisk10aStroke1 aKilarski, Laura, L1 aAchterberg, Sefanja1 aDevan, William, J1 aTraylor, Matthew1 aMalik, Rainer1 aLindgren, Arne1 aPare, Guillame1 aSharma, Pankaj1 aSlowik, Agniesczka1 aThijs, Vincent1 aWalters, Matthew1 aWorrall, Bradford, B1 aSale, Michèle, M1 aAlgra, Ale1 aKappelle, Jaap1 aWijmenga, Cisca1 aNorrving, Bo1 aSandling, Johanna, K1 aRönnblom, Lars1 aGoris, An1 aFranke, Andre1 aSudlow, Cathie1 aRothwell, Peter, M1 aLevi, Christopher1 aHolliday, Elizabeth, G1 aFornage, Myriam1 aPsaty, Bruce1 aGretarsdottir, Solveig1 aThorsteinsdottir, Unnar1 aSeshadri, Sudha1 aMitchell, Braxton, D1 aKittner, Steven1 aClarke, Robert1 aHopewell, Jemma, C1 aBis, Joshua, C1 aBoncoraglio, Giorgio, B1 aMeschia, James1 aIkram, Arfan, M1 aHansen, Bjorn, M1 aMontaner, Joan1 aThorleifsson, Gudmar1 aStefanson, Kari1 aRosand, Jonathan1 ade Bakker, Paul, I W1 aFarrall, Martin1 aDichgans, Martin1 aMarkus, Hugh, S1 aBevan, Steve1 aGARNET Collaborative Research Group, Wellcome Trust Case Control Consortium 2, Australian Stroke Genetic Collaborative, the METASTROKE Consortium, and the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/657405814nas a2201345 4500008004100000022001400041245014200055210006900197260001300266300001300279490000700292520193700299653002202236653003002258653003402288653002002322653001802342653001102360653002802371653002902399653003602428653004202464100001902506700002002525700001902545700001402564700001802578700001702596700001802613700002602631700001902657700002202676700002002698700003102718700002302749700002102772700001602793700001302809700002102822700001802843700001702861700002402878700002302902700001802925700002402943700002602967700001902993700002303012700002003035700002303055700002603078700001503104700002203119700002203141700001903163700002203182700001903204700001603223700001803239700002103257700002103278700002303299700001803322700001803340700002303358700002203381700002503403700002303428700001903451700001903470700002503489700002403514700002203538700001803560700001703578700001903595700001403614700002403628700001603652700002503668700002403693700002003717700001603737700001503753700002103768700002103789700002503810700002203835700002003857700002103877700002003898700001703918700002003935700002303955700002403978700002404002700002004026700002004046700002204066700002204088700002104110700002004131700002104151700002204172700002204194700001504216700002304231700002204254710002004276710002204296710002304318710002204341710006904363856003604432 2014 eng d a1553-740400aMeta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.0 aMetaanalysis of genomewide association studies in African Americ c2014 Aug ae10045170 v103 aType 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)
10aAfrican Americans10aDiabetes Mellitus, Type 210aGenome-Wide Association Study10aHLA-B27 Antigen10aHMGA2 Protein10aHumans10aKCNQ1 Potassium Channel10aMutant Chimeric Proteins10aPolymorphism, Single Nucleotide10aTranscription Factor 7-Like 2 Protein1 aC Y Ng, Maggie1 aShriner, Daniel1 aChen, Brian, H1 aLi, Jiang1 aChen, Wei-Min1 aGuo, Xiuqing1 aLiu, Jiankang1 aBielinski, Suzette, J1 aYanek, Lisa, R1 aNalls, Michael, A1 aComeau, Mary, E1 aRasmussen-Torvik, Laura, J1 aJensen, Richard, A1 aEvans, Daniel, S1 aSun, Yan, V1 aAn, Ping1 aPatel, Sanjay, R1 aLu, Yingchang1 aLong, Jirong1 aArmstrong, Loren, L1 aWagenknecht, Lynne1 aYang, Lingyao1 aSnively, Beverly, M1 aPalmer, Nicholette, D1 aMudgal, Poorva1 aLangefeld, Carl, D1 aKeene, Keith, L1 aFreedman, Barry, I1 aMychaleckyj, Josyf, C1 aNayak, Uma1 aRaffel, Leslie, J1 aGoodarzi, Mark, O1 aChen, Y-D, Ida1 aTaylor, Herman, A1 aCorrea, Adolfo1 aSims, Mario1 aCouper, David1 aPankow, James, S1 aBoerwinkle, Eric1 aAdeyemo, Adebowale1 aDoumatey, Ayo1 aChen, Guanjie1 aMathias, Rasika, A1 aVaidya, Dhananjay1 aSingleton, Andrew, B1 aZonderman, Alan, B1 aIgo, Robert, P1 aSedor, John, R1 aKabagambe, Edmond, K1 aSiscovick, David, S1 aMcKnight, Barbara1 aRice, Kenneth1 aLiu, Yongmei1 aHsueh, Wen-Chi1 aZhao, Wei1 aBielak, Lawrence, F1 aKraja, Aldi1 aProvince, Michael, A1 aBottinger, Erwin, P1 aGottesman, Omri1 aCai, Qiuyin1 aZheng, Wei1 aBlot, William, J1 aLowe, William, L1 aPacheco, Jennifer, A1 aCrawford, Dana, C1 aGrundberg, Elin1 aRich, Stephen, S1 aHayes, Geoffrey1 aShu, Xiao-Ou1 aLoos, Ruth, J F1 aBorecki, Ingrid, B1 aPeyser, Patricia, A1 aCummings, Steven, R1 aPsaty, Bruce, M1 aFornage, Myriam1 aIyengar, Sudha, K1 aEvans, Michele, K1 aBecker, Diane, M1 aKao, Linda, W H1 aWilson, James, G1 aRotter, Jerome, I1 aSale, Michèle, M1 aLiu, Simin1 aRotimi, Charles, N1 aBowden, Donald, W1 aFIND Consortium1 aeMERGE Consortium1 aDIAGRAM Consortium1 aMuTHER Consortium1 aMEta-analysis of type 2 DIabetes in African Americans Consortium uhttps://chs-nhlbi.org/node/658503769nas a2200937 4500008004100000022001400041245009400055210006900149260001600218300001200234490000700246520111800253653002201371653001601393653002301409653004001432653001101472653001701483653002201500653003401522653001101556653001401567653001801581100002501599700001801624700001801642700002501660700002101685700001801706700002301724700002301747700002201770700001201792700002001804700002301824700002201847700002201869700002001891700002801911700002201939700002201961700002001983700002302003700001802026700002802044700001802072700002202090700002202112700001902134700002002153700001702173700002302190700002302213700002202236700002102258700001802279700002202297700002202319700002202341700002002363700002202383700001402405700001502419700002202434700002202456700002402478700002402502700002402526700001702550700002202567700001702589700002102606700002402627700002302651700002502674700002302699700002402722700002402746700002502770856003602795 2014 eng d a1460-208300aMeta-analysis of loci associated with age at natural menopause in African-American women.0 aMetaanalysis of loci associated with age at natural menopause in c2014 Jun 15 a3327-420 v233 a
Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.
10aAfrican Americans10aAge Factors10aChromosomes, Human10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMenopause10aUnited States1 aChen, Christina, T L1 aLiu, Ching-Ti1 aChen, Gary, K1 aAndrews, Jeanette, S1 aArnold, Alice, M1 aDreyfus, Jill1 aFranceschini, Nora1 aGarcia, Melissa, E1 aKerr, Kathleen, F1 aLi, Guo1 aLohman, Kurt, K1 aMusani, Solomon, K1 aNalls, Michael, A1 aRaffel, Leslie, J1 aSmith, Jennifer1 aAmbrosone, Christine, B1 aBandera, Elisa, V1 aBernstein, Leslie1 aBritton, Angela1 aBrzyski, Robert, G1 aCappola, Anne1 aCarlson, Christopher, S1 aCouper, David1 aDeming, Sandra, L1 aGoodarzi, Mark, O1 aHeiss, Gerardo1 aJohn, Esther, M1 aLu, Xiaoning1 aLe Marchand, Loïc1 aMarciante, Kristin1 aMcKnight, Barbara1 aMillikan, Robert1 aNock, Nora, L1 aOlshan, Andrew, F1 aPress, Michael, F1 aVaiyda, Dhananjay1 aWoods, Nancy, F1 aTaylor, Herman, A1 aZhao, Wei1 aZheng, Wei1 aEvans, Michele, K1 aHarris, Tamara, B1 aHenderson, Brian, E1 aKardia, Sharon, L R1 aKooperberg, Charles1 aLiu, Yongmei1 aMosley, Thomas, H1 aPsaty, Bruce1 aWellons, Melissa1 aWindham, Beverly, G1 aZonderman, Alan, B1 aCupples, Adrienne, L1 aDemerath, Ellen, W1 aHaiman, Christopher1 aMurabito, Joanne, M1 aRajkovic, Aleksandar uhttps://chs-nhlbi.org/node/655204252nas a2200745 4500008004100000022001400041245016200055210006900217260001300286300001100299490000600310520207600316653001002392653003902402653000902441653003702450653002302487653001102510653002202521653003402543653002302577653001102600653002802611653001702639653000902656653001602665653003602681653001802717653001602735100002602751700002602777700001902803700002102822700002802843700001602871700001702887700002302904700001702927700001902944700001502963700002602978700002003004700002603024700001803050700001803068700002103086700002103107700002103128700002203149700002103171700002303192700002003215700002203235700002703257700002503284700002003309700001603329700002103345700002303366700002303389700002203412700001703434700001903451856003603470 2014 eng d a1942-326800aMultiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study.0 aMultiancestral analysis of inflammationrelated genetic variants c2014 Apr a178-880 v73 aBACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.
METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).
CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
10aAdult10aAfrican Continental Ancestry Group10aAged10aAsian Continental Ancestry Group10aC-Reactive Protein10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHispanic Americans10aHumans10aIndians, North American10aInflammation10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aUnited States10aYoung Adult1 aKocarnik, Jonathan, M1 aPendergrass, Sarah, A1 aCarty, Cara, L1 aPankow, James, S1 aSchumacher, Fredrick, R1 aCheng, Iona1 aDurda, Peter1 aAmbite, Jose, Luis1 aDeelman, Ewa1 aCook, Nancy, R1 aLiu, Simin1 aWactawski-Wende, Jean1 aHutter, Carolyn1 aBrown-Gentry, Kristin1 aWilson, Sarah1 aBest, Lyle, G1 aPankratz, Nathan1 aHong, Ching-Ping1 aCole, Shelley, A1 aVoruganti, Saroja1 aBůzková, Petra1 aJorgensen, Neal, W1 aJenny, Nancy, S1 aWilkens, Lynne, R1 aHaiman, Christopher, A1 aKolonel, Laurence, N1 aLaCroix, Andrea1 aNorth, Kari1 aJackson, Rebecca1 aLe Marchand, Loïc1 aHindorff, Lucia, A1 aCrawford, Dana, C1 aGross, Myron1 aPeters, Ulrike uhttps://chs-nhlbi.org/node/636004102nas a2200769 4500008004100000022001400041245011400055210006900169260001300238300001200251490000700263520188300270653001002153653000902163653002202172653002402194653001902218653001902237653002502256653001902281653002802300653001102328653003802339653002202377653003402399653001102433653001702444653000902461653001602470653003102486653003602517653001502553653002402568653003102592653002002623653001702643653001602660653001102676100001802687700001702705700002202722700002702744700002202771700002002793700003002813700002902843700001902872700001802891700002502909700002002934700002002954700002002974700002202994700002303016700001903039700002503058700002103083700002203104700002203126700002303148700001903171700002003190700002003210700002103230710004503251856003603296 2014 eng d a1524-462800aMultilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.0 aMultilocus genetic risk score associates with ischemic stroke in c2014 Feb a394-4020 v453 aBACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.
METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.
RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.
CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.
10aAdult10aAged10aAged, 80 and over10aAtrial Fibrillation10aBlood Pressure10aBrain Ischemia10aCase-Control Studies10aCohort Studies10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMiddle Aged10aMultilocus Sequence Typing10aPolymorphism, Single Nucleotide10aPopulation10aProspective Studies10aReproducibility of Results10aRisk Assessment10aRisk Factors10aSex Factors10aStroke1 aMalik, Rainer1 aBevan, Steve1 aNalls, Michael, A1 aHolliday, Elizabeth, G1 aDevan, William, J1 aCheng, Yu-Ching1 aIbrahim-Verbaas, Carla, A1 aVerhaaren, Benjamin, F J1 aBis, Joshua, C1 aJoon, Aron, Y1 ade Stefano, Anita, L1 aFornage, Myriam1 aPsaty, Bruce, M1 aIkram, Arfan, M1 aLauner, Lenore, J1 aDuijn, Cornelia, M1 aSharma, Pankaj1 aMitchell, Braxton, D1 aRosand, Jonathan1 aMeschia, James, F1 aLevi, Christopher1 aRothwell, Peter, M1 aSudlow, Cathie1 aMarkus, Hugh, S1 aSeshadri, Sudha1 aDichgans, Martin1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/629703240nas a2200517 4500008004100000022001400041245009600055210006900151260001300220300000900233490000700242520182300249653000902072653002202081653002902103653003602132653003102168653001102199653002202210653003402232653001302266653001502279653001102294653001702305653004602322653001902368653000902387653003602396100001902432700001002451700001602461700001402477700001602491700001502507700001202522700001602534700001602550700001702566700001902583700001502602700001802617700001602635700001702651700001802668856003602686 2014 eng d a1096-002300aNovel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.0 aNovel gene variants predict serum levels of the cytokines IL18 a c2014 Jan a10-60 v653 aActivation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9×10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3×10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7×10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.
10aAged10aAged, 80 and over10aCalcium-Binding Proteins10aCARD Signaling Adaptor Proteins10aChromosomes, Human, Pair 210aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHaplotypes10aHumans10aInflammation10aInterleukin 1 Receptor Antagonist Protein10aInterleukin-1810aMale10aPolymorphism, Single Nucleotide1 aMatteini, A, M1 aLi, J1 aLange, E, M1 aTanaka, T1 aLange, L, A1 aTracy, R P1 aWang, Y1 aBiggs, M, L1 aArking, D E1 aFallin, M, D1 aChakravarti, A1 aPsaty, B M1 aBandinelli, S1 aFerrucci, L1 aReiner, A, P1 aWalston, J, D uhttps://chs-nhlbi.org/node/613304872nas a2201453 4500008004100000022001400041245010900055210006900164260001600233300000900249490000600258520072200264653002100986653003401007653001101041653005101052653002101103653003601124100001801160700002001178700002501198700002301223700001601246700002101262700002301283700001701306700002501323700002401348700002201372700002201394700001901416700001701435700002001452700001201472700002101484700002101505700002801526700002301554700002501577700002001602700002401622700001401646700002601660700002001686700001901706700002401725700001701749700001801766700001901784700002201803700001801825700002201843700001901865700002601884700002101910700002501931700002401956700001801980700002501998700002202023700002102045700001702066700002402083700001602107700001602123700001902139700002202158700001602180700001902196700001902215700001802234700002302252700001902275700002102294700001802315700002102333700002002354700003002374700002702404700001602431700002202447700001802469700001602487700001702503700002302520700001602543700002202559700002102581700002602602700002002628700002502648700002802673700002402701700002302725700002202748700001902770700002302789700002302812700002202835700002002857700002302877700002802900700001902928700002602947700002002973700002102993700002003014700002403034700001703058700002103075700002803096700002203124700002203146700002003168700002303188700002403211700002203235700001903257700002203276700001903298700002303317710004203340856003603382 2014 eng d a2041-172300aPharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.0 aPharmacogenetic metaanalysis of genomewide association studies o c2014 Oct 28 a50680 v53 aStatins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
10aCholesterol, LDL10aGenome-Wide Association Study10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aPharmacogenetics10aPolymorphism, Single Nucleotide1 aPostmus, Iris1 aTrompet, Stella1 aDeshmukh, Harshal, A1 aBarnes, Michael, R1 aLi, Xiaohui1 aWarren, Helen, R1 aChasman, Daniel, I1 aZhou, Kaixin1 aArsenault, Benoit, J1 aDonnelly, Louise, A1 aWiggins, Kerri, L1 aAvery, Christy, L1 aGriffin, Paula1 aFeng, QiPing1 aTaylor, Kent, D1 aLi, Guo1 aEvans, Daniel, S1 aSmith, Albert, V1 ade Keyser, Catherine, E1 aJohnson, Andrew, D1 ade Craen, Anton, J M1 aStott, David, J1 aBuckley, Brendan, M1 aFord, Ian1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aSattar, Naveed1 aMunroe, Patricia, B1 aSever, Peter1 aPoulter, Neil1 aStanton, Alice1 aShields, Denis, C1 aO'Brien, Eoin1 aShaw-Hawkins, Sue1 aChen, Y-D, Ida1 aNickerson, Deborah, A1 aSmith, Joshua, D1 aDubé, Marie, Pierre1 aBoekholdt, Matthijs1 aHovingh, Kees1 aKastelein, John, J P1 aMcKeigue, Paul, M1 aBetteridge, John1 aNeil, Andrew1 aDurrington, Paul, N1 aDoney, Alex1 aCarr, Fiona1 aMorris, Andrew1 aMcCarthy, Mark, I1 aGroop, Leif1 aAhlqvist, Emma1 aBis, Joshua, C1 aRice, Kenneth1 aSmith, Nicholas, L1 aLumley, Thomas1 aWhitsel, Eric, A1 aStürmer, Til1 aBoerwinkle, Eric1 aNgwa, Julius, S1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWei, Wei-Qi1 aWilke, Russell, A1 aLiu, Ching-Ti1 aSun, Fangui1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aPost, Wendy1 aSotoodehnia, Nona1 aArnold, Alice, M1 aStafford, Jeanette, M1 aDing, Jingzhong1 aHerrington, David, M1 aKritchevsky, Stephen, B1 aEiriksdottir, Gudny1 aLauner, Leonore, J1 aHarris, Tamara, B1 aChu, Audrey, Y1 aGiulianini, Franco1 aMacFadyen, Jean, G1 aBarratt, Bryan, J1 aNyberg, Fredrik1 aStricker, Bruno, H1 aUitterlinden, André, G1 aHofman, Albert1 aRivadeneira, Fernando1 aEmilsson, Valur1 aFranco, Oscar, H1 aRidker, Paul, M1 aGudnason, Vilmundur1 aLiu, Yongmei1 aDenny, Joshua, C1 aBallantyne, Christie, M1 aRotter, Jerome, I1 aCupples, Adrienne1 aPsaty, Bruce, M1 aPalmer, Colin, N A1 aTardif, Jean-Claude1 aColhoun, Helen, M1 aHitman, Graham1 aKrauss, Ronald, M1 aJukema, Wouter1 aCaulfield, Mark, J1 aWelcome Trust Case Control Consortium uhttps://chs-nhlbi.org/node/659104219nas a2200913 4500008004100000022001400041245008500055210006900140260001300209300001100222490000700233520168500240653001601925653000901941653002201950653002101972653002501993653001902018653004002037653001102077653003802088653003402126653001302160653001102173653000902184653001602193653003602209653002402245653001702269653001402286653001602300653001102316100003002327700002002357700001902377700002202396700002002418700002002438700001502458700001602473700002102489700003002510700002202540700002002562700002102582700001802603700002102621700002002642700001602662700002302678700001902701700001802720700002202738700002002760700002102780700002102801700002302822700001702845700002602862700002402888700001602912700002602928700001902954700001902973700002802992700002403020700002303044700001603067700001803083700002003101700002103121700002003142700002003162700002203182700002003204700002303224700002203247856003603269 2014 eng d a1524-462800aPredicting stroke through genetic risk functions: the CHARGE Risk Score Project.0 aPredicting stroke through genetic risk functions the CHARGE Risk c2014 Feb a403-120 v453 aBACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.
METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.
RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).
CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.
10aAge Factors10aAged10aAged, 80 and over10aArea Under Curve10aCase-Control Studies10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aROC Curve10aSex Factors10aStroke1 aIbrahim-Verbaas, Carla, A1 aFornage, Myriam1 aBis, Joshua, C1 aChoi, Seung, Hoan1 aPsaty, Bruce, M1 aMeigs, James, B1 aRao, Madhu1 aNalls, Mike1 aFontes, João, D1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aEhret, Georg, B1 aFox, Caroline, S1 aMalik, Rainer1 aDichgans, Martin1 aSchmidt, Helena1 aLahti, Jari1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Kenneth1 aRotter, Jerome, I1 aTaylor, Kent, D1 aFolsom, Aaron, R1 aBoerwinkle, Eric1 aRosamond, Wayne, D1 aShahar, Eyal1 aGottesman, Rebecca, F1 aKoudstaal, Peter, J1 aAmin, Najaf1 aWieberdink, Renske, G1 aDehghan, Abbas1 aHofman, Albert1 aUitterlinden, André, G1 aDeStefano, Anita, L1 aDebette, Stephanie1 aXue, Luting1 aBeiser, Alexa1 aWolf, Philip, A1 aDeCarli, Charles1 aIkram, Arfan, M1 aSeshadri, Sudha1 aMosley, Thomas, H1 aLongstreth, W T1 aDuijn, Cornelia, M1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/622002590nas a2200349 4500008004100000022001400041245014300055210006900198260001300267300001100280490000700291520150600298653002401804653002001828653001101848653003401859653001101893653003301904653002701937653002001964653003601984653001602020100001402036700001602050700001702066700002502083700002502108700002202133700002702155700002202182856003602204 2014 eng d a1098-227200aA robust method for genome-wide association meta-analysis with the application to circulating insulin-like growth factor I concentrations.0 arobust method for genomewide association metaanalysis with the a c2014 Feb a162-710 v383 aGenome-wide association studies (GWAS) offer an excellent opportunity to identify the genetic variants underlying complex human diseases. Successful utilization of this approach requires a large sample size to identify single nucleotide polymorphisms (SNPs) with subtle effects. Meta-analysis is a cost-efficient means to achieve large sample size by combining data from multiple independent GWAS; however, results from studies performed on different populations can be variable due to various reasons, including varied linkage equilibrium structures as well as gene-gene and gene-environment interactions. Nevertheless, one should expect effects of the SNP are more similar between similar populations than those between populations with quite different genetic and environmental backgrounds. Prior information on populations of GWAS is often not considered in current meta-analysis methods, rendering such analyses less optimal for the detecting association. This article describes a test that improves meta-analysis to incorporate variable heterogeneity among populations. The proposed method is remarkably simple in computation and hence can be performed in a rapid fashion in the setting of GWAS. Simulation results demonstrate the validity and higher power of the proposed method over conventional methods in the presence of heterogeneity. As a demonstration, we applied the test to real GWAS data to identify SNPs associated with circulating insulin-like growth factor I concentrations.
10aComputer Simulation10aGenetic Linkage10aGenome10aGenome-Wide Association Study10aHumans10aInsulin-Like Growth Factor I10aMeta-Analysis as Topic10aModels, Genetic10aPolymorphism, Single Nucleotide10aSample Size1 aWang, Tao1 aZhou, Baiyu1 aGuo, Tingwei1 aBidlingmaier, Martin1 aWallaschofski, Henri1 aTeumer, Alexander1 aVasan, Ramachandran, S1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/629603475nas a2200601 4500008004100000022001400041245017800055210006900233260001300302300001000315490000600325520173700331653001002068653000902078653001002087653002002097653001902117653001102136653003202147653002202179653003402201653001302235653001902248653001102267653000902278653002202287653001602309653003602325653002702361653001602388100001802404700002202422700002302444700002002467700002402487700002302511700001202534700002402546700001702570700002202587700002102609700001702630700001702647700002102664700001902685700002302704700002202727700002302749700002102772700001902793700002502812856003602837 2014 eng d a1942-326800aSequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aSequence variation in TMEM18 in association with body mass index c2014 Jun a344-90 v73 aBACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.
METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46×10(-4)) using a Bonferroni threshold of P<4.6×10(-4). Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11×10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3' genome-wide association study region.
CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.
10aAdult10aAged10aAging10aBody Mass Index10aCohort Studies10aFemale10aGenetic Association Studies10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aMale10aMembrane Proteins10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA10aYoung Adult1 aLiu, Ching-Ti1 aYoung, Kristin, L1 aBrody, Jennifer, A1 aOlden, Matthias1 aWojczynski, Mary, K1 aHeard-Costa, Nancy1 aLi, Guo1 aMorrison, Alanna, C1 aMuzny, Donna1 aGibbs, Richard, A1 aReid, Jeffrey, G1 aShao, Yaming1 aZhou, Yanhua1 aBoerwinkle, Eric1 aHeiss, Gerardo1 aWagenknecht, Lynne1 aMcKnight, Barbara1 aBorecki, Ingrid, B1 aFox, Caroline, S1 aNorth, Kari, E1 aCupples, Adrienne, L uhttps://chs-nhlbi.org/node/657903673nas a2200529 4500008004100000022001400041245019500055210006900250260001300319300001100332490000600343520199700349653000902346653002202355653001002377653002002387653004302407653001902450653004002469653001102509653002202520653003402542653001302576653001102589653000902600653001602609653003602625653002702661653005202688100001902740700002202759700002302781700002002804700002002824700001702844700002202861700001902883700001802902700001902920700002102939700002002960700001902980700002502999700003003024710005303054856003603107 2014 eng d a1942-326800aSequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aSequencing of 2 subclinical atherosclerosis candidate regions in c2014 Jun a359-640 v73 aBACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).
METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).
CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.
10aAged10aAged, 80 and over10aAging10aAtherosclerosis10aClass Ib Phosphatidylinositol 3-Kinase10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA10aSodium-Phosphate Cotransporter Proteins, Type I1 aBis, Joshua, C1 aWhite, Charles, C1 aFranceschini, Nora1 aBrody, Jennifer1 aZhang, Xiaoling1 aMuzny, Donna1 aSantibanez, Jireh1 aGibbs, Richard1 aLiu, Xiaoming1 aLin, Honghuang1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aNorth, Kari, E1 aCupples, Adrienne, L1 aO'Donnell, Christopher, J1 aCHARGE Subclinical Atherosclerosis Working Group uhttps://chs-nhlbi.org/node/654704324nas a2200793 4500008004100000022001400041245017800055210006900233260001300302300001100315490000600326520200100332653001002333653000902343653002202352653001002374653001902384653001102403653002202414653003402436653001302470653002802483653001902511653001102530653000902541653001602550653004002566653003602606653002702642100002202669700002302691700001902714700001902733700001902752700001702771700001802788700002402806700001602830700002002846700001902866700001902885700002302904700001902927700002402946700002502970700002202995700002403017700001903041700002903060700003003089700002403119700002403143700002003167700002203187700002203209700002203231700002203253700002103275700002003296700002103316700002103337700002103358700002003379700002203399710002203421710004103443710001003484856003603494 2014 eng d a1942-326800aSequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.0 aSequencing of SCN5A identifies rare and common variants associat c2014 Jun a365-730 v73 aBACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.
METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).
CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.
10aAdult10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Conduction System10aHeart Diseases10aHumans10aMale10aMiddle Aged10aNAV1.5 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aMagnani, Jared, W1 aBrody, Jennifer, A1 aPrins, Bram, P1 aArking, Dan, E1 aLin, Honghuang1 aYin, Xiaoyan1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aZhang, Feng1 aSpector, Tim, D1 aAlonso, Alvaro1 aBis, Joshua, C1 aHeckbert, Susan, R1 aLumley, Thomas1 aSitlani, Colleen, M1 aCupples, Adrienne, L1 aLubitz, Steven, A1 aSoliman, Elsayed, Z1 aPulit, Sara, L1 aNewton-Cheh, Christopher1 aO'Donnell, Christopher, J1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aMuzny, Donna, M1 aGibbs, Richard, A1 aSantibanez, Jireh1 aTaylor, Herman, A1 aRotter, Jerome, I1 aLange, Leslie, A1 aPsaty, Bruce, M1 aJackson, Rebecca1 aRich, Stephen, S1 aBoerwinkle, Eric1 aJamshidi, Yalda1 aSotoodehnia, Nona1 aCHARGE Consortium1 aNHLBI Exome Sequencing Project (ESP)1 aUK10K uhttps://chs-nhlbi.org/node/658304329nas a2200781 4500008004100000022001400041245012500055210006900180260001300249300001000262490000700272520197700279653001902256653002802275653003702303653003802340653003402378653001102412653001402423653003602437653003102473653001702504653001102521100002102532700001802553700002002571700002102591700001902612700002702631700002502658700002502683700002902708700002202737700003002759700002002789700002802809700002002837700002802857700002002885700002202905700001902927700002002946700002802966700002002994700002203014700002203036700002003058700002003078700002103098700001903119700002403138700002203162700001903184700002303203700002203226700001803248700002303266700002003289700002003309700002203329700002003351700002403371710002603395710002603421710001903447710004503466856003603511 2014 eng d a1524-462800aShared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.0 aShared genetic susceptibility to ischemic stroke and coronary ar c2014 Jan a24-360 v453 aBACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.
RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).
CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
10aBrain Ischemia10aCoronary Artery Disease10aData Interpretation, Statistical10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPhenotype10aPolymorphism, Single Nucleotide10aReproducibility of Results10aRisk Factors10aStroke1 aDichgans, Martin1 aMalik, Rainer1 aKönig, Inke, R1 aRosand, Jonathan1 aClarke, Robert1 aGretarsdottir, Solveig1 aThorleifsson, Gudmar1 aMitchell, Braxton, D1 aAssimes, Themistocles, L1 aLevi, Christopher1 aO'Donnell, Christopher, J1 aFornage, Myriam1 aThorsteinsdottir, Unnur1 aPsaty, Bruce, M1 aHengstenberg, Christian1 aSeshadri, Sudha1 aErdmann, Jeanette1 aBis, Joshua, C1 aPeters, Annette1 aBoncoraglio, Giorgio, B1 aMärz, Winfried1 aMeschia, James, F1 aKathiresan, Sekar1 aIkram, Arfan, M1 aMcPherson, Ruth1 aStefansson, Kari1 aSudlow, Cathie1 aReilly, Muredach, P1 aThompson, John, R1 aSharma, Pankaj1 aHopewell, Jemma, C1 aChambers, John, C1 aWatkins, Hugh1 aRothwell, Peter, M1 aRoberts, Robert1 aMarkus, Hugh, S1 aSamani, Nilesh, J1 aFarrall, Martin1 aSchunkert, Heribert1 aMETASTROKE Consortium1 aCARDIoGRAM consortium1 aC4D Consortium1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/637003990nas a2200757 4500008004100000022001400041245017100055210006900226260001300295300001100308490000600319520184400325653001002169653000902179653002202188653001002210653001902220653001102239653002202250653003402272653001302306653001902319653001102338653000902349653001602358653003602374653002002410653002702430100001902457700001402476700002302490700001902513700001902532700001902551700002202570700002102592700002402613700002102637700001802658700001802676700002002694700002302714700003002737700002302767700001602790700001702806700001902823700001402842700001602856700002402872700001902896700002402915700001802939700002202957700001902979700001702998700002403015700002403039700002303063700002003086700002003106700002503126700002403151700002103175856003603196 2014 eng d a1942-326800aStrategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aStrategies to design and analyze targeted sequencing data cohort c2014 Jun a335-430 v73 aBACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.
METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.
CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.
10aAdult10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aResearch Design10aSequence Analysis, DNA1 aLin, Honghuang1 aWang, Min1 aBrody, Jennifer, A1 aBis, Joshua, C1 aDupuis, Josée1 aLumley, Thomas1 aMcKnight, Barbara1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aReid, Jeffrey, G1 aBressler, Jan1 aLiu, Xiaoming1 aDavis, Brian, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aKovar, Christie, L1 aDinh, Huyen1 aWu, Yuanqing1 aNewsham, Irene1 aChen, Han1 aBroka, Andi1 aDeStefano, Anita, L1 aGupta, Mayetri1 aLunetta, Kathryn, L1 aLiu, Ching-Ti1 aWhite, Charles, C1 aXing, Chuanhua1 aZhou, Yanhua1 aBenjamin, Emelia, J1 aSchnabel, Renate, B1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aMuzny, Donna, M1 aCupples, Adrienne, L1 aMorrison, Alanna, C1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/657803677nas a2200613 4500008004100000022001400041245016900055210006900224260001300293300001000306490000700316520181200323653000902135653002402144653001102168653003802179653002202217653003402239653002502273653001102298653002702309653000902336653001602345653003602361653002902397100001902426700002202445700002302467700001902490700002402509700002202533700002202555700002202577700002202599700002202621700002202643700002102665700002002686700002202706700001902728700002202747700001702769700002302786700002402809700001902833700002102852700001902873700002302892700001902915700002402934700002402958710004502982856003603027 2014 eng d a1556-387100aTargeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.0 aTargeted sequencing in candidate genes for atrial fibrillation t c2014 Mar a452-70 v113 aBACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.
OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.
METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.
RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).
CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
10aAged10aAtrial Fibrillation10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHomeodomain Proteins10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-61 aLin, Honghuang1 aSinner, Moritz, F1 aBrody, Jennifer, A1 aArking, Dan, E1 aLunetta, Kathryn, L1 aRienstra, Michiel1 aLubitz, Steven, A1 aMagnani, Jared, W1 aSotoodehnia, Nona1 aMcKnight, Barbara1 aMcManus, David, D1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aBis, Joshua, C1 aGibbs, Richard, A1 aMuzny, Donna1 aKovar, Christie, L1 aMorrison, Alanna, C1 aGupta, Mayetri1 aFolsom, Aaron, R1 aKääb, Stefan1 aHeckbert, Susan, R1 aAlonso, Alvaro1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aCHARGE Atrial Fibrillation Working Group uhttps://chs-nhlbi.org/node/614904315nas a2200901 4500008004100000022001400041245006300055210006000118260001600178300001200194490000700206520174600213653002201959653003701981653001802018653004002036653001802076653003402094653001302128653001102141653002002152653001502172653002702187653001402214653003602228653002802264100002302292700002502315700002002340700002602360700002302386700002002409700002102429700002202450700002002472700002002492700002302512700002202535700001902557700002002576700002502596700001802621700001902639700002102658700002102679700002402700700002102724700001602745700001402761700002102775700002302796700002002819700002202839700002102861700001902882700001502901700001902916700002102935700001902956700002802975700002303003700002103026700001803047700002503065700002003090700002303110700002503133700002203158700003003180700002303210700002103233700002203254700001903276710002203295710001103317710004903328856003603377 2014 eng d a1460-208300aTrans-ethnic meta-analysis of white blood cell phenotypes.0 aTransethnic metaanalysis of white blood cell phenotypes c2014 Dec 20 a6944-600 v233 aWhite blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.
10aAfrican Americans10aAsian Continental Ancestry Group10aBayes Theorem10aEuropean Continental Ancestry Group10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLeukocyte Count10aLeukocytes10aLinkage Disequilibrium10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aKeller, Margaux, F1 aReiner, Alexander, P1 aOkada, Yukinori1 avan Rooij, Frank, J A1 aJohnson, Andrew, D1 aChen, Ming-Huei1 aSmith, Albert, V1 aMorris, Andrew, P1 aTanaka, Toshiko1 aFerrucci, Luigi1 aZonderman, Alan, B1 aLettre, Guillaume1 aHarris, Tamara1 aGarcia, Melissa1 aBandinelli, Stefania1 aQayyum, Rehan1 aYanek, Lisa, R1 aBecker, Diane, M1 aBecker, Lewis, C1 aKooperberg, Charles1 aKeating, Brendan1 aReis, Jared1 aTang, Hua1 aBoerwinkle, Eric1 aKamatani, Yoichiro1 aMatsuda, Koichi1 aKamatani, Naoyuki1 aNakamura, Yusuke1 aKubo, Michiaki1 aLiu, Simin1 aDehghan, Abbas1 aFelix, Janine, F1 aHofman, Albert1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aFranco, Oscar, H1 aLongo, Dan, L1 aSingleton, Andrew, B1 aPsaty, Bruce, M1 aEvans, Michelle, K1 aCupples, Adrienne, L1 aRotter, Jerome, I1 aO'Donnell, Christopher, J1 aTakahashi, Atsushi1 aWilson, James, G1 aGanesh, Santhi, K1 aNalls, Mike, A1 aCHARGE Hematology1 aCOGENT1 aBioBank Japan Project (RIKEN) Working Groups uhttps://chs-nhlbi.org/node/657305955nas a2201657 4500008004100000022001400041245011000055210006900165260001600234300001100250490000700261520138800268653001001656653000901666653002201675653002101697653001901718653001801737653001001755653001101765653002201776653001901798653001701817653003401834653001301868653001101881653001101892653000901903653001601912653001401928653003601942653002801978653002702006653001902033653002702052653002602079100002102105700001402126700001402140700001602154700002202170700002202192700001702214700002002231700002102251700002102272700001302293700002002306700001702326700001502343700001702358700002002375700001402395700002702409700001802436700002202454700001602476700001902492700001702511700002102528700002302549700002002572700001802592700002202610700001802632700001502650700001202665700001702677700001502694700001802709700001902727700001902746700001902765700002502784700002602809700002102835700002502856700002102881700001902902700002502921700001702946700002502963700001202988700002303000700002003023700002603043700002903069700002303098700002803121700001803149700002003167700002303187700002103210700001903231700001803250700002803268700001903296700002403315700002303339700002803362700001703390700002203407700002203429700002403451700002403475700002003499700002303519700002203542700001603564700001703580700002403597700002003621700001803641700002003659700002103679700001603700700001903716700002203735700002803757700002303785700003003808700001903838700001903857700002503876700002103901700002003922700002103942700002203963700001603985700002004001700002504021700002404046700002104070700002604091700002504117700002104142700002204163700002304185710005304208856003604261 2014 eng d a1537-660500aWhole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.0 aWholeexome sequencing identifies rare and lowfrequency coding va c2014 Feb 06 a233-450 v943 aElevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
10aAdult10aAged10aApolipoproteins E10aCholesterol, LDL10aCohort Studies10aDyslipidemias10aExome10aFemale10aFollow-Up Studies10aGene Frequency10aGenetic Code10aGenome-Wide Association Study10aGenotype10aHumans10aLipase10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aProprotein Convertase 910aProprotein Convertases10aReceptors, LDL10aSequence Analysis, DNA10aSerine Endopeptidases1 aLange, Leslie, A1 aHu, Youna1 aZhang, He1 aXue, Chenyi1 aSchmidt, Ellen, M1 aTang, Zheng-Zheng1 aBizon, Chris1 aLange, Ethan, M1 aSmith, Joshua, D1 aTurner, Emily, H1 aJun, Goo1 aKang, Hyun, Min1 aPeloso, Gina1 aAuer, Paul1 aLi, Kuo-Ping1 aFlannick, Jason1 aZhang, Ji1 aFuchsberger, Christian1 aGaulton, Kyle1 aLindgren, Cecilia1 aLocke, Adam1 aManning, Alisa1 aSim, Xueling1 aRivas, Manuel, A1 aHolmen, Oddgeir, L1 aGottesman, Omri1 aLu, Yingchang1 aRuderfer, Douglas1 aStahl, Eli, A1 aDuan, Qing1 aLi, Yun1 aDurda, Peter1 aJiao, Shuo1 aIsaacs, Aaron1 aHofman, Albert1 aBis, Joshua, C1 aCorrea, Adolfo1 aGriswold, Michael, E1 aJakobsdottir, Johanna1 aSmith, Albert, V1 aSchreiner, Pamela, J1 aFeitosa, Mary, F1 aZhang, Qunyuan1 aHuffman, Jennifer, E1 aCrosby, Jacy1 aWassel, Christina, L1 aDo, Ron1 aFranceschini, Nora1 aMartin, Lisa, W1 aRobinson, Jennifer, G1 aAssimes, Themistocles, L1 aCrosslin, David, R1 aRosenthal, Elisabeth, A1 aTsai, Michael1 aRieder, Mark, J1 aFarlow, Deborah, N1 aFolsom, Aaron, R1 aLumley, Thomas1 aFox, Ervin, R1 aCarlson, Christopher, S1 aPeters, Ulrike1 aJackson, Rebecca, D1 aDuijn, Cornelia, M1 aUitterlinden, André, G1 aLevy, Daniel1 aRotter, Jerome, I1 aTaylor, Herman, A1 aGudnason, Vilmundur1 aSiscovick, David, S1 aFornage, Myriam1 aBorecki, Ingrid, B1 aHayward, Caroline1 aRudan, Igor1 aChen, Eugene1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSætrom, Pål1 aHveem, Kristian1 aBoehnke, Michael1 aGroop, Leif1 aMcCarthy, Mark1 aMeitinger, Thomas1 aBallantyne, Christie, M1 aGabriel, Stacey, B1 aO'Donnell, Christopher, J1 aPost, Wendy, S1 aNorth, Kari, E1 aReiner, Alexander, P1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aAltshuler, David1 aKathiresan, Sekar1 aLin, Dan-Yu1 aJarvik, Gail, P1 aCupples, Adrienne, L1 aKooperberg, Charles1 aWilson, James, G1 aNickerson, Deborah, A1 aAbecasis, Goncalo, R1 aRich, Stephen, S1 aTracy, Russell, P1 aWiller, Cristen, J1 aNHLBI Grand Opportunity Exome Sequencing Project uhttps://chs-nhlbi.org/node/657703472nas a2200781 4500008004100000022001400041245008200055210006900137260001300206300001500219490000700234520128200241653001001523653001201533653002201545653002201567653001001589653001101599653003401610653001601644653001101660653003101671653000901702653001501711653003601726653000901762653004101771100002001812700002201832700001901854700002101873700001201894700002801906700002601934700002501960700002601985700002102011700001502032700001602047700002102063700002002084700002102104700001902125700002202144700002802166700002202194700002302216700002102239700002002260700002302280700002202303700002202325700002202347700001902369700002102388700002402409700002302433700002202456700002202478700002702500700002202527700002002549700002202569700002002591700002002611700002302631856003602654 2015 eng d a1558-149700aAssociation of Alzheimer's disease GWAS loci with MRI markers of brain aging.0 aAssociation of Alzheimers disease GWAS loci with MRI markers of c2015 Apr a1765.e7-160 v363 aWhether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.
10aAging10aAlleles10aAlzheimer Disease10aApolipoproteins E10aBrain10aFemale10aGenome-Wide Association Study10aHippocampus10aHumans10aMagnetic Resonance Imaging10aMale10aOrgan Size10aPolymorphism, Single Nucleotide10aRisk10aSialic Acid Binding Ig-like Lectin 31 aChauhan, Ganesh1 aAdams, Hieab, H H1 aBis, Joshua, C1 aWeinstein, Galit1 aYu, Lei1 aTöglhofer, Anna, Maria1 aSmith, Albert, Vernon1 avan der Lee, Sven, J1 aGottesman, Rebecca, F1 aThomson, Russell1 aWang, Jing1 aYang, Qiong1 aNiessen, Wiro, J1 aLopez, Oscar, L1 aBecker, James, T1 aPhan, Thanh, G1 aBeare, Richard, J1 aArfanakis, Konstantinos1 aFleischman, Debra1 aVernooij, Meike, W1 aMazoyer, Bernard1 aSchmidt, Helena1 aSrikanth, Velandai1 aKnopman, David, S1 aJack, Clifford, R1 aAmouyel, Philippe1 aHofman, Albert1 aDeCarli, Charles1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aBennett, David, A1 aSchmidt, Reinhold1 aLongstreth, William, T1 aMosley, Thomas, H1 aFornage, Myriam1 aLauner, Lenore, J1 aSeshadri, Sudha1 aIkram, Arfan, M1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/681504486nas a2200901 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520184700254653001002101653002202111653002302133653002802156653001902184653004002203653001002243653001102253653001902264653003802283653003402321653003802355653001102393653000902404653001102413653003602424653002902460653001702489100002202506700001802528700001902546700001902565700001402584700002102598700002102619700002002640700002402660700001902684700002802703700002002731700002202751700001202773700002402785700002402809700002102833700002002854700002102874700001902895700002102914700001602935700002002951700001502971700001902986700002003005700001803025700002103043700001803064700002203082700002403104700002303128700002303151700001903174700002603193700002203219700001903241700001903260700002103279700002103300700002403321700002403345700002003369700002003389710006503409710007403474856003603548 2015 eng d a1460-208300aAssociation of exome sequences with plasma C-reactive protein levels in >9000 participants.0 aAssociation of exome sequences with plasma Creactive protein lev c2015 Jan 15 a559-710 v243 aC-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.
10aAdult10aAfrican Americans10aC-Reactive Protein10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aExome10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHepatocyte Nuclear Factor 1-alpha10aHumans10aMale10aPlasma10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-610aRisk Factors1 aSchick, Ursula, M1 aAuer, Paul, L1 aBis, Joshua, C1 aLin, Honghuang1 aWei, Peng1 aPankratz, Nathan1 aLange, Leslie, A1 aBrody, Jennifer1 aStitziel, Nathan, O1 aKim, Daniel, S1 aCarlson, Christopher, S1 aFornage, Myriam1 aHaessler, Jeffery1 aHsu, Li1 aJackson, Rebecca, D1 aKooperberg, Charles1 aLeal, Suzanne, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aTracy, Russell1 aArdissino, Diego1 aShah, Svati1 aWiller, Cristen1 aLoos, Ruth1 aMelander, Olle1 aMcPherson, Ruth1 aHovingh, Kees1 aReilly, Muredach1 aWatkins, Hugh1 aGirelli, Domenico1 aFontanillas, Pierre1 aChasman, Daniel, I1 aGabriel, Stacey, B1 aGibbs, Richard1 aNickerson, Deborah, A1 aKathiresan, Sekar1 aPeters, Ulrike1 aDupuis, Josée1 aWilson, James, G1 aRich, Stephen, S1 aMorrison, Alanna, C1 aBenjamin, Emelia, J1 aGross, Myron, D1 aReiner, Alex, P1 aCohorts for Heart and Aging Research in Genomic Epidemiology1 aNational Heart, Lung, and Blood Institute GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659705848nas a2201069 4500008004100000022001400041245018600055210006900241260001300310300001200323490000800335520268400343653001803027653001903045653003203064653003803096653003403134653001103168653001803179653002003197653001203217653002303229653002803252653000903280653001803289653001603307653003603323653001703359100002203376700002003398700002703418700002403445700002003469700002403489700003203513700002003545700002803565700002303593700001603616700002003632700002903652700001903681700003203700700002503732700001803757700002003775700001903795700002303814700002103837700002203858700002003880700002303900700002403923700002103947700002103968700002603989700002104015700002004036700002104056700001804077700002504095700001704120700002004137700002304157700002404180700002204204700001904226700001604245700002004261700002104281700002404302700002104326700001704347700002104364700002804385700002004413700002104433700002004454700002504474700002304499700002004522700002104542700001904563700002304582700002504605700002104630700002204651700002504673700002004698700002404718856003604742 2015 eng d a1938-320700aConsumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians.0 aConsumption of meat is associated with higher fasting glucose an c2015 Nov a1266-780 v1023 aBACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.
OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.
DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.
RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.
CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
10aBlood Glucose10aCohort Studies10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHyperglycemia10aHyperinsulinism10aInsulin10aInsulin Resistance10aInsulin-Secreting Cells10aMeat10aMeat Products10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aFretts, Amanda, M1 aFollis, Jack, L1 aNettleton, Jennifer, A1 aLemaitre, Rozenn, N1 aNgwa, Julius, S1 aWojczynski, Mary, K1 aKalafati, Ioanna, Panagiota1 aVarga, Tibor, V1 aFrazier-Wood, Alexis, C1 aHouston, Denise, K1 aLahti, Jari1 aEricson, Ulrika1 avan den Hooven, Edith, H1 aMikkilä, Vera1 ade Jong, Jessica, C Kiefte-1 aMozaffarian, Dariush1 aRice, Kenneth1 aRenstrom, Frida1 aNorth, Kari, E1 aMcKeown, Nicola, M1 aFeitosa, Mary, F1 aKanoni, Stavroula1 aSmith, Caren, E1 aGarcia, Melissa, E1 aTiainen, Anna-Maija1 aSonestedt, Emily1 aManichaikul, Ani1 avan Rooij, Frank, J A1 aDimitriou, Maria1 aRaitakari, Olli1 aPankow, James, S1 aDjoussé, Luc1 aProvince, Michael, A1 aHu, Frank, B1 aLai, Chao-Qiang1 aKeller, Margaux, F1 aPerälä, Mia-Maria1 aRotter, Jerome, I1 aHofman, Albert1 aGraff, Misa1 aKähönen, Mika1 aMukamal, Kenneth1 aJohansson, Ingegerd1 aOrdovas, Jose, M1 aLiu, Yongmei1 aMännistö, Satu1 aUitterlinden, André, G1 aDeloukas, Panos1 aSeppälä, Ilkka1 aPsaty, Bruce, M1 aCupples, Adrienne, L1 aBorecki, Ingrid, B1 aFranks, Paul, W1 aArnett, Donna, K1 aNalls, Mike, A1 aEriksson, Johan, G1 aOrho-Melander, Marju1 aFranco, Oscar, H1 aLehtimäki, Terho1 aDedoussis, George, V1 aMeigs, James, B1 aSiscovick, David, S uhttps://chs-nhlbi.org/node/684401913nas a2200229 4500008004100000022001400041245008600055210006900141260001300210300001100223490000700234520117200241653001501413653002201428653001001450653003801460653003401498653001101532653003601543110006801579856003601647 2015 eng d a1552-527900aConvergent genetic and expression data implicate immunity in Alzheimer's disease.0 aConvergent genetic and expression data implicate immunity in Alz c2015 Jun a658-710 v113 aBACKGROUND: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.
METHODS: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.
RESULTS: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10(-11)), cholesterol transport (P = 2.96 × 10(-9)), and proteasome-ubiquitin activity (P = 1.34 × 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05).
CONCLUSIONS: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
10aAlgorithms10aAlzheimer Disease10aBrain10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide1 aInternational Genomics of Alzheimer's Disease Consortium (IGAP) uhttps://chs-nhlbi.org/node/701803409nas a2200625 4500008004100000022001400041245006700055210006500122260001300187300001100200490000700211520169000218653001201908653002101920653003101941653003401972653001102006653001502017653001302032653001702045653001302062653002502075100002102100700002302121700001702144700002002161700001802181700002402199700002102223700001902244700002002263700001602283700002002299700002202319700001702341700002002358700002102378700002302399700001902422700002002441700001702461700002402478700002802502700001402530700002402544700002202568700002402590700002002614700002402634700002302658700002402681700002402705700001802729856003602747 2015 eng d a1468-624400aDCAF4, a novel gene associated with leucocyte telomere length.0 aDCAF4 a novel gene associated with leucocyte telomere length c2015 Mar a157-620 v523 aBACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).
RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24).
CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.
10aAlleles10aCarrier Proteins10aGene Expression Regulation10aGenome-Wide Association Study10aHumans10aLeukocytes10aMelanoma10aRisk Factors10aTelomere10aTelomere Homeostasis1 aMangino, Massimo1 aChristiansen, Lene1 aStone, Rivka1 aHunt, Steven, C1 aHorvath, Kent1 aEisenberg, Dan, T A1 aKimura, Masayuki1 aPetersen, Inge1 aKark, Jeremy, D1 aHerbig, Utz1 aReiner, Alex, P1 aBenetos, Athanase1 aCodd, Veryan1 aNyholt, Dale, R1 aSinnreich, Ronit1 aChristensen, Kaare1 aNassar, Hisham1 aHwang, Shih-Jen1 aLevy, Daniel1 aBataille, Veronique1 aFitzpatrick, Annette, L1 aChen, Wei1 aBerenson, Gerald, S1 aSamani, Nilesh, J1 aMartin, Nicholas, G1 aTishkoff, Sarah1 aSchork, Nicholas, J1 aKyvik, Kirsten Ohm1 aDalgård, Christine1 aSpector, Timothy, D1 aAviv, Abraham uhttps://chs-nhlbi.org/node/681705255nas a2200949 4500008004100000022001400041245015700055210006900212260000900281300001300290490000700303520251800310653002202828653000902850653002802859653002802887653004002915653001102955653003402966653001103000653001703011653001403028653000903042653001603051653003603067653002203103100001903125700002103144700001603165700002203181700002603203700001603229700002103245700002303266700001603289700002003305700002203325700002203347700002103369700002303390700002303413700002003436700002203456700002303478700002103501700002203522700002003544700002103564700002203585700001803607700002003625700002503645700002203670700002303692700001703715700002103732700002303753700002403776700002003800700002103820700002203841700002503863700002803888700002203916700001403938700001903952700001903971700002003990700002604010700002404036700002704060700001904087700002404106700002204130700001604152700001904168700002304187700002104210700002004231700001804251856003604269 2015 eng d a1932-620300aDrug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.0 aDrugGene Interactions of Antihypertensive Medications and Risk o c2015 ae01404960 v103 aBACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.
10aAfrican Americans10aAged10aAntihypertensive Agents10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aHypertension10aIncidence10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTreatment Outcome1 aBis, Joshua, C1 aSitlani, Colleen1 aIrvin, Ryan1 aAvery, Christy, L1 aSmith, Albert, Vernon1 aSun, Fangui1 aEvans, Daniel, S1 aMusani, Solomon, K1 aLi, Xiaohui1 aTrompet, Stella1 aKrijthe, Bouwe, P1 aHarris, Tamara, B1 aQuibrera, Miguel1 aBrody, Jennifer, A1 aDemissie, Serkalem1 aDavis, Barry, R1 aWiggins, Kerri, L1 aTranah, Gregory, J1 aLange, Leslie, A1 aSotoodehnia, Nona1 aStott, David, J1 aFranco, Oscar, H1 aLauner, Lenore, J1 aStürmer, Til1 aTaylor, Kent, D1 aCupples, Adrienne, L1 aEckfeldt, John, H1 aSmith, Nicholas, L1 aLiu, Yongmei1 aWilson, James, G1 aHeckbert, Susan, R1 aBuckley, Brendan, M1 aIkram, Arfan, M1 aBoerwinkle, Eric1 aChen, Yii-Der Ida1 ade Craen, Anton, J M1 aUitterlinden, André, G1 aRotter, Jerome, I1 aFord, Ian1 aHofman, Albert1 aSattar, Naveed1 aSlagboom, Eline1 aWestendorp, Rudi, G J1 aGudnason, Vilmundur1 aVasan, Ramachandran, S1 aLumley, Thomas1 aCummings, Steven, R1 aTaylor, Herman, A1 aPost, Wendy1 aJukema, Wouter1 aStricker, Bruno, H1 aWhitsel, Eric, A1 aPsaty, Bruce, M1 aArnett, Donna uhttps://chs-nhlbi.org/node/687504825nas a2201141 4500008004100000022001400041245010700055210007000162260001600232300001200248490000700260520164000267653001001907653002001917653002501937653001801962653002301980653004002003653001102043653001702054653003402071653001102105653000902116653001202125653003602137100002702173700002002200700002002220700002002240700001902260700002002279700002402299700002002323700002402343700002302367700002402390700002302414700002402437700001402461700002102475700002102496700002202517700001802539700001902557700001902576700002402595700001902619700002302638700002402661700002002685700001702705700001602722700001702738700002502755700001502780700001802795700001902813700002002832700001402852700002002866700002102886700002102907700002102928700001602949700002002965700002102985700002603006700002003032700001703052700002003069700001803089700001903107700001903126700001903145700002303164700001903187700002803206700002403234700002103258700002503279700002003304700002303324700001603347700002803363700002303391700002503414700001103439700002003450700002503470700002503495700002003520700002203540700002003562700002503582700002003607700002003627856003603647 2015 eng d a1460-208300aGene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry.0 aGene × dietary pattern interactions in obesity analysis of up to c2015 Aug 15 a4728-380 v243 aObesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.
10aAdult10aBody Mass Index10aCase-Control Studies10aDiet, Western10aEpistasis, Genetic10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aObesity10aPolymorphism, Single Nucleotide1 aNettleton, Jennifer, A1 aFollis, Jack, L1 aNgwa, Julius, S1 aSmith, Caren, E1 aAhmad, Shafqat1 aTanaka, Toshiko1 aWojczynski, Mary, K1 aVoortman, Trudy1 aLemaitre, Rozenn, N1 aKristiansson, Kati1 aNuotio, Marja-Liisa1 aHouston, Denise, K1 aPerälä, Mia-Maria1 aQi, Qibin1 aSonestedt, Emily1 aManichaikul, Ani1 aKanoni, Stavroula1 aGanna, Andrea1 aMikkilä, Vera1 aNorth, Kari, E1 aSiscovick, David, S1 aHarald, Kennet1 aMcKeown, Nicola, M1 aJohansson, Ingegerd1 aRissanen, Harri1 aLiu, Yongmei1 aLahti, Jari1 aHu, Frank, B1 aBandinelli, Stefania1 aRukh, Gull1 aRich, Stephen1 aBooij, Lisanne1 aDmitriou, Maria1 aAx, Erika1 aRaitakari, Olli1 aMukamal, Kenneth1 aMännistö, Satu1 aHallmans, Göran1 aJula, Antti1 aEricson, Ulrika1 aJacobs, David, R1 avan Rooij, Frank, J A1 aDeloukas, Panos1 aSjogren, Per1 aKähönen, Mika1 aDjoussé, Luc1 aPerola, Markus1 aBarroso, Inês1 aHofman, Albert1 aStirrups, Kathleen1 aViikari, Jorma1 aUitterlinden, André, G1 aKalafati, Ioanna, P1 aFranco, Oscar, H1 aMozaffarian, Dariush1 aSalomaa, Veikko1 aBorecki, Ingrid, B1 aKnekt, Paul1 aKritchevsky, Stephen, B1 aEriksson, Johan, G1 aDedoussis, George, V1 aQi, Lu1 aFerrucci, Luigi1 aOrho-Melander, Marju1 aZillikens, Carola, M1 aIngelsson, Erik1 aLehtimäki, Terho1 aRenstrom, Frida1 aCupples, Adrienne, L1 aLoos, Ruth, J F1 aFranks, Paul, W uhttps://chs-nhlbi.org/node/680203195nas a2200577 4500008004100000022001400041245014300055210006900198260001300267300001100280490000700291520150000298653001001798653002201808653000901830653004001839653001601879653001101895653001701906653003401923653001101957653000901968653003501977653001602012653003602028653002702064653002602091100001802117700001802135700001702153700002102170700002102191700001602212700002202228700002402250700001702274700002102291700002402312700001802336700002202354700002102376700002302397700002302420700001802443700002102461700003002482700002302512700002502535700002102560856003602581 2015 eng d a1096-865200aGene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.0 aGenecentric approach identifies new and known loci for FVIII act c2015 Jun a534-400 v903 aCoagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.
10aAdult10aAfrican Americans10aAged10aEuropean Continental Ancestry Group10aFactor VIII10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMethionine Adenosyltransferase10aMiddle Aged10aPolymorphism, Single Nucleotide10aVenous Thromboembolism10avon Willebrand Factor1 aTang, Weihong1 aCushman, Mary1 aGreen, David1 aRich, Stephen, S1 aLange, Leslie, A1 aYang, Qiong1 aTracy, Russell, P1 aTofler, Geoffrey, H1 aBasu, Saonli1 aWilson, James, G1 aKeating, Brendan, J1 aWeng, Lu-Chen1 aTaylor, Herman, A1 aJacobs, David, R1 aDelaney, Joseph, A1 aPalmer, Cameron, D1 aYoung, Taylor1 aPankow, James, S1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aReiner, Alexander, P1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/737602719nas a2200469 4500008004100000022001400041245010800055210006900163260001600232300001100248490000700259520132600266653000901592653001001601653002801611653001901639653002401658653002801682653003401710653003301744653002201777653001801799653003401817653001101851653002501862653002701887653002001914653002101934653002001955653001801975100002401993700002102017700001902038700002202057700002502079700002202104700002102126700002502147700002102172700002002193856003602213 2015 eng d a1097-025800aGeneralized estimating equations for genome-wide association studies using longitudinal phenotype data.0 aGeneralized estimating equations for genomewide association stud c2015 Jan 15 a118-300 v343 aMany longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.
10aAged10aAging10aCardiovascular Diseases10aCohort Studies10aComputer Simulation10aCross-Sectional Studies10aEpidemiologic Research Design10aGene-Environment Interaction10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aMeta-Analysis as Topic10aModels, Genetic10aPharmacogenetics10aRisk Assessment10aUnited States1 aSitlani, Colleen, M1 aRice, Kenneth, M1 aLumley, Thomas1 aMcKnight, Barbara1 aCupples, Adrienne, L1 aAvery, Christy, L1 aNoordam, Raymond1 aStricker, Bruno, H C1 aWhitsel, Eric, A1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/660203799nas a2200637 4500008004100000022001400041245010600055210006900161260001300230300001000243490000700253520205800260653000902318653002202327653001202349653001002361653001402371653001302385653001102398653003402409653001102443653002602454653000902480653003602489653000902525653002102534653001702555653001702572653003502589653001702624100002002641700001602661700002102677700002902698700002702727700002002754700001702774700001702791700002002808700001802828700001902846700002102865700001602886700002002902700002002922700002302942700001902965700001902984700002203003700002003025700002303045700001603068700001803084700002303102856003603125 2015 eng d a1524-462800aGenes from a translational analysis support a multifactorial nature of white matter hyperintensities.0 aGenes from a translational analysis support a multifactorial nat c2015 Feb a341-70 v463 aBACKGROUND AND PURPOSE: White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative.
METHODS: We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE.
RESULTS: Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1).
CONCLUSIONS: Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.
10aAged10aAlzheimer Disease10aAnimals10aBrain10aCausality10aDementia10aFemale10aGenome-Wide Association Study10aHumans10aLeukoencephalopathies10aMale10aPolymorphism, Single Nucleotide10aRats10aRats, Inbred SHR10aRats, Wistar10aRisk Factors10aTranslational Medical Research10aWhite Matter1 aLopez, Lorna, M1 aHill, David1 aHarris, Sarah, E1 aHernandez, Maria, Valdes1 aManiega, Susana, Munoz1 aBastin, Mark, E1 aBailey, Emma1 aSmith, Colin1 aMcBride, Martin1 aMcClure, John1 aGraham, Delyth1 aDominiczak, Anna1 aYang, Qiong1 aFornage, Myriam1 aIkram, Arfan, M1 aDebette, Stephanie1 aLauner, Lenore1 aBis, Joshua, C1 aSchmidt, Reinhold1 aSeshadri, Sudha1 aPorteous, David, J1 aStarr, John1 aDeary, Ian, J1 aWardlaw, Joanna, M uhttps://chs-nhlbi.org/node/681806452nas a2201885 4500008004100000022001400041245015700055210006900212260001300281300001100294490000700305520181900312653000902131653002202140653002002162653001402182653002402196653001902220653001102239653003802250653003402288653001802322653001102340653000902351653001602360653002902376653001402405653003602419653001302455100001402468700001702482700001302499700001602512700001602528700001702544700001302561700002602574700001302600700001302613700002202626700001802648700001102666700001802677700001702695700001502712700001502727700001602742700001802758700001502776700001402791700001202805700001002817700001302827700001202840700001402852700001702866700001502883700001802898700001502916700001302931700001202944700001202956700001502968700001802983700001003001700001703011700001403028700001203042700001503054700001803069700001803087700001603105700001403121700001903135700001503154700001903169700001603188700001503204700001203219700002003231700001903251700001603270700001603286700001303302700001403315700001903329700001503348700001903363700001403382700001803396700001503414700001703429700001103446700001003457700001203467700001803479700001603497700002103513700001703534700001703551700001603568700001403584700001603598700001503614700001703629700001403646700001603660700001503676700001503691700001503706700001803721700001603739700001503755700001403770700002003784700001603804700001603820700001603836700002203852700001703874700001503891700001503906700002203921700001703943700001303960700001803973700001703991700001604008700001704024700001204041700001404053700001604067700001804083700001504101700002104116700001504137700001604152700002004168700001704188700001904205700001904224700001604243700001304259700001804272700001504290700002004305700001604325700001604341700001604357700001504373700001604388700001704404700001404421700002204435700001604457700001704473700001604490710002404506856003604530 2015 eng d a1476-557800aGenetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).0 aGenetic contributions to variation in general cognitive function c2015 Feb a183-920 v203 aGeneral cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
10aAged10aAged, 80 and over10aAtherosclerosis10aCognition10aCognition Disorders10aCohort Studies10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHMGN1 Protein10aHumans10aMale10aMiddle Aged10aNeuropsychological Tests10aPhenotype10aPolymorphism, Single Nucleotide10aScotland1 aDavies, G1 aArmstrong, N1 aBis, J C1 aBressler, J1 aChouraki, V1 aGiddaluru, S1 aHofer, E1 aIbrahim-Verbaas, C, A1 aKirin, M1 aLahti, J1 avan der Lee, S, J1 aLe Hellard, S1 aLiu, T1 aMarioni, R, E1 aOldmeadow, C1 aPostmus, I1 aSmith, A V1 aSmith, J, A1 aThalamuthu, A1 aThomson, R1 aVitart, V1 aWang, J1 aYu, L1 aZgaga, L1 aZhao, W1 aBoxall, R1 aHarris, S, E1 aHill, W, D1 aLiewald, D, C1 aLuciano, M1 aAdams, H1 aAmes, D1 aAmin, N1 aAmouyel, P1 aAssareh, A, A1 aAu, R1 aBecker, J, T1 aBeiser, A1 aBerr, C1 aBertram, L1 aBoerwinkle, E1 aBuckley, B, M1 aCampbell, H1 aCorley, J1 aDe Jager, P, L1 aDufouil, C1 aEriksson, J, G1 aEspeseth, T1 aFaul, J, D1 aFord, I1 aGottesman, R, F1 aGriswold, M, E1 aGudnason, V1 aHarris, T B1 aHeiss, G1 aHofman, A1 aHolliday, E, G1 aHuffman, J1 aKardia, S, L R1 aKochan, N1 aKnopman, D, S1 aKwok, J, B1 aLambert, J-C1 aLee, T1 aLi, G1 aLi, S-C1 aLoitfelder, M1 aLopez, O, L1 aLundervold, A, J1 aLundqvist, A1 aMather, K, A1 aMirza, S, S1 aNyberg, L1 aOostra, B A1 aPalotie, A1 aPapenberg, G1 aPattie, A1 aPetrovic, K1 aPolasek, O1 aPsaty, B M1 aRedmond, P1 aReppermund, S1 aRotter, J I1 aSchmidt, H1 aSchuur, M1 aSchofield, P, W1 aScott, R, J1 aSteen, V, M1 aStott, D, J1 avan Swieten, J, C1 aTaylor, K, D1 aTrollor, J1 aTrompet, S1 aUitterlinden, A G1 aWeinstein, G1 aWiden, E1 aWindham, B, G1 aJukema, J, W1 aWright, A F1 aWright, M, J1 aYang, Q1 aAmieva, H1 aAttia, J, R1 aBennett, D, A1 aBrodaty, H1 ade Craen, A, J M1 aHayward, C1 aIkram, M, A1 aLindenberger, U1 aNilsson, L-G1 aPorteous, D, J1 aRäikkönen, K1 aReinvang, I1 aRudan, I1 aSachdev, P, S1 aSchmidt, R1 aSchofield, P, R1 aSrikanth, V1 aStarr, J, M1 aTurner, S T1 aWeir, D, R1 aWilson, J F1 avan Duijn, C1 aLauner, L1 aFitzpatrick, A, L1 aSeshadri, S1 aMosley, T, H1 aDeary, I, J1 aGeneration Scotland uhttps://chs-nhlbi.org/node/681602945nas a2200589 4500008004100000022001400041245009400055210006900149260001300218300001100231490000700242520132000249653001901569653001601588653001701604653002201621653003401643653001101677100002401688700001901712700002501731700001801756700002201774700002101796700001701817700001201834700002301846700001901869700001301888700001701901700002401918700002101942700002101963700002001984700001802004700002102022700001802043700001802061700001502079700002202094700001902116700002102135700002102156700002502177700001702202700001802219700001702237700002002254700002002274700002502294856003602319 2015 eng d a1539-726200aGenetic loci associated with circulating levels of very long-chain saturated fatty acids.0 aGenetic loci associated with circulating levels of very longchai c2015 Jan a176-840 v563 aVery long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.
10aCohort Studies10aFatty Acids10aGenetic Loci10aGenetic Variation10aGenome-Wide Association Study10aHumans1 aLemaitre, Rozenn, N1 aKing, Irena, B1 aKabagambe, Edmond, K1 aH Y Wu, Jason1 aMcKnight, Barbara1 aManichaikul, Ani1 aGuan, Weihua1 aSun, Qi1 aChasman, Daniel, I1 aFoy, Millennia1 aWang, Lu1 aZhu, Jingwen1 aSiscovick, David, S1 aTsai, Michael, Y1 aArnett, Donna, K1 aPsaty, Bruce, M1 aDjoussé, Luc1 aChen, Yii-der, I1 aTang, Weihong1 aWeng, Lu-Chen1 aWu, Hongyu1 aJensen, Majken, K1 aChu, Audrey, Y1 aJacobs, David, R1 aRich, Stephen, S1 aMozaffarian, Dariush1 aSteffen, Lyn1 aRimm, Eric, B1 aHu, Frank, B1 aRidker, Paul, M1 aFornage, Myriam1 aFriedlander, Yechiel uhttps://chs-nhlbi.org/node/661504154nas a2200829 4500008004100000022001400041245006800055210006700123260001300190300001000203490000700213520178300220653001202003653002002015653003502035653001902070653003702089653001302126653003402139653001302173653001102186653001302197653001802210653002702228653001402255653003602269653001102305100002702316700002102343700001802364700001702382700001902399700002302418700002002441700002202461700001902483700002102502700002802523700001902551700001802570700002002588700002002608700002002628700001602648700002302664700001902687700002102706700002202727700002202749700001902771700002702790700002302817700002002840700002302860700002002883700002102903700001902924700001902943700002202962700002502984700002103009700002503030700002103055700002003076700002203096700001603118700001903134710004503153710004503198710004503243856003603288 2015 eng d a1524-462800aGenetic overlap between diagnostic subtypes of ischemic stroke.0 aGenetic overlap between diagnostic subtypes of ischemic stroke c2015 Mar a615-90 v463 aBACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.
METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.
RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.
CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
10aAlleles10aAtherosclerosis10aCerebral Small Vessel Diseases10aCohort Studies10aData Interpretation, Statistical10aEmbolism10aGenome-Wide Association Study10aGenotype10aHumans10aIschemia10aLinear Models10aMeta-Analysis as Topic10aPhenotype10aPolymorphism, Single Nucleotide10aStroke1 aHolliday, Elizabeth, G1 aTraylor, Matthew1 aMalik, Rainer1 aBevan, Steve1 aFalcone, Guido1 aHopewell, Jemma, C1 aCheng, Yu-Ching1 aCotlarciuc, Ioana1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBoncoraglio, Giorgio, B1 aClarke, Robert1 aCole, John, W1 aFornage, Myriam1 aFurie, Karen, L1 aIkram, Arfan, M1 aJannes, Jim1 aKittner, Steven, J1 aLincz, Lisa, F1 aMaguire, Jane, M1 aMeschia, James, F1 aMosley, Thomas, H1 aNalls, Mike, A1 aOldmeadow, Christopher1 aParati, Eugenio, A1 aPsaty, Bruce, M1 aRothwell, Peter, M1 aSeshadri, Sudha1 aScott, Rodney, J1 aSharma, Pankaj1 aSudlow, Cathie1 aWiggins, Kerri, L1 aWorrall, Bradford, B1 aRosand, Jonathan1 aMitchell, Braxton, D1 aDichgans, Martin1 aMarkus, Hugh, S1 aLevi, Christopher1 aAttia, John1 aWray, Naomi, R1 aAustralian Stroke Genetics Collaborative1 aWellcome Trust Case Control Consortium 21 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/668802703nas a2200445 4500008004100000022001400041245008300055210006900138260001300207300001100220490000700231520140200238653001001640653002201650653003501672653002001707653003401727653001101761653001401772653003601786653002801822100002101850700002201871700002001893700002501913700002101938700002101959700001901980700002401999700001702023700002302040700002102063700002402084700002402108700002302132700002102155700002502176700002002201856003602221 2015 ENG d a1758-535X00aGenome-Wide Association Study and Linkage Analysis of the Healthy Aging Index.0 aGenomeWide Association Study and Linkage Analysis of the Healthy c2015 Aug a1003-80 v703 aBACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.
METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.
RESULTS: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.
CONCLUSIONS: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.
10aAging10aApolipoproteins E10aForkhead Transcription Factors10aGenetic Linkage10aGenome-Wide Association Study10aHumans10aLongevity10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aMinster, Ryan, L1 aSanders, Jason, L1 aSingh, Jatinder1 aKammerer, Candace, M1 aBarmada, Michael1 aMatteini, Amy, M1 aZhang, Qunyuan1 aWojczynski, Mary, K1 aDaw, Warwick1 aBrody, Jennifer, A1 aArnold, Alice, M1 aLunetta, Kathryn, L1 aMurabito, Joanne, M1 aChristensen, Kaare1 aPerls, Thomas, T1 aProvince, Michael, A1 aNewman, Anne, B uhttps://chs-nhlbi.org/node/670307237nas a2202149 4500008004100000022001400041245010100055210006900156260001300225300001100238490000700249520180600256653004102062653006402103653003802167653001102205653002802216653001602244653003402260653001102294653001402305653003602319110004402355700001802399700001602417700001202433700001602445700001302461700001502474700001602489700001202505700001502517700001602532700001502548700001502563700001602578700001602594700001402610700001002624700002102634700001302655700001902668700002102687700001502708700001502723700001702738700001302755700001602768700001902784700001602803700001702819700001402836700001402850700001202864700001102876700001302887700001702900700001702917700001202934700001702946700001502963700002202978700001903000700001403019700001603033700001403049700001603063700001903079700002203098700002203120700001503142700001703157700001103174700001603185700001403201700001303215700001503228700001603243700002103259700001403280700001003294700001703304700001503321700001703336700001703353700001603370700001203386700001603398700002003414700001403434700001403448700001403462700001603476700001503492700001803507700001803525700001703543700001803560700001503578700001903593700001503612700001503627700001503642700001603657700002103673700001403694700001703708700001703725700001603742700001503758700001403773700001603787700001803803700001903821700001803840700001503858700001603873700001403889700001703903700001803920700001103938700001403949700001503963700001603978700002003994700001404014700001804028700001904046700001504065700001604080700001604096700001604112700001604128700001704144700001404161700001604175700001404191700001904205700001604224700001804240700001904258700001504277700001404292700001504306700001404321700001704335700002004352700002004372700001704392700001904409700001604428700001704444700001304461700001504474700001804489700001804507700001704525700001704542700002004559700001604579700001604595700002004611700002604631700001204657700001604669700001904685700001804704700001704722700001604739700001504755700001304770700001604783700001604799700001704815700002004832700001804852700001704870710006604887710005504953710004305008856003605051 2015 ENG d a1476-557800aGenome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.0 aGenomewide metaanalysis identifies six novel loci associated wit c2015 May a647-560 v203 aCoffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.
10aAdaptor Proteins, Signal Transducing10aBasic Helix-Loop-Helix Leucine Zipper Transcription Factors10aBrain-Derived Neurotrophic Factor10aCoffea10aCytochrome P-450 CYP1A210aFood Habits10aGenome-Wide Association Study10aHumans10aPhenotype10aPolymorphism, Single Nucleotide1 aCoffee and Caffeine Genetics Consortium1 aCornelis, M C1 aByrne, E, M1 aEsko, T1 aNalls, M, A1 aGanna, A1 aPaynter, N1 aMonda, K, L1 aAmin, N1 aFischer, K1 aRenstrom, F1 aNgwa, J, S1 aHuikari, V1 aCavadino, A1 aNolte, I, M1 aTeumer, A1 aYu, K1 aMarques-Vidal, P1 aRawal, R1 aManichaikul, A1 aWojczynski, M, K1 aVink, J, M1 aZhao, J, H1 aBurlutsky, G1 aLahti, J1 aMikkilä, V1 aLemaitre, R, N1 aEriksson, J1 aMusani, S, K1 aTanaka, T1 aGeller, F1 aLuan, J1 aHui, J1 aMägi, R1 aDimitriou, M1 aGarcia, M, E1 aHo, W-K1 aWright, M, J1 aRose, L, M1 aMagnusson, P, K E1 aPedersen, N, L1 aCouper, D1 aOostra, B A1 aHofman, A1 aIkram, M, A1 aTiemeier, H, W1 aUitterlinden, A G1 avan Rooij, F, J A1 aBarroso, I1 aJohansson, I1 aXue, L1 aKaakinen, M1 aMilani, L1 aPower, C1 aSnieder, H1 aStolk, R, P1 aBaumeister, S, E1 aBiffar, R1 aGu, F1 aBastardot, F1 aKutalik, Z1 aJacobs, D, R1 aForouhi, N G1 aMihailov, E1 aLind, L1 aLindgren, C1 aMichaëlsson, K1 aMorris, A1 aJensen, M1 aKhaw, K-T1 aLuben, R, N1 aWang, J, J1 aMännistö, S1 aPerälä, M-M1 aKähönen, M1 aLehtimäki, T1 aViikari, J1 aMozaffarian, D1 aMukamal, K1 aPsaty, B M1 aDöring, A1 aHeath, A, C1 aMontgomery, G, W1 aDahmen, N1 aCarithers, T1 aTucker, K, L1 aFerrucci, L1 aBoyd, H, A1 aMelbye, M1 aTreur, J, L1 aMellström, D1 aHottenga, J, J1 aProkopenko, I1 aTönjes, A1 aDeloukas, P1 aKanoni, S1 aLorentzon, M1 aHouston, D, K1 aLiu, Y1 aDanesh, J1 aRasheed, A1 aMason, M, A1 aZonderman, A, B1 aFranke, L1 aKristal, B, S1 aKarjalainen, J1 aReed, D, R1 aWestra, H-J1 aEvans, M, K1 aSaleheen, D1 aHarris, T B1 aDedoussis, G1 aCurhan, G1 aStumvoll, M1 aBeilby, J1 aPasquale, L, R1 aFeenstra, B1 aBandinelli, S1 aOrdovás, J, M1 aChan, A, T1 aPeters, U1 aOhlsson, C1 aGieger, C1 aMartin, N, G1 aWaldenberger, M1 aSiscovick, D, S1 aRaitakari, O1 aEriksson, J, G1 aMitchell, P1 aHunter, D, J1 aKraft, P1 aRimm, E, B1 aBoomsma, D, I1 aBorecki, I, B1 aLoos, R, J F1 aWareham, N J1 aVollenweider, P1 aCaporaso, N1 aGrabe, H, J1 aNeuhouser, M, L1 aWolffenbuttel, B, H R1 aHu, F B1 aHypponen, E1 aJärvelin, M-R1 aCupples, L, A1 aFranks, P, W1 aRidker, P M1 aDuijn, C M1 aHeiss, G1 aMetspalu, A1 aNorth, K, E1 aIngelsson, E1 aNettleton, J, A1 avan Dam, R, M1 aChasman, D I1 aInternational Parkinson's Disease Genomics Consortium (IPDGC)1 aNorth American Brain Expression Consortium (NABEC)1 aUK Brain Expression Consortium (UKBEC) uhttps://chs-nhlbi.org/node/660607065nas a2201873 4500008004100000022001400041245015900055210006900214260001600283300001100299490000700310520180500317653000902122653002202131653001002153653002202163653001402185653001902199653001102218653003402229653001302263653001102276653000902287653002102296653001602317653003602333653001302369653001802382653002402400653002202424653002002446100002302466700003002489700001802519700001902537700001802556700001902574700001702593700002102610700002402631700002102655700001602676700002402692700003202716700002302748700001602771700001902787700002302806700001702829700001202846700002202858700002202880700002102902700002002923700002002943700002002963700002002983700001503003700001703018700001803035700001903053700002103072700002203093700001203115700001903127700001903146700002703165700001703192700002003209700002503229700001403254700001903268700001603287700001903303700002303322700002403345700001603369700001803385700002003403700001403423700002203437700001903459700002503478700002603503700002203529700002403551700001603575700001603591700001903607700002703626700002103653700002203674700002003696700001303716700002103729700002403750700002203774700001503796700002403811700002203835700002003857700001703877700001903894700001903913700002003932700001403952700002103966700002503987700002404012700002304036700002204059700002104081700001904102700001904121700002304140700002204163700002504185700002304210700001804233700001904251700002404270700002304294700002304317700002004340700001604360700002804376700002204404700003004426700002104456700002304477700002004500700002004520700001904540700002004559700002004579700002104599700002304620700002604643700002204669700002704691700002204718700002004740700001704760700002304777700002404800700002804824700002404852700003104876700002204907700002004929700001804949700002304967700001904990700002805009700002005037700002205057710007605079856003605155 2015 eng d a1873-240200aGenome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.0 aGenomewide studies of verbal declarative memory in nondemented o c2015 Apr 15 a749-630 v773 aBACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
10aAged10aAged, 80 and over10aAging10aApolipoproteins E10aClaudin-510aCohort Studies10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMemory Disorders10aMiddle Aged10aPolymorphism, Single Nucleotide10aProteins10aProteoglycans10aRegression Analysis10aSulfotransferases10aVerbal Learning1 aDebette, Stephanie1 aVerbaas, Carla, A Ibrahim1 aBressler, Jan1 aSchuur, Maaike1 aSmith, Albert1 aBis, Joshua, C1 aDavies, Gail1 aWolf, Christiane1 aGudnason, Vilmundur1 aChibnik, Lori, B1 aYang, Qiong1 aDeStefano, Anita, L1 ade Quervain, Dominique, J F1 aSrikanth, Velandai1 aLahti, Jari1 aGrabe, Hans, J1 aSmith, Jennifer, A1 aPriebe, Lutz1 aYu, Lei1 aKarbalai, Nazanin1 aHayward, Caroline1 aWilson, James, F1 aCampbell, Harry1 aPetrovic, Katja1 aFornage, Myriam1 aChauhan, Ganesh1 aYeo, Robin1 aBoxall, Ruth1 aBecker, James1 aStegle, Oliver1 aMather, Karen, A1 aChouraki, Vincent1 aSun, Qi1 aRose, Lynda, M1 aResnick, Susan1 aOldmeadow, Christopher1 aKirin, Mirna1 aWright, Alan, F1 aJonsdottir, Maria, K1 aAu, Rhoda1 aBecker, Albert1 aAmin, Najaf1 aNalls, Mike, A1 aTurner, Stephen, T1 aKardia, Sharon, L R1 aOostra, Ben1 aWindham, Gwen1 aCoker, Laura, H1 aZhao, Wei1 aKnopman, David, S1 aHeiss, Gerardo1 aGriswold, Michael, E1 aGottesman, Rebecca, F1 aVitart, Veronique1 aHastie, Nicholas, D1 aZgaga, Lina1 aRudan, Igor1 aPolasek, Ozren1 aHolliday, Elizabeth, G1 aSchofield, Peter1 aChoi, Seung, Hoan1 aTanaka, Toshiko1 aAn, Yang1 aPerry, Rodney, T1 aKennedy, Richard, E1 aSale, Michèle, M1 aWang, Jing1 aWadley, Virginia, G1 aLiewald, David, C1 aRidker, Paul, M1 aGow, Alan, J1 aPattie, Alison1 aStarr, John, M1 aPorteous, David1 aLiu, Xuan1 aThomson, Russell1 aArmstrong, Nicola, J1 aEiriksdottir, Gudny1 aAssareh, Arezoo, A1 aKochan, Nicole, A1 aWiden, Elisabeth1 aPalotie, Aarno1 aHsieh, Yi-Chen1 aEriksson, Johan, G1 aVogler, Christian1 avan Swieten, John, C1 aShulman, Joshua, M1 aBeiser, Alexa1 aRotter, Jerome1 aSchmidt, Carsten, O1 aHoffmann, Wolfgang1 aNöthen, Markus, M1 aFerrucci, Luigi1 aAttia, John1 aUitterlinden, André, G1 aAmouyel, Philippe1 aDartigues, Jean-François1 aAmieva, Hélène1 aRäikkönen, Katri1 aGarcia, Melissa1 aWolf, Philip, A1 aHofman, Albert1 aLongstreth, W T1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aDeJager, Philip, L1 aSachdev, Perminder, S1 aSchmidt, Reinhold1 aBreteler, Monique, M B1 aTeumer, Alexander1 aLopez, Oscar, L1 aCichon, Sven1 aChasman, Daniel, I1 aGrodstein, Francine1 aMüller-Myhsok, Bertram1 aTzourio, Christophe1 aPapassotiropoulos, Andreas1 aBennett, David, A1 aIkram, Arfan, M1 aDeary, Ian, J1 aDuijn, Cornelia, M1 aLauner, Lenore1 aFitzpatrick, Annette, L1 aSeshadri, Sudha1 aMosley, Thomas, H1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium uhttps://chs-nhlbi.org/node/668404127nas a2200877 4500008004100000022001400041245007800055210006900133260001300202300001000215490000700225520166400232653000901896653002201905653002201927653002801949653001901977653001101996653002802007653003502035653003402070653001102104653001402115653000902129653001602138653003602154653002702190100001702217700002102234700001802255700002102273700002102294700002402315700002202339700002302361700002102384700002002405700001202425700002102437700001902458700002402477700002402501700002402525700002002549700002302569700001902592700002202611700002402633700002102657700001902678700002002697700001802717700002002735700002602755700002202781700002002803700002202823700002202845700002802867700001402895700002502909700002202934700002002956700002402976700002203000700001903022700002203041700002103063700002003084700002303104700001903127700002003146700002303166700002403189856003603213 2015 eng d a1758-535X00aGWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.0 aGWAS of longevity in CHARGE consortium confirms APOE and FOXO3 c c2015 Jan a110-80 v703 aBACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.
METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.
RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).
CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.
10aAged10aAged, 80 and over10aApolipoproteins E10aCell Adhesion Molecules10aCohort Studies10aFemale10aForkhead Box Protein O310aForkhead Transcription Factors10aGenome-Wide Association Study10aHumans10aLongevity10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Kainic Acid1 aBroer, Linda1 aBuchman, Aron, S1 aDeelen, Joris1 aEvans, Daniel, S1 aFaul, Jessica, D1 aLunetta, Kathryn, L1 aSebastiani, Paola1 aSmith, Jennifer, A1 aSmith, Albert, V1 aTanaka, Toshiko1 aYu, Lei1 aArnold, Alice, M1 aAspelund, Thor1 aBenjamin, Emelia, J1 aDe Jager, Philip, L1 aEirkisdottir, Gudny1 aEvans, Denis, A1 aGarcia, Melissa, E1 aHofman, Albert1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKiel, Douglas, P1 aOostra, Ben, A1 aOrwoll, Eric, S1 aParimi, Neeta1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSeshadri, Sudha1 aSingleton, Andrew1 aTiemeier, Henning1 aUitterlinden, André, G1 aZhao, Wei1 aBandinelli, Stefania1 aBennett, David, A1 aFerrucci, Luigi1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aKarasik, David1 aLauner, Lenore, J1 aPerls, Thomas, T1 aSlagboom, Eline1 aTranah, Gregory, J1 aWeir, David, R1 aNewman, Anne, B1 aDuijn, Cornelia, M1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/655004486nas a2200925 4500008004100000022001400041245007500055210006900130260001500199300001200214490000700226520186200233653002302095653001202118653002302130653004002153653003802193653003402231653001302265653001102278653001802289653000902307653000902316653003602325653000902361653001402370653003602384653002402420100002002444700001802464700002602482700002502508700001902533700002002552700002302572700001902595700002102614700001602635700001802651700001902669700001902688700002502707700001902732700002702751700002102778700001602799700002402815700002602839700002602865700002402891700001702915700002202932700002002954700002302974700001802997700001903015700001803034700002103052700001903073700001903092700002303111700002303134700002603157700001903183700001703202700002703219700002403246700002003270700002503290700001903315700001903334700002203353700002003375700001703395700002203412700002103434700002503455710004403480856003603524 2015 eng d a1460-208300aIntegrative pathway genomics of lung function and airflow obstruction.0 aIntegrative pathway genomics of lung function and airflow obstru c2015 Dec 1 a6836-480 v243 aChronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.
10aAirway Obstruction10aAnimals10aCell Proliferation10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenomics10aHumans10aImmune System10aLung10aMale10aMetabolic Networks and Pathways10aMice10aPhenotype10aPolymorphism, Single Nucleotide10aSignal Transduction1 aGharib, Sina, A1 aLoth, Daan, W1 aArtigas, Maria, Soler1 aBirkland, Timothy, P1 aWilk, Jemma, B1 aWain, Louise, V1 aBrody, Jennifer, A1 aObeidat, Ma'en1 aHancock, Dana, B1 aTang, Wenbo1 aRawal, Rajesh1 aBoezen, Marike1 aImboden, Medea1 aHuffman, Jennifer, E1 aLahousse, Lies1 aAlves, Alexessander, C1 aManichaikul, Ani1 aHui, Jennie1 aMorrison, Alanna, C1 aRamasamy, Adaikalavan1 aSmith, Albert, Vernon1 aGudnason, Vilmundur1 aSurakka, Ida1 aVitart, Veronique1 aEvans, David, M1 aStrachan, David, P1 aDeary, Ian, J1 aHofman, Albert1 aGläser, Sven1 aWilson, James, F1 aNorth, Kari, E1 aZhao, Jing Hua1 aHeckbert, Susan, R1 aJarvis, Deborah, L1 aProbst-Hensch, Nicole1 aSchulz, Holger1 aBarr, Graham1 aJarvelin, Marjo-Riitta1 aO'Connor, George, T1 aKähönen, Mika1 aCassano, Patricia, A1 aHysi, Pirro, G1 aDupuis, Josée1 aHayward, Caroline1 aPsaty, Bruce, M1 aHall, Ian, P1 aParks, William, C1 aTobin, Martin, D1 aLondon, Stephanie, J1 aCHARGE Consortium; SpiroMeta Consortium uhttps://chs-nhlbi.org/node/686004273nas a2200853 4500008004100000022001400041245012600055210006900181260001500250300001100265490000700276520176600283653003802049653003402087653001302121653001102134653002702145653003202172653001502204653001702219653002702236100002002263700002302283700002202306700001802328700002102346700001802367700002302385700002802408700002202436700001902458700001802477700002102495700002202516700003002538700002202568700001202590700002702602700002302629700002102652700002002673700001902693700002302712700002002735700001802755700001902773700002702792700002002819700002402839700003002863700001902893700002002912700001802932700001802950700002002968700003202988700002303020700002203043700001703065700002203082700002203104700001703126700002003143700002403163700002503187700002103212700001503233700002303248700003203271700002303303700002903326710002803355856003603383 2015 eng d a1537-660500aMeta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.0 aMetaanalysis of 65734 individuals identifies TSPAN15 and SLC44A2 c2015 Apr 2 a532-420 v963 aVenous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.
10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMembrane Glycoproteins10aMembrane Transport Proteins10aOdds Ratio10aTetraspanins10aVenous Thromboembolism1 aGermain, Marine1 aChasman, Daniel, I1 ade Haan, Hugoline1 aTang, Weihong1 aLindström, Sara1 aWeng, Lu-Chen1 ade Andrade, Mariza1 ade Visser, Marieke, C H1 aWiggins, Kerri, L1 aSuchon, Pierre1 aSaut, Noémie1 aSmadja, David, M1 aLe Gal, Grégoire1 aVlieg, Astrid, van Hylcka1 aDi Narzo, Antonio1 aHao, Ke1 aNelson, Christopher, P1 aRocanin-Arjo, Ares1 aFolkersen, Lasse1 aMonajemi, Ramin1 aRose, Lynda, M1 aBrody, Jennifer, A1 aSlagboom, Eline1 aAïssi, Dylan1 aGagnon, France1 aDeleuze, Jean-Francois1 aDeloukas, Panos1 aTzourio, Christophe1 aDartigues, Jean-François1 aBerr, Claudine1 aTaylor, Kent, D1 aCivelek, Mete1 aEriksson, Per1 aPsaty, Bruce, M1 aHouwing-Duitermaat, Jeanine1 aGoodall, Alison, H1 aCambien, Francois1 aKraft, Peter1 aAmouyel, Philippe1 aSamani, Nilesh, J1 aBasu, Saonli1 aRidker, Paul, M1 aRosendaal, Frits, R1 aKabrhel, Christopher1 aFolsom, Aaron, R1 aHeit, John1 aReitsma, Pieter, H1 aTrégouët, David-Alexandre1 aSmith, Nicholas, L1 aMorange, Pierre-Emmanuel1 aCardiogenics consortium uhttps://chs-nhlbi.org/node/668103753nas a2200601 4500008004100000022001400041245011800055210006900173260001300242300001100255490000700266520199300273653002202266653002502288653001902313653003802332653003402370653001102404653003602415653001702451653001102468100001902479700002002498700002002518700002202538700001802560700001602578700001902594700002302613700002102636700002102657700002302678700002202701700002302723700002302746700002202769700001702791700001602808700002002824700001702844700002202861700002102883700001802904700002002922700002502942700002002967700002402987700002203011700002503033700002003058710003703078856003603115 2015 eng d a1524-462800aMeta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.0 aMetaAnalysis of GenomeWide Association Studies Identifies Geneti c2015 Aug a2063-80 v463 aBACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.
METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.
RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.
CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.
10aAfrican Americans10aCase-Control Studies10aCohort Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke1 aCarty, Cara, L1 aKeene, Keith, L1 aCheng, Yu-Ching1 aMeschia, James, F1 aChen, Wei-Min1 aNalls, Mike1 aBis, Joshua, C1 aKittner, Steven, J1 aRich, Stephen, S1 aTajuddin, Salman1 aZonderman, Alan, B1 aEvans, Michele, K1 aLangefeld, Carl, D1 aGottesman, Rebecca1 aMosley, Thomas, H1 aShahar, Eyal1 aWoo, Daniel1 aYaffe, Kristine1 aLiu, Yongmei1 aSale, Michèle, M1 aDichgans, Martin1 aMalik, Rainer1 aLongstreth, W T1 aMitchell, Braxton, D1 aPsaty, Bruce, M1 aKooperberg, Charles1 aReiner, Alexander1 aWorrall, Bradford, B1 aFornage, Myriam1 aCOMPASS and METASTROKE Consortia uhttps://chs-nhlbi.org/node/681206153nas a2201525 4500008004100000022001400041245009600055210006900151260001300220300001200233490000600245520187500251653000902126653002202135653002302157653003402180653001102214653001702225653003402242653001102276653000902287653002702296653001602323653002002339653001102359653001702370100002902387700002302416700001902439700002302458700001802481700002002499700002302519700002002542700002002562700001902582700002402601700002602625700002102651700002402672700002402696700002302720700002702743700002002770700002102790700002202811700002102833700002202854700001602876700002002892700002902912700002202941700002502963700002202988700001803010700001803028700002403046700002003070700002603090700002003116700002403136700002603160700002503186700001903211700002303230700001903253700001703272700001703289700001903306700003003325700002203355700001903377700001703396700002403413700002203437700002203459700002403481700002003505700002103525700001603546700002003562700002103582700001903603700002003622700002103642700002203663700002703685700002003712700002503732700001903757700002303776700002503799700002003824700002203844700002503866700002203891700002803913700002103941700002003962700002303982700002404005700001604029700002804045700002304073700001804096700001804114700002304132700001804155700002404173700002104197700002304218700001604241700001404257700002004271700001904291700002004310700002404330700002204354700002204376700002004398700002404418700002304442700002204465700002204487700001904509700002304528700002004551700002004571856003604591 2015 eng d a1942-326800aMultiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.0 aMultiethnic genomewide association study of cerebral white matte c2015 Apr a398-4090 v83 aBACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
10aAged10aAged, 80 and over10aChromosomes, Human10aContinental Population Groups10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aModels, Genetic10aStroke10aWhite Matter1 aVerhaaren, Benjamin, F J1 aDebette, Stephanie1 aBis, Joshua, C1 aSmith, Jennifer, A1 aIkram, Kamran1 aAdams, Hieab, H1 aBeecham, Ashley, H1 aRajan, Kumar, B1 aLopez, Lorna, M1 aBarral, Sandra1 avan Buchem, Mark, A1 avan der Grond, Jeroen1 aSmith, Albert, V1 aHegenscheid, Katrin1 aAggarwal, Neelum, T1 ade Andrade, Mariza1 aAtkinson, Elizabeth, J1 aBeekman, Marian1 aBeiser, Alexa, S1 aBlanton, Susan, H1 aBoerwinkle, Eric1 aBrickman, Adam, M1 aBryan, Nick1 aChauhan, Ganesh1 aChen, Christopher, P L H1 aChouraki, Vincent1 ade Craen, Anton, J M1 aCrivello, Fabrice1 aDeary, Ian, J1 aDeelen, Joris1 aDe Jager, Philip, L1 aDufouil, Carole1 aElkind, Mitchell, S V1 aEvans, Denis, A1 aFreudenberger, Paul1 aGottesman, Rebecca, F1 aGuðnason, Vilmundur1 aHabes, Mohamad1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHilal, Saima1 aHofer, Edith1 aHofman, Albert1 aIbrahim-Verbaas, Carla, A1 aKnopman, David, S1 aLewis, Cora, E1 aLiao, Jiemin1 aLiewald, David, C M1 aLuciano, Michelle1 avan der Lugt, Aad1 aMartinez, Oliver, O1 aMayeux, Richard1 aMazoyer, Bernard1 aNalls, Mike1 aNauck, Matthias1 aNiessen, Wiro, J1 aOostra, Ben, A1 aPsaty, Bruce, M1 aRice, Kenneth, M1 aRotter, Jerome, I1 avon Sarnowski, Bettina1 aSchmidt, Helena1 aSchreiner, Pamela, J1 aSchuur, Maaike1 aSidney, Stephen, S1 aSigurdsson, Sigurdur1 aSlagboom, Eline1 aStott, David, J M1 avan Swieten, John, C1 aTeumer, Alexander1 aTöglhofer, Anna, Maria1 aTraylor, Matthew1 aTrompet, Stella1 aTurner, Stephen, T1 aTzourio, Christophe1 aUh, Hae-Won1 aUitterlinden, André, G1 aVernooij, Meike, W1 aWang, Jing, J1 aWong, Tien, Y1 aWardlaw, Joanna, M1 aWindham, Gwen1 aWittfeld, Katharina1 aWolf, Christiane1 aWright, Clinton, B1 aYang, Qiong1 aZhao, Wei1 aZijdenbos, Alex1 aJukema, Wouter1 aSacco, Ralph, L1 aKardia, Sharon, L R1 aAmouyel, Philippe1 aMosley, Thomas, H1 aLongstreth, W T1 aDeCarli, Charles, C1 aDuijn, Cornelia, M1 aSchmidt, Reinhold1 aLauner, Lenore, J1 aGrabe, Hans, J1 aSeshadri, Sudha, S1 aIkram, Arfan, M1 aFornage, Myriam uhttps://chs-nhlbi.org/node/668304596nas a2201333 4500008004100000022001400041245010600055210006900161260001300230300001100243490000700254520134600261653001001607653002201617653000901639653001501648653004001663653001101703653003201714653003401746653001101780653000901791653001601800653003601816653001601852653001001868100001901878700001101897700001401908700001701922700002001939700001601959700001601975700001601991700001802007700001502025700001602040700001602056700001302072700001002085700001802095700001402113700002002127700001602147700001502163700001502178700001702193700001502210700001502225700001902240700001402259700001402273700001602287700001202303700001602315700001902331700001302350700001602363700001502379700001802394700001502412700001602427700001602443700001702459700001402476700001802490700001702508700001702525700001702542700001702559700001102576700001302587700001702600700002102617700001502638700001402653700002102667700001502688700001602703700001402719700001302733700001302746700001702759700001502776700001502791700001602806700001502822700001702837700001402854700002202868700001402890700001302904700001702917700001302934700001302947700001102960700001602971700001802987700001603005700001003021700001503031700001703046700001903063700001603082700001403098700001503112700001703127700001803144700001903162700001503181700001403196700001603210856003603226 2015 eng d a1476-557800aNovel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.0 aNovel loci associated with usual sleep duration the CHARGE Conso c2015 Oct a1232-90 v203 aUsual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
10aAdult10aAfrican Americans10aAged10aDyssomnias10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSelf Report10aSleep1 aGottlieb, D, J1 aHek, K1 aChen, T-H1 aWatson, N, F1 aEiriksdottir, G1 aByrne, E, M1 aCornelis, M1 aWarby, S, C1 aBandinelli, S1 aCherkas, L1 aEvans, D, S1 aGrabe, H, J1 aLahti, J1 aLi, M1 aLehtimäki, T1 aLumley, T1 aMarciante, K, D1 aPérusse, L1 aPsaty, B M1 aRobbins, J1 aTranah, G, J1 aVink, J, M1 aWilk, J, B1 aStafford, J, M1 aBellis, C1 aBiffar, R1 aBouchard, C1 aCade, B1 aCurhan, G C1 aEriksson, J, G1 aEwert, R1 aFerrucci, L1 aFülöp, T1 aGehrman, P, R1 aGoodloe, R1 aHarris, T B1 aHeath, A, C1 aHernandez, D1 aHofman, A1 aHottenga, J-J1 aHunter, D, J1 aJensen, M, K1 aJohnson, A D1 aKähönen, M1 aKao, L1 aKraft, P1 aLarkin, E, K1 aLauderdale, D, S1 aLuik, A, I1 aMedici, M1 aMontgomery, G, W1 aPalotie, A1 aPatel, S, R1 aPistis, G1 aPorcu, E1 aQuaye, L1 aRaitakari, O1 aRedline, S1 aRimm, E, B1 aRotter, J I1 aSmith, A V1 aSpector, T D1 aTeumer, A1 aUitterlinden, A G1 aVohl, M-C1 aWiden, E1 aWillemsen, G1 aYoung, T1 aZhang, X1 aLiu, Y1 aBlangero, J1 aBoomsma, D, I1 aGudnason, V1 aHu, F1 aMangino, M1 aMartin, N, G1 aO'Connor, G, T1 aStone, K, L1 aTanaka, T1 aViikari, J1 aGharib, S, A1 aPunjabi, N, M1 aRäikkönen, K1 aVölzke, H1 aMignot, E1 aTiemeier, H uhttps://chs-nhlbi.org/node/656603704nas a2200589 4500008004100000022001400041245013900055210007000194260001300264300001200277490000700289520197000296653001002266653002202276653002102298653000902319653002802328653001902356653002802375653001102403653003802414653003402452653001102486653001402497653004102511653002602552653000902578653001602587653003602603653003202639653002402671653002002695653002102715653002202736100001702758700002102775700002002796700001902816700002602835700002502861700001202886700002002898700002202918700002002940700002002960700001702980700001802997700002003015700002203035700002103057856003603078 2015 eng d a1524-463600aPlasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan.0 aPlasma Levels of Soluble Interleukin2 Receptor α Associations Wi c2015 Oct a2246-530 v353 aOBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.
APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5×10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31×10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.
CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.
10aAdult10aAfrican Americans10aAge Distribution10aAged10aCardiovascular Diseases10aCohort Studies10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aIncidence10aInterleukin-2 Receptor alpha Subunit10aKaplan-Meier Estimate10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aProspective Studies10aRisk Assessment10aSex Distribution10aSurvival Analysis1 aDurda, Peter1 aSabourin, Jeremy1 aLange, Ethan, M1 aNalls, Mike, A1 aMychaleckyj, Josyf, C1 aJenny, Nancy, Swords1 aLi, Jin1 aWalston, Jeremy1 aHarris, Tamara, B1 aPsaty, Bruce, M1 aValdar, William1 aLiu, Yongmei1 aCushman, Mary1 aReiner, Alex, P1 aTracy, Russell, P1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/680904841nas a2200685 4500008004100000022001400041245011900055210006900174260001300243300001000256490000700266520281800273653000903091653001903100653001003119653001103129653003803140653002203178653003403200653001103234653000903245653001603254653002003270653005303290653002103343653002403364653002803388653001103416653001803427100001803445700001603463700002203479700002503501700002003526700002003546700002403566700002403590700002803614700001903642700001803661700002503679700002403704700002003728700001603748700001203764700002403776700002003800700001903820700002903839700002103868700002103889700002203910700002503932700002503957700002603982700001904008700002104027710007104048856003604119 2015 eng d a2168-615700aRare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.0 aRare and Coding Region Genetic Variants Associated With Risk of c2015 Jul a781-80 v723 aIMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.
OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.
DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.
MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).
RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).
CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.
10aAged10aBrain Ischemia10aExome10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMuscle Proteins10aNational Heart, Lung, and Blood Institute (U.S.)10aNuclear Proteins10aOpen Reading Frames10aPalmitoyl-CoA Hydrolase10aStroke10aUnited States1 aAuer, Paul, L1 aNalls, Mike1 aMeschia, James, F1 aWorrall, Bradford, B1 aLongstreth, W T1 aSeshadri, Sudha1 aKooperberg, Charles1 aBurger, Kathleen, M1 aCarlson, Christopher, S1 aCarty, Cara, L1 aChen, Wei-Min1 aCupples, Adrienne, L1 aDeStefano, Anita, L1 aFornage, Myriam1 aHardy, John1 aHsu, Li1 aJackson, Rebecca, D1 aJarvik, Gail, P1 aKim, Daniel, S1 aLakshminarayan, Kamakshi1 aLange, Leslie, A1 aManichaikul, Ani1 aQuinlan, Aaron, R1 aSingleton, Andrew, B1 aThornton, Timothy, A1 aNickerson, Deborah, A1 aPeters, Ulrike1 aRich, Stephen, S1 aNational Heart, Lung, and Blood Institute Exome Sequencing Project uhttps://chs-nhlbi.org/node/684904070nas a2200865 4500008004100000022001400041245010200055210006900157260001600226300001200242490000700254520151500261653001901776653003401795653001101829653002301840653002601863653001101889100001801900700002301918700002401941700002101965700002601986700002102012700002102033700002702054700002402081700002002105700001902125700002302144700002302167700002502190700001902215700001902234700002302253700002002276700002202296700002202318700001902340700001902359700002302378700002502401700001802426700001902444700002002463700002302483700001802506700002002524700002002544700002002564700002302584700002302607700001902630700002002649700001702669700001802686700002102704700002102725700002102746700002802767700002502795700002302820700002102843700002502864700002002889700002002909700003602929700002002965700001902985700001903004700002103023710004703044710007703091856003603168 2015 eng d a1526-632X00aShared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.0 aShared genetic basis for migraine and ischemic stroke A genomewi c2015 May 26 a2132-450 v843 aOBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.
METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.
RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).
CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.
10aBrain Ischemia10aGenome-Wide Association Study10aHumans10aMigraine with Aura10aMigraine without Aura10aStroke1 aMalik, Rainer1 aFreilinger, Tobias1 aWinsvold, Bendik, S1 aAnttila, Verneri1 aHeiden, Jason, Vander1 aTraylor, Matthew1 ade Vries, Boukje1 aHolliday, Elizabeth, G1 aTerwindt, Gisela, M1 aSturm, Jonathan1 aBis, Joshua, C1 aHopewell, Jemma, C1 aFerrari, Michel, D1 aRannikmae, Kristiina1 aWessman, Maija1 aKallela, Mikko1 aKubisch, Christian1 aFornage, Myriam1 aMeschia, James, F1 aLehtimäki, Terho1 aSudlow, Cathie1 aClarke, Robert1 aChasman, Daniel, I1 aMitchell, Braxton, D1 aMaguire, Jane1 aKaprio, Jaakko1 aFarrall, Martin1 aRaitakari, Olli, T1 aKurth, Tobias1 aIkram, Arfan, M1 aReiner, Alex, P1 aLongstreth, W T1 aRothwell, Peter, M1 aStrachan, David, P1 aSharma, Pankaj1 aSeshadri, Sudha1 aQuaye, Lydia1 aCherkas, Lynn1 aSchürks, Markus1 aRosand, Jonathan1 aLigthart, Lannie1 aBoncoraglio, Giorgio, B1 aSmith, George, Davey1 aDuijn, Cornelia, M1 aStefansson, Kari1 aWorrall, Bradford, B1 aNyholt, Dale, R1 aMarkus, Hugh, S1 avan den Maagdenberg, Arn, M J M1 aCotsapas, Chris1 aZwart, John, A1 aPalotie, Aarno1 aDichgans, Martin1 aInternational Headache Genetics Consortium1 aMETASTROKE Collaboration of the International Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/681304741nas a2201021 4500008004100000022001400041245008000055210006900135260001300204300001200217490000700229520186200236653001002098653000902108653001902117653002402136653001102160653003802171653003402209653001102243653002602254653000902280653001602289653002402305653001702329100001702346700002602363700001902389700002102408700002002429700002502449700002302474700002002497700002902517700002102546700001602567700002202583700002202605700001802627700002402645700002302669700002002692700002502712700002002737700002302757700001402780700002402794700002602818700002402844700001902868700001902887700001902906700002102925700002102946700001702967700002102984700001603005700002003021700002603041700001903067700002303086700002103109700002003130700001803150700002003168700002003188700002103208700002403229700002403253700002103277700001503298700002603313700001803339700002303357700002003380700001903400700002303419700002003442700001903462700002203481700002003503700002203523700002003545700002003565700002203585710007603607856003603683 2015 eng d a1524-462800aWhite Matter Lesion Progression: Genome-Wide Search for Genetic Influences.0 aWhite Matter Lesion Progression GenomeWide Search for Genetic In c2015 Nov a3048-570 v463 aBACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.
RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.
CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
10aAdult10aAged10aCohort Studies10aDisease Progression10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLeukoencephalopathies10aMale10aMiddle Aged10aProspective Studies10aWhite Matter1 aHofer, Edith1 aCavalieri, Margherita1 aBis, Joshua, C1 aDeCarli, Charles1 aFornage, Myriam1 aSigurdsson, Sigurdur1 aSrikanth, Velandai1 aTrompet, Stella1 aVerhaaren, Benjamin, F J1 aWolf, Christiane1 aYang, Qiong1 aAdams, Hieab, H H1 aAmouyel, Philippe1 aBeiser, Alexa1 aBuckley, Brendan, M1 aCallisaya, Michele1 aChauhan, Ganesh1 ade Craen, Anton, J M1 aDufouil, Carole1 aDuijn, Cornelia, M1 aFord, Ian1 aFreudenberger, Paul1 aGottesman, Rebecca, F1 aGudnason, Vilmundur1 aHeiss, Gerardo1 aHofman, Albert1 aLumley, Thomas1 aMartinez, Oliver1 aMazoyer, Bernard1 aMoran, Chris1 aNiessen, Wiro, J1 aPhan, Thanh1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aSattar, Naveed1 aSchilling, Sabrina1 aShibata, Dean, K1 aSlagboom, Eline1 aSmith, Albert1 aStott, David, J1 aTaylor, Kent, D1 aThomson, Russell1 aTöglhofer, Anna, M1 aTzourio, Christophe1 avan Buchem, Mark1 aWang, Jing1 aWestendorp, Rudi, G J1 aWindham, Gwen1 aVernooij, Meike, W1 aZijdenbos, Alex1 aBeare, Richard1 aDebette, Stephanie1 aIkram, Arfan, M1 aJukema, Wouter1 aLauner, Lenore, J1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aSchmidt, Helena1 aSchmidt, Reinhold1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium uhttps://chs-nhlbi.org/node/686104818nas a2201141 4500008004100000022001400041245011000055210006900165260001300234300001100247490000700258520157500265653001001840653003901850653001701889653000901906653003701915653001901952653003201971653002402003653002002027653004002047653001102087653003802098653003402136653001102170653000902181653001602190653001502206653003602221653002602257653001102283100002002294700002002314700002302334700001902357700002102376700002202397700002702419700001802446700001602464700002302480700001802503700002602521700001702547700001802564700001402582700002102596700002702617700002302644700001802667700001702685700001902702700002002721700002302741700002402764700002302788700001702811700001702828700002302845700001902868700002202887700001902909700002402928700001602952700001502968700002002983700002103003700002103024700002103045700001903066700002003085700002203105700002303127700002403150700003003174700002203204700002603226700002003252700002503272700002003297700002003317700002203337700002003359700001903379700002203398700002003420700002203440700002103462700002803483700002003511700002303531700001703554700002103571700002503592710002303617856003603640 2016 eng d a1524-462800aGenome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.0 aGenomeWide Association Analysis of YoungOnset Stroke Identifies c2016 Feb a307-160 v473 aBACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.
METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.
RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.
CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
10aAdult10aAfrican Continental Ancestry Group10aAge of Onset10aAged10aAsian Continental Ancestry Group10aBrain Ischemia10aChromosomes, Human, Pair 1010aComputer Simulation10aDNA, Intergenic10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aOdds Ratio10aPolymorphism, Single Nucleotide10aSerine Endopeptidases10aStroke1 aCheng, Yu-Ching1 aStanne, Tara, M1 aGiese, Anne-Katrin1 aHo, Weang, Kee1 aTraylor, Matthew1 aAmouyel, Philippe1 aHolliday, Elizabeth, G1 aMalik, Rainer1 aXu, Huichun1 aKittner, Steven, J1 aCole, John, W1 aO'Connell, Jeffrey, R1 aDanesh, John1 aRasheed, Asif1 aZhao, Wei1 aEngelter, Stefan1 aGrond-Ginsbach, Caspar1 aKamatani, Yoichiro1 aLathrop, Mark1 aLeys, Didier1 aThijs, Vincent1 aMetso, Tiina, M1 aTatlisumak, Turgut1 aPezzini, Alessandro1 aParati, Eugenio, A1 aNorrving, Bo1 aBevan, Steve1 aRothwell, Peter, M1 aSudlow, Cathie1 aSlowik, Agnieszka1 aLindgren, Arne1 aWalters, Matthew, R1 aJannes, Jim1 aShen, Jess1 aCrosslin, David1 aDoheny, Kimberly1 aLaurie, Cathy, C1 aKanse, Sandip, M1 aBis, Joshua, C1 aFornage, Myriam1 aMosley, Thomas, H1 aHopewell, Jemma, C1 aStrauch, Konstantin1 aMüller-Nurasyid, Martina1 aGieger, Christian1 aWaldenberger, Melanie1 aPeters, Annette1 aMeisinger, Christine1 aIkram, Arfan, M1 aLongstreth, W T1 aMeschia, James, F1 aSeshadri, Sudha1 aSharma, Pankaj1 aWorrall, Bradford1 aJern, Christina1 aLevi, Christopher1 aDichgans, Martin1 aBoncoraglio, Giorgio, B1 aMarkus, Hugh, S1 aDebette, Stephanie1 aRolfs, Arndt1 aSaleheen, Danish1 aMitchell, Braxton, D1 aWTCCC-2 Consortium uhttps://chs-nhlbi.org/node/699105079nas a2201093 4500008004100000022001400041245015000055210006900205260000900274300001300283490000700296520193900303653000902242653001902251653002502270653002802295653001102323653003802334653003402372653001102406653000902417653001602426653002602442653003602468653002402504100001902528700001902547700002202566700002602588700002402614700002502638700002002663700002302683700001902706700001702725700002402742700002002766700002202786700002102808700002802829700002302857700001402880700001802894700002002912700002802932700002402960700002702984700002303011700001903034700001903053700002303072700002203095700002403117700002303141700002003164700002403184700002303208700001803231700002403249700002103273700002403294700002003318700001603338700001503354700002203369700001903391700002003410700001903430700001703449700002203466700001903488700002603507700001903533700002003552700001803572700002403590700001703614700002003631700002603651700002203677700001703699700001703716700001803733700001903751700001903770700002003789700002403809700002103833700002403854700002003878700002103898700003003919856003603949 2016 eng d a1932-620300aGenome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.0 aGenomeWide Association Study for Incident Myocardial Infarction c2016 ae01449970 v113 aBACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).
CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
10aAged10aCohort Studies10aCooperative Behavior10aCoronary Artery Disease10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies1 aDehghan, Abbas1 aBis, Joshua, C1 aWhite, Charles, C1 aSmith, Albert, Vernon1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aTrompet, Stella1 aChasman, Daniel, I1 aLumley, Thomas1 aVölker, Uwe1 aBuckley, Brendan, M1 aDing, Jingzhong1 aJensen, Majken, K1 aFolsom, Aaron, R1 aKritchevsky, Stephen, B1 aGirman, Cynthia, J1 aFord, Ian1 aDörr, Marcus1 aSalomaa, Veikko1 aUitterlinden, André, G1 aEiriksdottir, Gudny1 aVasan, Ramachandran, S1 aFranceschini, Nora1 aCarty, Cara, L1 aVirtamo, Jarmo1 aDemissie, Serkalem1 aAmouyel, Philippe1 aArveiler, Dominique1 aHeckbert, Susan, R1 aFerrieres, Jean1 aDucimetiere, Pierre1 aSmith, Nicholas, L1 aWang, Ying, A1 aSiscovick, David, S1 aRice, Kenneth, M1 aWiklund, Per-Gunnar1 aTaylor, Kent, D1 aEvans, Alun1 aKee, Frank1 aRotter, Jerome, I1 aKarvanen, Juha1 aKuulasmaa, Kari1 aHeiss, Gerardo1 aKraft, Peter1 aLauner, Lenore, J1 aHofman, Albert1 aMarkus, Marcello, R P1 aRose, Lynda, M1 aSilander, Kaisa1 aWagner, Peter1 aBenjamin, Emelia, J1 aLohman, Kurt1 aStott, David, J1 aRivadeneira, Fernando1 aHarris, Tamara, B1 aLevy, Daniel1 aLiu, Yongmei1 aRimm, Eric, B1 aJukema, Wouter1 aVölzke, Henry1 aRidker, Paul, M1 aBlankenberg, Stefan1 aFranco, Oscar, H1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/700406633nas a2201633 4500008004100000022001400041245008000055210006900135260001300204300001100217490000700228520260200235653002202837653002202859653003202881653003402913653001102947653003602958653001702994100001103011700002603022700001703048700001703065700001303082700001403095700001703109700001403126700001303140700001803153700001403171700001803185700002003203700002103223700001203244700001803256700001503274700001603289700002603305700001603331700001503347700001503362700001703377700001503394700001603409700001803425700001803443700001503461700001603476700001503492700001703507700001403524700001403538700001403552700001703566700002203583700001603605700001603621700001403637700002203651700001303673700001203686700001403698700001603712700001503728700001203743700001803755700001203773700001203785700001903797700001803816700001603834700001903850700001403869700001903883700001603902700001503918700001303933700001603946700002003962700001703982700001403999700001304013700001704026700001704043700001404060700001304074700001604087700001604103700001904119700001404138700001704152700002404169700001504193700001404208700001704222700001604239700002004255700001804275700001604293700001204309700001704321700001804338700001404356700002704370700001304397700001604410700001904426700001504445700001404460700001804474700001704492700001904509700001804528700002104546700001804567700002104585700001504606700001804621700001404639700001304653700001704666700001504683700002304698700001504721700001604736700001404752700001504766700001604781700002004797700001604817700002404833700001504857700001604872700001504888700002304903700001704926710002004943856003604963 2016 eng d a1476-557800aA novel Alzheimer disease locus located near the gene encoding tau protein.0 anovel Alzheimer disease locus located near the gene encoding tau c2016 Jan a108-170 v213 aAPOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
10aAlzheimer Disease10aApolipoprotein E410aChromosomes, Human, Pair 1710aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10atau Proteins1 aJun, G1 aIbrahim-Verbaas, C, A1 aVronskaya, M1 aLambert, J-C1 aChung, J1 aNaj, A, C1 aKunkle, B, W1 aWang, L-S1 aBis, J C1 aBellenguez, C1 aHarold, D1 aLunetta, K, L1 aDeStefano, A, L1 aGrenier-Boley, B1 aSims, R1 aBeecham, G, W1 aSmith, A V1 aChouraki, V1 aHamilton-Nelson, K, L1 aIkram, M, A1 aFiévet, N1 aDenning, N1 aMartin, E, R1 aSchmidt, H1 aKamatani, Y1 aDunstan, M, L1 aValladares, O1 aLaza, A, R1 aZelenika, D1 aRamirez, A1 aForoud, T, M1 aChoi, S-H1 aBoland, A1 aBecker, T1 aKukull, W, A1 avan der Lee, S, J1 aPasquier, F1 aCruchaga, C1 aBeekly, D1 aFitzpatrick, A, L1 aHanon, O1 aGill, M1 aBarber, R1 aGudnason, V1 aCampion, D1 aLove, S1 aBennett, D, A1 aAmin, N1 aBerr, C1 aTsolaki, Magda1 aBuxbaum, J, D1 aLopez, O, L1 aDeramecourt, V1 aFox, N, C1 aCantwell, L, B1 aTárraga, L1 aDufouil, C1 aHardy, J1 aCrane, P, K1 aEiriksdottir, G1 aHannequin, D1 aClarke, R1 aEvans, D1 aMosley, T, H1 aLetenneur, L1 aBrayne, C1 aMaier, W1 aDe Jager, P1 aEmilsson, V1 aDartigues, J-F1 aHampel, H1 aKamboh, M, I1 ade Bruijn, R, F A G1 aTzourio, C1 aPastor, P1 aLarson, E, B1 aRotter, J I1 aO'Donovan, M, C1 aMontine, T, J1 aNalls, M, A1 aMead, S1 aReiman, E, M1 aJonsson, P, V1 aHolmes, C1 aSt George-Hyslop, P, H1 aBoada, M1 aPassmore, P1 aWendland, J, R1 aSchmidt, R1 aMorgan, K1 aWinslow, A, R1 aPowell, J, F1 aCarasquillo, M1 aYounkin, S, G1 aJakobsdóttir, J1 aKauwe, J, S K1 aWilhelmsen, K, C1 aRujescu, D1 aNöthen, M, M1 aHofman, A1 aJones, L1 aHaines, J, L1 aPsaty, B M1 aVan Broeckhoven, C1 aHolmans, P1 aLauner, L J1 aMayeux, R1 aLathrop, M1 aGoate, A, M1 aEscott-Price, V1 aSeshadri, S1 aPericak-Vance, M, A1 aAmouyel, P1 aWilliams, J1 aDuijn, C M1 aSchellenberg, G, D1 aFarrer, L, A1 aIGAP Consortium uhttps://chs-nhlbi.org/node/668010963nas a2203529 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2016 eng d a2041-172300aA principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.0 aprincipal component metaanalysis on multiple anthropometric trai c2016 11 23 a133570 v73 aLarge consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
10aAnthropometry10aBody Size10aGenome-Wide Association Study10aGenotype10aHumans10aModels, Genetic10aPrincipal Component Analysis1 aRied, Janina, S1 aM, Janina, Jeff1 aChu, Audrey, Y1 aBragg-Gresham, Jennifer, L1 avan Dongen, Jenny1 aHuffman, Jennifer, E1 aAhluwalia, Tarunveer, S1 aCadby, Gemma1 aEklund, Niina1 aEriksson, Joel1 aEsko, Tõnu1 aFeitosa, Mary, F1 aGoel, Anuj1 aGorski, Mathias1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aJackson, Anne, U1 aJokinen, Eero1 aKanoni, Stavroula1 aKristiansson, Kati1 aKutalik, Zoltán1 aLahti, Jari1 aLuan, Jian'an1 aMägi, Reedik1 aMahajan, Anubha1 aMangino, Massimo1 aMedina-Gómez, Carolina1 aMonda, Keri, L1 aNolte, Ilja, M1 aPerusse, Louis1 aProkopenko, Inga1 aQi, Lu1 aRose, Lynda, M1 aSalvi, Erika1 aSmith, Megan, T1 aSnieder, Harold1 aStančáková, Alena1 aSung, Yun, Ju1 aTachmazidou, Ioanna1 aTeumer, Alexander1 aThorleifsson, Gudmar1 aHarst, Pim1 aWalker, Ryan, W1 aWang, Sophie, R1 aWild, Sarah, H1 aWillems, Sara, M1 aWong, Andrew1 aZhang, Weihua1 aAlbrecht, Eva1 aAlves, Alexessander, Couto1 aBakker, Stephan, J L1 aBarlassina, Cristina1 aBartz, Traci, M1 aBeilby, John1 aBellis, Claire1 aBergman, Richard, N1 aBergmann, Sven1 aBlangero, John1 aBlüher, Matthias1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBruinenberg, Marcel1 aCampbell, Harry1 aChen, Yii-Der Ida1 aChiang, Charleston, W K1 aChines, Peter, S1 aCollins, Francis, S1 aCucca, Fracensco1 aCupples, Adrienne, L1 aD'Avila, Francesca1 aGeus, Eco, J C1 aDedoussis, George1 aDimitriou, Maria1 aDöring, Angela1 aEriksson, Johan, G1 aFarmaki, Aliki-Eleni1 aFarrall, Martin1 aFerreira, Teresa1 aFischer, Krista1 aForouhi, Nita, G1 aFriedrich, Nele1 aGjesing, Anette, Prior1 aGlorioso, Nicola1 aGraff, Mariaelisa1 aGrallert, Harald1 aGrarup, Niels1 aGräßler, Jürgen1 aGrewal, Jagvir1 aHamsten, Anders1 aHarder, Marie, Neergaard1 aHartman, Catharina, A1 aHassinen, Maija1 aHastie, Nicholas1 aHattersley, Andrew, Tym1 aHavulinna, Aki, S1 aHeliövaara, Markku1 aHillege, Hans1 aHofman, Albert1 aHolmen, Oddgeir1 aHomuth, Georg1 aHottenga, Jouke-Jan1 aHui, Jennie1 aHusemoen, Lise, Lotte1 aHysi, Pirro, G1 aIsaacs, Aaron1 aIttermann, Till1 aJalilzadeh, Shapour1 aJames, Alan, L1 aJørgensen, Torben1 aJousilahti, Pekka1 aJula, Antti1 aJustesen, Johanne, Marie1 aJustice, Anne, E1 aKähönen, Mika1 aKaraleftheri, Maria1 aKhaw, Kay, Tee1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKinnunen, Leena1 aKnekt, Paul, B1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooner, Ishminder, K1 aKoskinen, Seppo1 aKovacs, Peter1 aKyriakou, Theodosios1 aLaitinen, Tomi1 aLangenberg, Claudia1 aLewin, Alexandra, M1 aLichtner, Peter1 aLindgren, Cecilia, M1 aLindström, Jaana1 aLinneberg, Allan1 aLorbeer, Roberto1 aLorentzon, Mattias1 aLuben, Robert1 aLyssenko, Valeriya1 aMännistö, Satu1 aManunta, Paolo1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcKnight, Barbara1 aMohlke, Karen, L1 aMihailov, Evelin1 aMilani, Lili1 aMills, Rebecca1 aMontasser, May, E1 aMorris, Andrew, P1 aMüller, Gabriele1 aMusk, Arthur, W1 aNarisu, Narisu1 aOng, Ken, K1 aOostra, Ben, A1 aOsmond, Clive1 aPalotie, Aarno1 aPankow, James, S1 aPaternoster, Lavinia1 aPenninx, Brenda, W1 aPichler, Irene1 aPilia, Maria, G1 aPolasek, Ozren1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRankinen, Tuomo1 aRao, D, C1 aRayner, Nigel, W1 aRibel-Madsen, Rasmus1 aRice, Treva, K1 aRichards, Marcus1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRyan, Kathy, A1 aSanna, Serena1 aSarzynski, Mark, A1 aScholtens, Salome1 aScott, Robert, A1 aSebert, Sylvain1 aSoutham, Lorraine1 aSparsø, Thomas, Hempel1 aSteinthorsdottir, Valgerdur1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStrauch, Konstantin1 aStringham, Heather, M1 aSwertz, Morris, A1 aSwift, Amy, J1 aTönjes, Anke1 aTsafantakis, Emmanouil1 avan der Most, Peter, J1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aVartiainen, Erkki1 aVenturini, Cristina1 aVerweij, Niek1 aViikari, Jorma, S1 aVitart, Veronique1 aVohl, Marie-Claude1 aVonk, Judith, M1 aWaeber, Gérard1 aWiden, Elisabeth1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWinkler, Thomas, W1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZhao, Jing, Hua1 aZillikens, Carola, M1 aBoomsma, Dorret, I1 aBouchard, Claude1 aChambers, John, C1 aChasman, Daniel, I1 aCusi, Daniele1 aGansevoort, Ron, T1 aGieger, Christian1 aHansen, Torben1 aHicks, Andrew, A1 aHu, Frank1 aHveem, Kristian1 aJarvelin, Marjo-Riitta1 aKajantie, Eero1 aKooner, Jaspal, S1 aKuh, Diana1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMetspalu, Andres1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aPalmer, Lyle, J1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPsaty, Bruce, M1 aPuolijoki, Hannu1 aRauramaa, Rainer1 aRudan, Igor1 aSalomaa, Veikko1 aSchwarz, Peter, E H1 aShudiner, Alan, R1 aSmit, Jan, H1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aStumvoll, Michael1 aTremblay, Angelo1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aVölker, Uwe1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWilson, James, F1 aZeggini, Eleftheria1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aDuijn, Cornelia, M1 aFox, Caroline1 aGroop, Leif, C1 aHeid, Iris, M1 aHunter, David, J1 aKaplan, Robert, C1 aMcCarthy, Mark, I1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aThorsteinsdottir, Unnur1 aStrachan, David, P1 aFrayling, Timothy1 aHirschhorn, Joel, N1 aMüller-Nurasyid, Martina1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/857003045nas a2200709 4500008004100000022001400041245009300055210006900148260001500217300001400232490000700246520089300253653004101146653002501187653004901212653002101261653003801282653002701320653002401347653001101371653003801382653003401420653002801454653001101482653000901493653004001502653003601542653002301578653002801601653002801629100001801657700002401675700001801699700001901717700001901736700001801755700002801773700002801801700001801829700001801847700002401865700002301889700002001912700002801932700001701960700002301977700002202000700002202022700002102044700002402065700002102089700001902110700001902129700002202148700002202170700002302192700002502215700001702240700001502257710002702272856003602299 2016 eng d a1460-208300aTwenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram.0 aTwentyeight genetic loci associated with STTwave amplitudes of t c2016 05 15 a2093-21030 v253 aThe ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
10aAdaptor Proteins, Signal Transducing10aArrhythmias, Cardiac10aBasic Helix-Loop-Helix Transcription Factors10aBrugada Syndrome10aCardiac Conduction System Disease10aDeath, Sudden, Cardiac10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMale10aNAV1.5 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aRepressor Proteins10aShab Potassium Channels10aShal Potassium Channels1 aVerweij, Niek1 aLeach, Irene, Mateo1 aIsaacs, Aaron1 aArking, Dan, E1 aBis, Joshua, C1 aPers, Tune, H1 avan den Berg, Marten, E1 aLyytikäinen, Leo-Pekka1 aBarnett, Phil1 aWang, Xinchen1 aSoliman, Elsayed, Z1 aDuijn, Cornelia, M1 aKähönen, Mika1 avan Veldhuisen, Dirk, J1 aKors, Jan, A1 aRaitakari, Olli, T1 aSilva, Claudia, T1 aLehtimäki, Terho1 aHillege, Hans, L1 aHirschhorn, Joel, N1 aBoyer, Laurie, A1 aGilst, Wiek, H1 aAlonso, Alvaro1 aSotoodehnia, Nona1 aEijgelsheim, Mark1 ade Boer, Rudolf, A1 ade Bakker, Paul, I W1 aFranke, Lude1 aHarst, Pim1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/760402737nas a2200541 4500008004100000022001400041245012200055210006900177260001200246300001200258490000800270520112500278653001001403653002001413653002501433653004001458653001101498653003401509653001101543653001401554653002001568653000901588653003701597653001201634653003601646653003201682653002701714100002101741700002001762700002101782700001901803700002901822700003001851700002501881700002001906700001701926700002001943700002301963700001801986700001802004700002302022700002402045700002302069700002002092700002502112710002202137856003602159 2017 eng d a1432-120300aAssessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study.0 aAssessing the causal relationship between obesity and venous thr c2017 07 a897-9020 v1363 aObservational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02-1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30-1.93 per standard deviation increase in BMI, P = 5.8 × 10). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.
10aAdult10aBody Mass Index10aCase-Control Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aIncidence10aLogistic Models10aMale10aMendelian Randomization Analysis10aObesity10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aVenous Thromboembolism1 aLindström, Sara1 aGermain, Marine1 aCrous-Bou, Marta1 aSmith, Erin, N1 aMorange, Pierre-Emmanuel1 aVlieg, Astrid, van Hylcka1 ade Haan, Hugoline, G1 aChasman, Daniel1 aRidker, Paul1 aBrody, Jennifer1 ade Andrade, Mariza1 aHeit, John, A1 aTang, Weihong1 aDeVivo, Immaculata1 aGrodstein, Francine1 aSmith, Nicholas, L1 aTregouet, David1 aKabrhel, Christopher1 aINVENT Consortium uhttps://chs-nhlbi.org/node/777710307nas a2202725 4500008004100000022001400041245012100055210006900176260001600245300001200261490000600273520278700279653001003066653000903076653002203085653002803107653001103135653003803146653003403184653002303218653001103241653000903252653003703261653001603298653001403314653003603328653002003364653001303384653002503397110005203422700002303474700002103497700001703518700001503535700002103550700001703571700002503588700002503613700002003638700001903658700001803677700001803695700001903713700002103732700002803753700002503781700002103806700002303827700002003850700001903870700001703889700002003906700002103926700001803947700001603965700002503981700002604006700002104032700001904053700002304072700002504095700002104120700001804141700002504159700003304184700002604217700003104243700001404274700001904288700002204307700002104329700001704350700002004367700002004387700002004407700001904427700002104446700002104467700002204488700002604510700001804536700002204554700002304576700002104599700002304620700001704643700002104660700002804681700002304709700001804732700002104750700002104771700001904792700002204811700001604833700002404849700002104873700002104894700001504915700002404930700002204954700002204976700001904998700001905017700002705036700002305063700002105086700001905107700002205126700001605148700002005164700002205184700002505206700001805231700002505249700002805274700001305302700002205315700001905337700001805356700002405374700002505398700002005423700002305443700001605466700001905482700002005501700002205521700001605543700002105559700002005580700001605600700002405616700002205640700002005662700001605682700002405698700002405722700002405746700002105770700002305791700002605814700002005840700002005860700001405880700001805894700001705912700002305929700002305952700001705975700001205992700002306004700002106027700002206048700002506070700002306095700001906118700002106137700002206158700001406180700002106194700002106215700001806236700002306254700001806277700001506295700001706310700001606327700001806343700002306361700002206384700001906406700002006425700002706445700001806472700001406490700002706504700001706531700001706548700001806565700001706583700001906600700001806619700002206637700002206659700001906681700001506700700001706715700001806732700001706750700001806767700001806785700002206803700002206825700002606847700001906873700002606892700002006918700001606938700001806954700002406972700001806996700002007014700001907034700001907053700002007072700002107092700001707113700002107130700002007151700001707171700001707188700002007205700002407225700001707249700002007266700002507286700003107311700002007342700001907362700002007381700001907401700001507420700002007435700001807455700002407473700002307497700002507520856003607545 2017 eng d a2374-244500aAssociation Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.0 aAssociation Between Telomere Length and Risk of Cancer and NonNe c2017 May 01 a636-6510 v33 aImportance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.
Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.
Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.
Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.
Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.
Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.
Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).
Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGerm-Line Mutation10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aNeoplasms10aPolymorphism, Single Nucleotide10aRisk Assessment10aTelomere10aTelomere Homeostasis1 aTelomeres Mendelian Randomization Collaboration1 aHaycock, Philip, C1 aBurgess, Stephen1 aNounu, Aayah1 aZheng, Jie1 aOkoli, George, N1 aBowden, Jack1 aWade, Kaitlin, Hazel1 aTimpson, Nicholas, J1 aEvans, David, M1 aWilleit, Peter1 aAviv, Abraham1 aGaunt, Tom, R1 aHemani, Gibran1 aMangino, Massimo1 aEllis, Hayley, Patricia1 aKurian, Kathreena, M1 aPooley, Karen, A1 aEeles, Rosalind, A1 aLee, Jeffrey, E1 aFang, Shenying1 aChen, Wei, V1 aLaw, Matthew, H1 aBowdler, Lisa, M1 aIles, Mark, M1 aYang, Qiong1 aWorrall, Bradford, B1 aMarkus, Hugh, Stephen1 aHung, Rayjean, J1 aAmos, Chris, I1 aSpurdle, Amanda, B1 aThompson, Deborah, J1 aO'Mara, Tracy, A1 aWolpin, Brian1 aAmundadottir, Laufey1 aStolzenberg-Solomon, Rachael1 aTrichopoulou, Antonia1 aOnland-Moret, Charlotte, N1 aLund, Eil1 aDuell, Eric, J1 aCanzian, Federico1 aSeveri, Gianluca1 aOvervad, Kim1 aGunter, Marc, J1 aTumino, Rosario1 aSvenson, Ulrika1 avan Rij, Andre1 aBaas, Annette, F1 aBown, Matthew, J1 aSamani, Nilesh, J1 avan t'Hof, Femke, N G1 aTromp, Gerard1 aJones, Gregory, T1 aKuivaniemi, Helena1 aElmore, James, R1 aJohansson, Mattias1 aMckay, James1 aScelo, Ghislaine1 aCarreras-Torres, Robert1 aGaborieau, Valerie1 aBrennan, Paul1 aBracci, Paige, M1 aNeale, Rachel, E1 aOlson, Sara, H1 aGallinger, Steven1 aLi, Donghui1 aPetersen, Gloria, M1 aRisch, Harvey, A1 aKlein, Alison, P1 aHan, Jiali1 aAbnet, Christian, C1 aFreedman, Neal, D1 aTaylor, Philip, R1 aMaris, John, M1 aAben, Katja, K1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aWiencke, John, K1 aWalsh, Kyle, M1 aWrensch, Margaret1 aRice, Terri1 aTurnbull, Clare1 aLitchfield, Kevin1 aPaternoster, Lavinia1 aStandl, Marie1 aAbecasis, Goncalo, R1 aSanGiovanni, John, Paul1 aLi, Yong1 aMijatovic, Vladan1 aSapkota, Yadav1 aLow, Siew-Kee1 aZondervan, Krina, T1 aMontgomery, Grant, W1 aNyholt, Dale, R1 avan Heel, David, A1 aHunt, Karen1 aArking, Dan, E1 aAshar, Foram, N1 aSotoodehnia, Nona1 aWoo, Daniel1 aRosand, Jonathan1 aComeau, Mary, E1 aBrown, Mark1 aSilverman, Edwin, K1 aHokanson, John, E1 aCho, Michael, H1 aHui, Jennie1 aFerreira, Manuel, A1 aThompson, Philip, J1 aMorrison, Alanna, C1 aFelix, Janine, F1 aSmith, Nicholas, L1 aChristiano, Angela, M1 aPetukhova, Lynn1 aBetz, Regina, C1 aFan, Xing1 aZhang, Xuejun1 aZhu, Caihong1 aLangefeld, Carl, D1 aThompson, Susan, D1 aWang, Feijie1 aLin, Xu1 aSchwartz, David, A1 aFingerlin, Tasha1 aRotter, Jerome, I1 aCotch, Mary, Frances1 aJensen, Richard, A1 aMunz, Matthias1 aDommisch, Henrik1 aSchaefer, Arne, S1 aHan, Fang1 aOllila, Hanna, M1 aHillary, Ryan, P1 aAlbagha, Omar1 aRalston, Stuart, H1 aZeng, Chenjie1 aZheng, Wei1 aShu, Xiao-Ou1 aReis, Andre1 aUebe, Steffen1 aHüffmeier, Ulrike1 aKawamura, Yoshiya1 aOtowa, Takeshi1 aSasaki, Tsukasa1 aHibberd, Martin, Lloyd1 aDavila, Sonia1 aXie, Gang1 aSiminovitch, Katherine1 aBei, Jin-Xin1 aZeng, Yi-Xin1 aFörsti, Asta1 aChen, Bowang1 aLandi, Stefano1 aFranke, Andre1 aFischer, Annegret1 aEllinghaus, David1 aFlores, Carlos1 aNoth, Imre1 aMa, Shwu-Fan1 aFoo, Jia, Nee1 aLiu, Jianjun1 aKim, Jong-Won1 aCox, David, G1 aDelattre, Olivier1 aMirabeau, Olivier1 aSkibola, Christine, F1 aTang, Clara, S1 aGarcia-Barcelo, Merce1 aChang, Kai-Ping1 aSu, Wen-Hui1 aChang, Yu-Sun1 aMartin, Nicholas, G1 aGordon, Scott1 aWade, Tracey, D1 aLee, Chaeyoung1 aKubo, Michiaki1 aCha, Pei-Chieng1 aNakamura, Yusuke1 aLevy, Daniel1 aKimura, Masayuki1 aHwang, Shih-Jen1 aHunt, Steven1 aSpector, Tim1 aSoranzo, Nicole1 aManichaikul, Ani, W1 aBarr, Graham1 aKahali, Bratati1 aSpeliotes, Elizabeth1 aYerges-Armstrong, Laura, M1 aCheng, Ching-Yu1 aJonas, Jost, B1 aWong, Tien, Yin1 aFogh, Isabella1 aLin, Kuang1 aPowell, John, F1 aRice, Kenneth1 aRelton, Caroline, L1 aMartin, Richard, M1 aSmith, George, Davey uhttps://chs-nhlbi.org/node/759404860nas a2201081 4500008004100000022001400041245007600055210006900131260001600200300001200216490000800228520186200236653000902098653001902107653001602126653002802142653002002170653002402190653002202214653003402236653001102270653003702281653001602318653002602334653002802360653001702388100002402405700001902429700002002448700002002468700001702488700002302505700002502528700002202553700001902575700002002594700002202614700001702636700001902653700002202672700002102694700001702715700002202732700001802754700002402772700001602796700002602812700002802838700002402866700002102890700002002911700001202931700002202943700001902965700002002984700002203004700002403026700001403050700002303064700001803087700002303105700001903128700002003147700001603167700001903183700002203202700002303224700002003247700002003267700002003287700002303307700002203330700001903352700001703371700001803388700001903406700002603425700001703451700002003468700002903488700002203517700002303539700002103562700001803583700002603601700002103627700001803648700001903666700001703685700002003702710002003722856003603742 2017 eng d a1537-660500aDNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.0 aDNA Methylation Analysis Identifies Loci for Blood Pressure Regu c2017 Dec 07 a888-9020 v1013 aGenome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
10aAged10aBlood Pressure10aCpG Islands10aCross-Sectional Studies10aDNA Methylation10aEpigenesis, Genetic10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMendelian Randomization Analysis10aMiddle Aged10aNerve Tissue Proteins10aQuantitative Trait Loci10aTetraspanins1 aRichard, Melissa, A1 aHuan, Tianxiao1 aLigthart, Symen1 aGondalia, Rahul1 aJhun, Min, A1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aMarioni, Riccardo1 aShen, Jincheng1 aTsai, Pei-Chien1 aMontasser, May, E1 aJia, Yucheng1 aSyme, Catriona1 aSalfati, Elias, L1 aBoerwinkle, Eric1 aGuan, Weihua1 aMosley, Thomas, H1 aBressler, Jan1 aMorrison, Alanna, C1 aLiu, Chunyu1 aMendelson, Michael, M1 aUitterlinden, André, G1 avan Meurs, Joyce, B1 aFranco, Oscar, H1 aZhang, Guosheng1 aLi, Yun1 aStewart, James, D1 aBis, Joshua, C1 aPsaty, Bruce, M1 aChen, Yii-Der Ida1 aKardia, Sharon, L R1 aZhao, Wei1 aTurner, Stephen, T1 aAbsher, Devin1 aAslibekyan, Stella1 aStarr, John, M1 aMcRae, Allan, F1 aHou, Lifang1 aJust, Allan, C1 aSchwartz, Joel, D1 aVokonas, Pantel, S1 aMenni, Cristina1 aSpector, Tim, D1 aShuldiner, Alan1 aDamcott, Coleen, M1 aRotter, Jerome, I1 aPalmas, Walter1 aLiu, Yongmei1 aPaus, Tomáš1 aHorvath, Steve1 aO'Connell, Jeffrey, R1 aGuo, Xiuqing1 aPausova, Zdenka1 aAssimes, Themistocles, L1 aSotoodehnia, Nona1 aSmith, Jennifer, A1 aArnett, Donna, K1 aDeary, Ian, J1 aBaccarelli, Andrea, A1 aBell, Jordana, T1 aWhitsel, Eric1 aDehghan, Abbas1 aLevy, Daniel1 aFornage, Myriam1 aBIOS Consortium uhttps://chs-nhlbi.org/node/758304297nas a2200889 4500008004100000022001400041245007400055210006900129260001300198490000700211520176700218653002501985653001502010653001502025653002402040653001702064653003402081653001302115653001602128653001102144653004002155653004002195653002602235100003002261700002202291700001702313700001802330700001802348700001902366700002602385700002202411700002202433700001502455700002202470700001902492700002202511700001802533700003002551700002302581700001902604700002002623700002202643700001702665700002202682700002302704700002202727700002102749700002302770700002602793700001702819700002602836700002002862700002202882700002402904700002402928700002002952700001902972700002402991700002203015700002003037700002403057700001903081700002003100700002203120700002203142700001803164700001203182700001903194700002403213700001903237700002103256700002303277700002403300700002303324700002403347856003603371 2017 eng d a1942-326800aFifteen Genetic Loci Associated With the Electrocardiographic P Wave.0 aFifteen Genetic Loci Associated With the Electrocardiographic P c2017 Aug0 v103 aBACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.
METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.
CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.
10aArrhythmias, Cardiac10aCaveolin 110aCaveolin 210aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHumans10aNAV1.5 Voltage-Gated Sodium Channel10aNAV1.8 Voltage-Gated Sodium Channel10aT-Box Domain Proteins1 aChristophersen, Ingrid, E1 aMagnani, Jared, W1 aYin, Xiaoyan1 aBarnard, John1 aWeng, Lu-Chen1 aArking, Dan, E1 aNiemeijer, Maartje, N1 aLubitz, Steven, A1 aAvery, Christy, L1 aDuan, Qing1 aFelix, Stephan, B1 aBis, Joshua, C1 aKerr, Kathleen, F1 aIsaacs, Aaron1 aMüller-Nurasyid, Martina1 aMüller, Christian1 aNorth, Kari, E1 aReiner, Alex, P1 aTinker, Lesley, F1 aKors, Jan, A1 aTeumer, Alexander1 aPetersmann, Astrid1 aSinner, Moritz, F1 aBůzková, Petra1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aVölker, Uwe1 aWaldenberger, Melanie1 aPeters, Annette1 aMeitinger, Thomas1 aLimacher, Marian, C1 aWilhelmsen, Kirk, C1 aPsaty, Bruce, M1 aHofman, Albert1 aUitterlinden, Andre1 aKrijthe, Bouwe, P1 aZhang, Zhu-Ming1 aSchnabel, Renate, B1 aKääb, Stefan1 aDuijn, Cornelia1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aDörr, Marcus1 aLi, Yun1 aChung, Mina, K1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aWhitsel, Eric, A1 aStricker, Bruno, H1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/755703502nas a2200793 4500008004100000022001400041245011400055210006900169260001200238300001400250490000700264520132200271653000901593653002501602653001101627653003401638653001101672653001101683653000901694653003701703653001601740653003601756653000901792100001801801700002001819700001401839700001601853700002201869700002201891700002001913700001501933700001901948700002001967700001801987700001702005700001702022700001402039700001302053700002102066700002102087700001702108700001702125700001902142700001702161700002102178700002402199700001502223700002402238700001402262700001602276700002602292700002002318700001802338700002302356700001802379700002502397700001902422700001702441700001902458700002202477700002202499700001802521700002002539700002302559700002002582700002002602710005002622856003602672 2017 eng d a1939-327X00aGenetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.0 aGenetically Determined Plasma Lipid Levels and Risk of Diabetic c2017 12 a3130-31410 v663 aResults from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
10aAged10aDiabetic Retinopathy10aFemale10aGenome-Wide Association Study10aHumans10aLipids10aMale10aMendelian Randomization Analysis10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk1 aSobrin, Lucia1 aChong, Yong, He1 aFan, Qiao1 aGan, Alfred1 aStanwyck, Lynn, K1 aKaidonis, Georgia1 aCraig, Jamie, E1 aKim, Jihye1 aLiao, Wen-Ling1 aHuang, Yu-Chuen1 aLee, Wen-Jane1 aHung, Yi-Jen1 aGuo, Xiuqing1 aHai, Yang1 aIpp, Eli1 aPollack, Samuela1 aHancock, Heather1 aPrice, Alkes1 aPenman, Alan1 aMitchell, Paul1 aLiew, Gerald1 aSmith, Albert, V1 aGudnason, Vilmundur1 aTan, Gavin1 aKlein, Barbara, E K1 aKuo, Jane1 aLi, Xiaohui1 aChristiansen, Mark, W1 aPsaty, Bruce, M1 aSandow, Kevin1 aJensen, Richard, A1 aKlein, Ronald1 aCotch, Mary, Frances1 aWang, Jie, Jin1 aJia, Yucheng1 aChen, Ching, J1 aChen, Yii-Der Ida1 aRotter, Jerome, I1 aTsai, Fuu-Jen1 aHanis, Craig, L1 aBurdon, Kathryn, P1 aWong, Tien, Yin1 aCheng, Ching-Yu1 aAsian Genetic Epidemiology Network Consortium uhttps://chs-nhlbi.org/node/759005076nas a2201081 4500008004100000022001400041245010500055210006900160260000900229300001300238490000700251520207300258653001002331653000902341653001902350653002602369653002602395653001102421653004002432653001102472653003402483653001102517653000902528653001602537653001202553653001802565100002502583700002202608700002402630700001902654700002702673700002102700700002302721700001802744700001602762700002302778700002502801700002602826700002102852700002202873700001902895700002002914700002902934700001102963700001702974700001802991700002203009700001903031700001903050700002003069700001603089700002003105700002103125700002103146700002003167700001603187700002103203700002403224700001903248700001703267700001903284700002003303700002003323700002103343700002103364700003203385700001903417700002803436700002403464700002003488700001903508700002103527700002203548700002003570700001903590700002103609700002003630700001603650700002103666700002303687700002503710700002303735700002803758700002503786700002103811700002103832700002003853700002203873700002303895700002003918700002003938856003603958 2017 eng d a1932-620300aGenome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts.0 aGenomewide association metaanalysis of fish and EPADHA consumpti c2017 ae01864560 v123 aBACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.
OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.
DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.
RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.
CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.
10aAdult10aAged10aCohort Studies10aDocosahexaenoic Acids10aEicosapentaenoic Acid10aEurope10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aSeafood10aUnited States1 aMozaffarian, Dariush1 aDashti, Hassan, S1 aWojczynski, Mary, K1 aChu, Audrey, Y1 aNettleton, Jennifer, A1 aMännistö, Satu1 aKristiansson, Kati1 aReedik, Mägi1 aLahti, Jari1 aHouston, Denise, K1 aCornelis, Marilyn, C1 avan Rooij, Frank, J A1 aDimitriou, Maria1 aKanoni, Stavroula1 aMikkilä, Vera1 aSteffen, Lyn, M1 aOtto, Marcia, C de Olive1 aQi, Lu1 aPsaty, Bruce1 aDjoussé, Luc1 aRotter, Jerome, I1 aHarald, Kennet1 aPerola, Markus1 aRissanen, Harri1 aJula, Antti1 aKrista, Fischer1 aMihailov, Evelin1 aFeitosa, Mary, F1 aNgwa, Julius, S1 aXue, Luting1 aJacques, Paul, F1 aPerälä, Mia-Maria1 aPalotie, Aarno1 aLiu, Yongmei1 aNalls, Nike, A1 aFerrucci, Luigi1 aHernandez, Dena1 aManichaikul, Ani1 aTsai, Michael, Y1 ade Jong, Jessica, C Kiefte-1 aHofman, Albert1 aUitterlinden, André, G1 aRallidis, Loukianos1 aRidker, Paul, M1 aRose, Lynda, M1 aBuring, Julie, E1 aLehtimäki, Terho1 aKähönen, Mika1 aViikari, Jorma1 aLemaitre, Rozenn1 aSalomaa, Veikko1 aKnekt, Paul1 aMetspalu, Andres1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aEriksson, Johan, G1 aKritchevsky, Stephen, B1 aBandinelli, Stefania1 aSiscovick, David1 aFranco, Oscar, H1 aDeloukas, Panos1 aDedoussis, George1 aChasman, Daniel, I1 aRaitakari, Olli1 aTanaka, Toshiko uhttps://chs-nhlbi.org/node/757804127nas a2200853 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520188400256653003702140653001902177653001302196653001102209653001702220653003402237653001102271653000902282653001402291653003602305100001702341700002102358700002202379700001702401700001402418700002002432700001402452700002102466700001702487700002202504700001402526700001702540700001702557700001202574700002002586700001802606700001702624700001202641700002002653700001902673700002102692700001502713700001802728700001602746700001502762700002202777700002002799700001602819700001802835700001302853700001702866700001802883700001702901700001502918700001802933700002202951700001902973700001602992700002003008700002203028700001903050700002203069700002303091700001703114700002003131700001803151700001203169700001803181700001703199700002103216856003603237 2017 eng d a1942-326800aGenome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.0 aGenomeWide Association Study MetaAnalysis of LongTerm Average Bl c2017 Apr ae0015270 v103 aBACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.
METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively).
CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.
10aAsian Continental Ancestry Group10aBlood Pressure10aFar East10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aPhenotype10aPolymorphism, Single Nucleotide1 aLi, Changwei1 aKim, Yun, Kyoung1 aDorajoo, Rajkumar1 aLi, Huaixing1 aLee, I-Te1 aCheng, Ching-Yu1 aHe, Meian1 aSheu, Wayne, H-H1 aGuo, Xiuqing1 aGanesh, Santhi, K1 aHe, Jiang1 aLee, Juyoung1 aLiu, Jianjun1 aHu, Yao1 aRao, Dabeeru, C1 aTsai, Fuu-Jen1 aKoh, Jia, Yu1 aHu, Hua1 aLiang, Kae-Woei1 aPalmas, Walter1 aHixson, James, E1 aHan, Sohee1 aTeo, Yik-Ying1 aWang, Yiqin1 aChen, Jing1 aLu, Chieh, Hsiang1 aZheng, Yingfeng1 aGui, Lixuan1 aLee, Wen-Jane1 aYao, Jie1 aGu, Dongfeng1 aHan, Bok-Ghee1 aSim, Xueling1 aSun, Liang1 aZhao, Jinying1 aChen, Chien-Hsiun1 aKumari, Neelam1 aHe, Yunfeng1 aTaylor, Kent, D1 aRaffel, Leslie, J1 aMoon, Sanghoon1 aRotter, Jerome, I1 aChen, Yii-Der, Ida1 aWu, Tangchun1 aWong, Tien, Yin1 aWu, Jer-Yuarn1 aLin, Xu1 aTai, E-Shyong1 aKim, Bong-Jo1 aKelly, Tanika, N uhttps://chs-nhlbi.org/node/757111080nas a2202833 4500008004100000022001400041245017500055210006900230260001300299300001300312490000700325520325900332653003003591653002203621653003403643653002603677653001103703653001403714653000903728100002103737700001703758700001803775700002503793700002503818700001903843700001203862700001303874700001703887700001903904700001903923700001803942700001303960700001503973700002203988700002404010700002204034700001704056700002504073700002004098700001804118700001904136700002104155700001404176700002304190700001604213700002404229700001204253700002104265700002204286700002004308700002204328700002104350700002104371700001804392700001804410700002004428700001804448700001904466700001704485700001904502700001904521700002004540700001804560700001404578700002104592700002304613700001804636700002704654700003504681700001704716700001604733700001804749700001504767700003004782700001804812700001704830700002004847700002604867700002204893700001604915700002504931700002204956700002304978700002205001700002405023700002005047700002105067700002205088700001905110700002005129700002205149700002205171700002105193700002005214700002605234700002205260700002405282700001505306700001905321700001805340700002205358700002205380700001905402700002205421700001805443700001705461700001805478700002005496700001705516700001705533700002205550700001805572700002305590700002205613700001805635700001905653700001905672700002105691700002205712700003005734700002205764700002005786700002105806700001905827700002105846700002005867700002805887700002305915700002105938700002305959700001905982700001906001700001606020700002106036700002206057700002006079700002406099700002406123700001506147700001906162700002406181700002006205700001806225700002106243700001806264700002506282700002306307700001906330700002406349700002006373700002006393700001806413700001606431700001906447700001806466700002106484700002306505700002706528700002206555700001806577700001406595700002206609700002106631700002306652700002506675700002206700700002306722700002206745700002206767700002006789700002106809700001906830700002006849700002206869700002006891700002506911700002206936700001606958700002006974700002206994700002207016700002007038700002007058700001907078700001707097700001907114700002207133700001907155700001507174700002207189700001907211700001207230700001707242700002007259700002707279700002007306700002207326700002907348700001607377700002307393700002107416700002007437700002007457700002807477700001807505700002107523700001807544700002307562700002107585700002007606700002407626700002107650700002307671700002007694700002107714700002107735700003007756700002007786700001807806700001907824700002307843700002007866700001707886700002207903700002007925700001907945700001907964700002207983700001808005700002208023700002208045700002408067700001908091700002008110710002408130710002908154710002708183856003608210 2017 eng d a1549-167600aImpact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.0 aImpact of common genetic determinants of Hemoglobin A1c on type c2017 Sep ae10023830 v143 aBACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.
METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.
CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
10aDiabetes Mellitus, Type 210aGenetic Variation10aGenome-Wide Association Study10aGlycated Hemoglobin A10aHumans10aPhenotype10aRisk1 aWheeler, Eleanor1 aLeong, Aaron1 aLiu, Ching-Ti1 aHivert, Marie-France1 aStrawbridge, Rona, J1 aPodmore, Clara1 aLi, Man1 aYao, Jie1 aSim, Xueling1 aHong, Jaeyoung1 aChu, Audrey, Y1 aZhang, Weihua1 aWang, Xu1 aChen, Peng1 aMaruthur, Nisa, M1 aPorneala, Bianca, C1 aSharp, Stephen, J1 aJia, Yucheng1 aKabagambe, Edmond, K1 aChang, Li-Ching1 aChen, Wei-Min1 aElks, Cathy, E1 aEvans, Daniel, S1 aFan, Qiao1 aGiulianini, Franco1 aGo, Min Jin1 aHottenga, Jouke-Jan1 aHu, Yao1 aJackson, Anne, U1 aKanoni, Stavroula1 aKim, Young, Jin1 aKleber, Marcus, E1 aLadenvall, Claes1 aLecoeur, Cécile1 aLim, Sing-Hui1 aLu, Yingchang1 aMahajan, Anubha1 aMarzi, Carola1 aNalls, Mike, A1 aNavarro, Pau1 aNolte, Ilja, M1 aRose, Lynda, M1 aRybin, Denis, V1 aSanna, Serena1 aShi, Yuan1 aStram, Daniel, O1 aTakeuchi, Fumihiko1 aTan, Shu, Pei1 avan der Most, Peter, J1 avan Vliet-Ostaptchouk, Jana, V1 aWong, Andrew1 aYengo, Loic1 aZhao, Wanting1 aGoel, Anuj1 aLarrad, Maria, Teresa Mar1 aRadke, Dörte1 aSalo, Perttu1 aTanaka, Toshiko1 avan Iperen, Erik, P A1 aAbecasis, Goncalo1 aAfaq, Saima1 aAlizadeh, Behrooz, Z1 aBertoni, Alain, G1 aBonnefond, Amélie1 aBöttcher, Yvonne1 aBottinger, Erwin, P1 aCampbell, Harry1 aCarlson, Olga, D1 aChen, Chien-Hsiun1 aCho, Yoon Shin1 aGarvey, Timothy1 aGieger, Christian1 aGoodarzi, Mark, O1 aGrallert, Harald1 aHamsten, Anders1 aHartman, Catharina, A1 aHerder, Christian1 aHsiung, Chao, Agnes1 aHuang, Jie1 aIgase, Michiya1 aIsono, Masato1 aKatsuya, Tomohiro1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKohara, Katsuhiko1 aKovacs, Peter1 aLee, Juyoung1 aLee, Wen-Jane1 aLehne, Benjamin1 aLi, Huaixing1 aLiu, Jianjun1 aLobbens, Stephane1 aLuan, Jian'an1 aLyssenko, Valeriya1 aMeitinger, Thomas1 aMiki, Tetsuro1 aMiljkovic, Iva1 aMoon, Sanghoon1 aMulas, Antonella1 aMüller, Gabriele1 aMüller-Nurasyid, Martina1 aNagaraja, Ramaiah1 aNauck, Matthias1 aPankow, James, S1 aPolasek, Ozren1 aProkopenko, Inga1 aRamos, Paula, S1 aRasmussen-Torvik, Laura1 aRathmann, Wolfgang1 aRich, Stephen, S1 aRobertson, Neil, R1 aRoden, Michael1 aRoussel, Ronan1 aRudan, Igor1 aScott, Robert, A1 aScott, William, R1 aSennblad, Bengt1 aSiscovick, David, S1 aStrauch, Konstantin1 aSun, Liang1 aSwertz, Morris1 aTajuddin, Salman, M1 aTaylor, Kent, D1 aTeo, Yik-Ying1 aTham, Yih, Chung1 aTönjes, Anke1 aWareham, Nicholas, J1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aHingorani, Aroon, D1 aEgan, Josephine1 aFerrucci, Luigi1 aHovingh, Kees1 aJula, Antti1 aKivimaki, Mika1 aKumari, Meena1 aNjølstad, Inger1 aPalmer, Colin, N A1 aRíos, Manuel, Serrano1 aStumvoll, Michael1 aWatkins, Hugh1 aAung, Tin1 aBlüher, Matthias1 aBoehnke, Michael1 aBoomsma, Dorret, I1 aBornstein, Stefan, R1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aChen, Yduan-Tsong1 aCheng, Ching-Yu1 aCucca, Francesco1 aGeus, Eco, J C1 aDeloukas, Panos1 aEvans, Michele, K1 aFornage, Myriam1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGroop, Leif1 aGross, Myron, D1 aHarris, Tamara, B1 aHayward, Caroline1 aHeng, Chew-Kiat1 aIngelsson, Erik1 aKato, Norihiro1 aKim, Bong-Jo1 aKoh, Woon-Puay1 aKooner, Jaspal, S1 aKörner, Antje1 aKuh, Diana1 aKuusisto, Johanna1 aLaakso, Markku1 aLin, Xu1 aLiu, Yongmei1 aLoos, Ruth, J F1 aMagnusson, Patrik, K E1 aMärz, Winfried1 aMcCarthy, Mark, I1 aOldehinkel, Albertine, J1 aOng, Ken, K1 aPedersen, Nancy, L1 aPereira, Mark, A1 aPeters, Annette1 aRidker, Paul, M1 aSabanayagam, Charumathi1 aSale, Michele1 aSaleheen, Danish1 aSaltevo, Juha1 aSchwarz, Peter, Eh1 aSheu, Wayne, H H1 aSnieder, Harold1 aSpector, Timothy, D1 aTabara, Yasuharu1 aTuomilehto, Jaakko1 avan Dam, Rob, M1 aWilson, James, G1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWong, Tien, Yin1 aWu, Jer-Yuarn1 aYuan, Jian-Min1 aZonderman, Alan, B1 aSoranzo, Nicole1 aGuo, Xiuqing1 aRoberts, David, J1 aFlorez, Jose, C1 aSladek, Robert1 aDupuis, Josée1 aMorris, Andrew, P1 aTai, E-Shyong1 aSelvin, Elizabeth1 aRotter, Jerome, I1 aLangenberg, Claudia1 aBarroso, Inês1 aMeigs, James, B1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/759604416nas a2200913 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520169200286653003701978653002902015653001902044653003802063653001802101653003402119653001102153653002302164653003602187653001702223653001402240653002502254100002402279700001702303700001902320700001902339700001802358700002802376700002002404700002802424700001902452700003002471700002402501700002102525700002402546700002102570700002302591700002602614700001902640700002002659700002202679700002202701700002602723700001802749700002302767700002102790700002502811700002202836700002702858700002102885700002602906700001702932700002702949700002102976700002002997700001903017700002303036700002403059700002403083700002003107700001503127700002003142700002903162700002303191700002203214700001903236700002003255700003103275700002303306700002103329700002503350700002603375700002003401700002503421700002003446856003603466 2017 eng d a1537-660500aLow-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.0 aLowFrequency Synonymous Coding Variation in CYP2R1 Has Large Eff c2017 Aug 03 a227-2380 v1013 aVitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
10aCholestanetriol 26-Monooxygenase10aCytochrome P450 Family 210aGene Frequency10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMultiple Sclerosis10aPolymorphism, Single Nucleotide10aRisk Factors10aVitamin D10aVitamin D Deficiency1 aManousaki, Despoina1 aDudding, Tom1 aHaworth, Simon1 aHsu, Yi-Hsiang1 aLiu, Ching-Ti1 aMedina-Gómez, Carolina1 aVoortman, Trudy1 avan der Velde, Nathalie1 aMelhus, Håkan1 aRobinson-Cohen, Cassianne1 aCousminer, Diana, L1 aNethander, Maria1 aVandenput, Liesbeth1 aNoordam, Raymond1 aForgetta, Vincenzo1 aGreenwood, Celia, M T1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aZemel, Babette, S1 aMitchell, Jonathan, A1 aTaylor, Bruce1 aLorentzon, Mattias1 aKarlsson, Magnus1 aJaddoe, Vincent, V W1 aTiemeier, Henning1 aCampos-Obando, Natalia1 aFranco, Oscar, H1 aUtterlinden, Andre, G1 aBroer, Linda1 avan Schoor, Natasja, M1 aHam, Annelies, C1 aIkram, Arfan, M1 aKarasik, David1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aHeijer, Martin, den1 aWang, Thomas, J1 aLind, Lars1 aOrwoll, Eric, S1 aMook-Kanamori, Dennis, O1 aMichaëlsson, Karl1 aKestenbaum, Bryan1 aOhlsson, Claes1 aMellström, Dan1 ade Groot, Lisette, C P G M1 aGrant, Struan, F A1 aKiel, Douglas, P1 aZillikens, Carola, M1 aRivadeneira, Fernando1 aSawcer, Stephen1 aTimpson, Nicholas, J1 aRichards, Brent uhttps://chs-nhlbi.org/node/748702532nas a2200457 4500008004100000022001400041245019300055210006900248260001300317300001200330490000700342520105800349653000901407653002601416653002301442653004001465653001101505653003001516653002001546653003801566653003401604653001801638653001101656653000901667653004401676653001401720653003601734653003001770653001401800653001801814653004701832653002001879653001701899653001801916653001801934100001801952700002201970700002701992700001902019856003602038 2017 eng d a1937-539500aPhenotype-Specific Association of Single-Nucleotide Polymorphisms with Heart Failure and Preserved Ejection Fraction: a Genome-Wide Association Analysis of the Cardiovascular Health Study.0 aPhenotypeSpecific Association of SingleNucleotide Polymorphisms c2017 Jun a285-2940 v103 aLittle is known about genetics of heart failure with preserved ejection fraction (HFpEF) in part because of the many comorbidities in this population. To identify single-nucleotide polymorphisms (SNPs) associated with HFpEF, we analyzed phenotypic and genotypic data from the Cardiovascular Health Study, which profiled patients using a 50,000 SNP array. Results were explored using novel SNP- and gene-centric tools. We performed analyses to determine whether some SNPs were relevant only in certain phenotypes. Among 3804 patients, 7 clinical factors and 9 SNPs were significantly associated with HFpEF; the most notable of which was rs6996224, a SNP associated with transforming growth factor-beta receptor 3. Most SNPs were associated with HFpEF only in the absence of a clinical predictor. Significant SNPs represented genes involved in myocyte proliferation, transforming growth factor-beta/erbB signaling, and extracellular matrix formation. These findings suggest that genetic factors may be more important in some phenotypes than others.
10aAged10aComputational Biology10aDatabases, Genetic10aEuropean Continental Ancestry Group10aFemale10aGene Expression Profiling10aGenetic Markers10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeart Failure10aHumans10aMale10aOligonucleotide Array Sequence Analysis10aPhenotype10aPolymorphism, Single Nucleotide10aPredictive Value of Tests10aPrognosis10aProteoglycans10aReceptors, Transforming Growth Factor beta10aRisk Assessment10aRisk Factors10aStroke Volume10aUnited States1 aKao, David, P1 aStevens, Laura, M1 aHinterberg, Michael, A1 aGörg, Carsten uhttps://chs-nhlbi.org/node/855503066nas a2200577 4500008004100000022001400041245008100055210006900136260001300205300001300218490000700231520143400238653001101672653002301683653001801706653001101724653004301735653001901778653001701797653001801814653003401832653001101866653001901877653001801896653002001914653000901934653002301943653001401966653001601980653001901996653003602015653003302051653002102084653002302105653002702128100001802155700002302173700002002196700001302216700002502229700002102254700001802275700002002293700001802313700002302331700002502354700002202379700002502401710002602426856003602452 2017 eng d a1553-740400aRare coding variants pinpoint genes that control human hematological traits.0 aRare coding variants pinpoint genes that control human hematolog c2017 Aug ae10069250 v133 aThe identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.
10aAsthma10aDatabases, Genetic10aEndometriosis10aFemale10aFibrin Fibrinogen Degradation Products10aGene Frequency10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aInterleukin-3310aLinear Models10aLogistic Models10aMale10aMutation, Missense10aPhenotype10aPlasminogen10aPlatelet Count10aPolymorphism, Single Nucleotide10aPrincipal Component Analysis10aProtein Splicing10aRhinitis, Allergic10aSequence Analysis, DNA1 aMousas, Abdou1 aNtritsos, Georgios1 aChen, Ming-Huei1 aSong, Ci1 aHuffman, Jennifer, E1 aTzoulaki, Ioanna1 aElliott, Paul1 aPsaty, Bruce, M1 aAuer, Paul, L1 aJohnson, Andrew, D1 aEvangelou, Evangelos1 aLettre, Guillaume1 aReiner, Alexander, P1 aBlood-Cell Consortium uhttps://chs-nhlbi.org/node/757705167nas a2201273 4500008004100000022001400041245013800055210006900193260001300262300001300275490000700288520164300295653002201938653001201960653004901972653001902021653001402040653002502054653001102079653001702090653003402107653001102141653001702152653000902169653002202178653000902200653003102209653003602240100002002276700001502296700002802311700002202339700002102361700002302382700001802405700002302423700001802446700001902464700002102483700002402504700001702528700001502545700001802560700002302578700001502601700002202616700002102638700001602659700002402675700002002699700001402719700001402733700002002747700002302767700001702790700001702807700002302824700002502847700002402872700001702896700001802913700002202931700002402953700002002977700002202997700001303019700001403032700002403046700001803070700002103088700002003109700001803129700002103147700002203168700001903190700001703209700002803226700002003254700002103274700001803295700001903313700002103332700002403353700001503377700001603392700002003408700002403428700002303452700002103475700002103496700001703517700002003534700002003554700001903574700002403593700002103617700001603638700002103654700001903675700002303694700001403717700002203731700002003753700001703773700002603790700001803816700002303834856003603857 2017 eng d a1553-740400aSingle-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.0 aSingletrait and multitrait genomewide association analyses ident c2017 May ae10067280 v133 aHypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
10aAfrican Americans10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aBlood Pressure10aCadherins10aCase-Control Studies10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMembrane Proteins10aMice10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide1 aLiang, Jingjing1 aLe, Thu, H1 aEdwards, Digna, R Velez1 aTayo, Bamidele, O1 aGaulton, Kyle, J1 aSmith, Jennifer, A1 aLu, Yingchang1 aJensen, Richard, A1 aChen, Guanjie1 aYanek, Lisa, R1 aSchwander, Karen1 aTajuddin, Salman, M1 aSofer, Tamar1 aKim, Wonji1 aKayima, James1 aMcKenzie, Colin, A1 aFox, Ervin1 aNalls, Michael, A1 aYoung, Hunter, J1 aSun, Yan, V1 aLane, Jacqueline, M1 aCechova, Sylvia1 aZhou, Jie1 aTang, Hua1 aFornage, Myriam1 aMusani, Solomon, K1 aWang, Heming1 aLee, Juyoung1 aAdeyemo, Adebowale1 aDreisbach, Albert, W1 aForrester, Terrence1 aChu, Pei-Lun1 aCappola, Anne1 aEvans, Michele, K1 aMorrison, Alanna, C1 aMartin, Lisa, W1 aWiggins, Kerri, L1 aHui, Qin1 aZhao, Wei1 aJackson, Rebecca, D1 aWare, Erin, B1 aFaul, Jessica, D1 aReiner, Alex, P1 aBray, Michael1 aDenny, Joshua, C1 aMosley, Thomas, H1 aPalmas, Walter1 aGuo, Xiuqing1 aPapanicolaou, George, J1 aPenman, Alan, D1 aPolak, Joseph, F1 aRice, Kenneth1 aTaylor, Ken, D1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aLiu, Kiang1 aRisch, Neil1 aHunt, Steven, C1 aKooperberg, Charles1 aZonderman, Alan, B1 aLaurie, Cathy, C1 aBecker, Diane, M1 aCai, Jianwen1 aLoos, Ruth, J F1 aPsaty, Bruce, M1 aWeir, David, R1 aKardia, Sharon, L R1 aArnett, Donna, K1 aWon, Sungho1 aEdwards, Todd, L1 aRedline, Susan1 aCooper, Richard, S1 aRao, D, C1 aRotter, Jerome, I1 aRotimi, Charles1 aLevy, Daniel1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/757203005nas a2200589 4500008004100000022001400041245020400055210006900259260001300328300001400341490000700355520109000362653002201452653002601474653003501500653001201535653003401547653002301581653002701604653002701631653003601658653001101694653003101705653003401736653004301770653001101813653000901824653003201833653004001865653002301905653003601928653002901964653002101993653002002014653001802034100002702052700002302079700002002102700002302122700001802145700002102163700002102184700002102205700001702226700002002243700002302263700002302286700002702309700002402336700001902360856003602379 2017 eng d a1552-527900aSystems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.0 aSystems biology approach to lateonset Alzheimers disease genomew c2017 Oct a1133-11420 v133 aINTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.
METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.
RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.
DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.
10aAlzheimer Disease10aAmyloid beta-Peptides10aAmyloid beta-Protein Precursor10aAnimals10aAnimals, Genetically Modified10aAntigens, Neoplasm10aCaenorhabditis elegans10aDisease Models, Animal10aEarly Growth Response Protein 110aFemale10aGene Expression Regulation10aGenome-Wide Association Study10aHeparin-binding EGF-like Growth Factor10aHumans10aMale10aMembrane Transport Proteins10aMitochondrial ADP, ATP Translocases10aNADH Dehydrogenase10aPolymorphism, Single Nucleotide10aProtein Interaction Maps10aRNA Interference10aSystems Biology10aTemporal Lobe1 aMukherjee, Shubhabrata1 aRussell, Joshua, C1 aCarr, Daniel, T1 aBurgess, Jeremy, D1 aAllen, Mariet1 aSerie, Daniel, J1 aBoehme, Kevin, L1 aKauwe, John, S K1 aNaj, Adam, C1 aFardo, David, W1 aDickson, Dennis, W1 aMontine, Thomas, J1 aErtekin-Taner, Nilufer1 aKaeberlein, Matt, R1 aCrane, Paul, K uhttps://chs-nhlbi.org/node/855803876nas a2200565 4500008004100000022001400041245013500055210006900190260000900259300001300268490000700281520223900288653001602527653003402543653001102577653001202588653001202600653001202612653003602624653001902660653003402679653003002713100002902743700002402772700001202796700001902808700001802827700002102845700002102866700002102887700001502908700002002923700001702943700002302960700002502983700002503008700002103033700002203054700002203076700002003098700002003118700002003138700001703158700001503175700001703190700001803207700002403225700002503249856003603274 2018 eng d a1932-620300aGenome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium.0 aGenomewide association metaanalysis of circulating oddnumbered c c2018 ae01969510 v133 aBACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.
OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.
DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.
RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37×10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07×10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4×10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5×10-2).
CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.
10aFatty Acids10aGenome-Wide Association Study10aHumans10aIntrons10aLactase10aMyosins10aPolymorphism, Single Nucleotide10aSphingomyelins10aSphingosine N-Acyltransferase10aTumor Suppressor Proteins1 aOtto, Marcia, C de Olive1 aLemaitre, Rozenn, N1 aSun, Qi1 aKing, Irena, B1 aH Y Wu, Jason1 aManichaikul, Ani1 aRich, Stephen, S1 aTsai, Michael, Y1 aChen, Y, D1 aFornage, Myriam1 aWeihua, Guan1 aAslibekyan, Stella1 aIrvin, Marguerite, R1 aKabagambe, Edmond, K1 aArnett, Donna, K1 aJensen, Majken, K1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aSteffen, Lyn, M1 aSmith, Caren, E1 aRiserus, Ulf1 aLind, Lars1 aHu, Frank, B1 aRimm, Eric, B1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/779107247nas a2202185 4500008004100000022001400041245013000055210006900185260001500254300000900269490000600278520110800284653002001392653003101412653003501443653002101478653003801499653003401537653001101571653001401582653002801596653003601624653002801660653001701688100002301705700002801728700002201756700001701778700001901795700002401814700002201838700002401860700002301884700001601907700002001923700001901943700002101962700001701983700003002000700001902030700001502049700001902064700003302083700002102116700002002137700002002157700002102177700002502198700002002223700002302243700001802266700001902284700001802303700001902321700002302340700001902363700002202382700001902404700002802423700001702451700002102468700002002489700001902509700002002528700002002548700001602568700002102584700002302605700002302628700002502651700002402676700002002700700002502720700002302745700002002768700001502788700001902803700002002822700001702842700002102859700002002880700002002900700002102920700002602941700001902967700002002986700001903006700002003025700002003045700001903065700002003084700001803104700001903122700002503141700002203166700001603188700002303204700002003227700002003247700002003267700001703287700001803304700002003322700001903342700003103361700001503392700002303407700002203430700002003452700001803472700002103490700002103511700002103532700001803553700001903571700001903590700001903609700002003628700002103648700002603669700001903695700002203714700002203736700002003758700001803778700001703796700001803813700002103831700002103852700001903873700002203892700002303914700002303937700002503960700002203985700001604007700001604023700002104039700002004060700002004080700001704100700002304117700001604140700002204156700002204178700002504200700001504225700001804240700002104258700002304279700001604302700001804318700002004336700001704356700001804373700001904391700002204410700002404432700002004456700002004476700002304496700002304519700002904542700002204571700002004593700002104613700002104634700002204655700002304677700002004700700001904720700002804739700002104767700002204788700002304810700002404833700001704857700002404874700002404898700002804922700001904950700003004969710002604999856003605025 2018 eng d a2041-172300aGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.0 aGWAS and colocalization analyses implicate carotid intimamedia t c2018 12 03 a51410 v93 aCarotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
10aADAMTS9 Protein10aAmino Acid Oxidoreductases10aCarotid Intima-Media Thickness10aCoronary Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLod Score10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors1 aFranceschini, Nora1 aGiambartolomei, Claudia1 ade Vries, Paul, S1 aFinan, Chris1 aBis, Joshua, C1 aHuntley, Rachael, P1 aLovering, Ruth, C1 aTajuddin, Salman, M1 aWinkler, Thomas, W1 aGraff, Misa1 aKavousi, Maryam1 aDale, Caroline1 aSmith, Albert, V1 aHofer, Edith1 avan Leeuwen, Elisabeth, M1 aNolte, Ilja, M1 aLu, Lingyi1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aPitkänen, Niina1 aFranzén, Oscar1 aJoshi, Peter, K1 aNoordam, Raymond1 aMarioni, Riccardo, E1 aHwang, Shih-Jen1 aMusani, Solomon, K1 aSchminke, Ulf1 aPalmas, Walter1 aIsaacs, Aaron1 aCorrea, Adolfo1 aZonderman, Alan, B1 aHofman, Albert1 aTeumer, Alexander1 aCox, Amanda, J1 aUitterlinden, André, G1 aWong, Andrew1 aSmit, Andries, J1 aNewman, Anne, B1 aBritton, Annie1 aRuusalepp, Arno1 aSennblad, Bengt1 aHedblad, Bo1 aPasaniuc, Bogdan1 aPenninx, Brenda, W1 aLangefeld, Carl, D1 aWassel, Christina, L1 aTzourio, Christophe1 aFava, Cristiano1 aBaldassarre, Damiano1 aO'Leary, Daniel, H1 aTeupser, Daniel1 aKuh, Diana1 aTremoli, Elena1 aMannarino, Elmo1 aGrossi, Enzo1 aBoerwinkle, Eric1 aSchadt, Eric, E1 aIngelsson, Erik1 aVeglia, Fabrizio1 aRivadeneira, Fernando1 aBeutner, Frank1 aChauhan, Ganesh1 aHeiss, Gerardo1 aSnieder, Harold1 aCampbell, Harry1 aVölzke, Henry1 aMarkus, Hugh, S1 aDeary, Ian, J1 aJukema, Wouter1 ade Graaf, Jacqueline1 aPrice, Jacqueline1 aPott, Janne1 aHopewell, Jemma, C1 aLiang, Jingjing1 aThiery, Joachim1 aEngmann, Jorgen1 aGertow, Karl1 aRice, Kenneth1 aTaylor, Kent, D1 aDhana, Klodian1 aKiemeney, Lambertus, A L M1 aLind, Lars1 aRaffield, Laura, M1 aLauner, Lenore, J1 aHoldt, Lesca, M1 aDörr, Marcus1 aDichgans, Martin1 aTraylor, Matthew1 aSitzer, Matthias1 aKumari, Meena1 aKivimaki, Mika1 aNalls, Mike, A1 aMelander, Olle1 aRaitakari, Olli1 aFranco, Oscar, H1 aRueda-Ochoa, Oscar, L1 aRoussos, Panos1 aWhincup, Peter, H1 aAmouyel, Philippe1 aGiral, Philippe1 aAnugu, Pramod1 aWong, Quenna1 aMalik, Rainer1 aRauramaa, Rainer1 aBurkhardt, Ralph1 aHardy, Rebecca1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aMorris, Richard, W1 aStrawbridge, Rona, J1 aWannamethee, Goya1 aHägg, Sara1 aShah, Sonia1 aMcLachlan, Stela1 aTrompet, Stella1 aSeshadri, Sudha1 aKurl, Sudhir1 aHeckbert, Susan, R1 aRing, Susan1 aHarris, Tamara, B1 aLehtimäki, Terho1 aGalesloot, Tessel, E1 aShah, Tina1 ade Faire, Ulf1 aPlagnol, Vincent1 aRosamond, Wayne, D1 aPost, Wendy1 aZhu, Xiaofeng1 aZhang, Xiaoling1 aGuo, Xiuqing1 aSaba, Yasaman1 aDehghan, Abbas1 aSeldenrijk, Adrie1 aMorrison, Alanna, C1 aHamsten, Anders1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLawlor, Deborah, A1 aMook-Kanamori, Dennis, O1 aBowden, Donald, W1 aSchmidt, Helena1 aWilson, James, F1 aWilson, James, G1 aRotter, Jerome, I1 aWardlaw, Joanna, M1 aDeanfield, John1 aHalcox, Julian1 aLyytikäinen, Leo-Pekka1 aLoeffler, Markus1 aEvans, Michele, K1 aDebette, Stephanie1 aHumphries, Steve, E1 aVölker, Uwe1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aBjörkegren, Johan, L M1 aCasas, Juan, P1 aO'Donnell, Christopher, J1 aMEGASTROKE Consortium uhttps://chs-nhlbi.org/node/791302525nas a2200313 4500008004100000022001400041245009700055210006900152260001500221300001200236490000700248520159500255653001001850653002601860653003101886653003401917653001301951653001101964653003601975100002802011700001602039700001602055700002602071700001902097700002102116700001502137700002302152856003602175 2018 eng d a1945-458900aStrong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.0 aStrong impact of naturalselectionfree heterogeneity in genetics c2018 03 29 a492-5140 v103 aA conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.
10aAging10aComputational Biology10aGene Expression Regulation10aGenome-Wide Association Study10aGenotype10aHumans10aPolymorphism, Single Nucleotide1 aKulminski, Alexander, M1 aHuang, Jian1 aLoika, Yury1 aArbeev, Konstantin, G1 aBagley, Olivia1 aYashkin, Arseniy1 aDuan, Matt1 aCulminskaya, Irina uhttps://chs-nhlbi.org/node/825704619nas a2201021 4500008004100000022001400041245012900055210006900184260001200253300001300265490000700278520172700285653001502012653001002027653000902037653002202046653003802068653002602106653003402132653001102166653002902177653002202206653003402228653001502262653001102277653001202288653004202300653000902342653001602351653002602367653005002393653001102443653001902454653003602473653002802509653002602537653001002563653002602573653001602599100001902615700001402634700002302648700001502671700002502686700001802711700002202729700002302751700001702774700002402791700002102815700002802836700002002864700002202884700002402906700002202930700001902952700002202971700001502993700002003008700001303028700002203041700002103063700001903084700002203103700002203125700002103147700001403168700001903182700001703201700002003218700002503238700001703263700002003280700002003300700002003320700002003340700002203360700002003382700002303402700002103425700002303446700002103469700001803490700001803508700001603526700001903542856003603561 2019 eng d a1553-740400aAssociations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.0 aAssociations of variants In the hexokinase 1 and interleukin 18 c2019 04 ae10077390 v153 aSleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCell Adhesion Molecules, Neuronal10aComputational Biology10aExtracellular Matrix Proteins10aFemale10aGene Regulatory Networks10aGenetic Variation10aGenome-Wide Association Study10aHexokinase10aHumans10aHypoxia10aInterleukin-18 Receptor alpha Subunit10aMale10aMiddle Aged10aNerve Tissue Proteins10aNLR Family, Pyrin Domain-Containing 3 Protein10aOxygen10aOxyhemoglobins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aSerine Endopeptidases10aSleep10aSleep Apnea Syndromes10aYoung Adult1 aCade, Brian, E1 aChen, Han1 aStilp, Adrienne, M1 aLouie, Tin1 aAncoli-Israel, Sonia1 aArens, Raanan1 aBarfield, Richard1 aBelow, Jennifer, E1 aCai, Jianwen1 aConomos, Matthew, P1 aEvans, Daniel, S1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aGleason, Kevin, J1 aGottlieb, Daniel, J1 aHillman, David, R1 aJohnson, Craig1 aLederer, David, J1 aLee, Jiwon1 aLoredo, Jose, S1 aMei, Hao1 aMukherjee, Sutapa1 aPatel, Sanjay, R1 aPost, Wendy, S1 aPurcell, Shaun, M1 aRamos, Alberto, R1 aReid, Kathryn, J1 aRice, Ken1 aShah, Neomi, A1 aSofer, Tamar1 aTaylor, Kent, D1 aThornton, Timothy, A1 aWang, Heming1 aYaffe, Kristine1 aZee, Phyllis, C1 aHanis, Craig, L1 aPalmer, Lyle, J1 aRotter, Jerome, I1 aStone, Katie, L1 aTranah, Gregory, J1 aWilson, James, G1 aSunyaev, Shamil, R1 aLaurie, Cathy, C1 aZhu, Xiaofeng1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/804404760nas a2201057 4500008004100000022001400041245011000055210006900165260001500234300001200249490000800261520187700269653001002146653000902156653001902165653002102184653001602205653002002221653001102241653001102252653003402263653001102297653001402308653001502322653000902337653001602346653002602362653002202388653001402410653002402424653000902448653001802457100001802475700002602493700002802519700001902547700001902566700002002585700001902605700002302624700002202647700001802669700001902687700002002706700002402726700002002750700001902770700001702789700002202806700002102828700002002849700002302869700002102892700002502913700002402938700002002962700002202982700002003004700001203024700002003036700002203056700002003078700002203098700002203120700002203142700002003164700002003184700002003204700002103224700002003245700002103265700002003286700001603306700002503322700002103347700001903368700002203387700002003409700002403429700001603453700002003469700002203489700002203511700002003533700002003553700002903573700002103602700001703623700002603640856003603666 2019 eng d a1524-453900aBlood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.0 aBlood Leukocyte DNA Methylation Predicts Risk of Future Myocardi c2019 08 20 a645-6570 v1403 aBACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.
METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.
RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.
CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
10aAdult10aAged10aCohort Studies10aCoronary Disease10aCpG Islands10aDNA Methylation10aEurope10aFemale10aGenome-Wide Association Study10aHumans10aIncidence10aLeukocytes10aMale10aMiddle Aged10aMyocardial Infarction10aPopulation Groups10aPrognosis10aProspective Studies10aRisk10aUnited States1 aAgha, Golareh1 aMendelson, Michael, M1 aWard-Caviness, Cavin, K1 aJoehanes, Roby1 aHuan, Tianxiao1 aGondalia, Rahul1 aSalfati, Elias1 aBrody, Jennifer, A1 aFiorito, Giovanni1 aBressler, Jan1 aChen, Brian, H1 aLigthart, Symen1 aGuarrera, Simonetta1 aColicino, Elena1 aJust, Allan, C1 aWahl, Simone1 aGieger, Christian1 aVandiver, Amy, R1 aTanaka, Toshiko1 aHernandez, Dena, G1 aPilling, Luke, C1 aSingleton, Andrew, B1 aSacerdote, Carlotta1 aKrogh, Vittorio1 aPanico, Salvatore1 aTumino, Rosario1 aLi, Yun1 aZhang, Guosheng1 aStewart, James, D1 aFloyd, James, S1 aWiggins, Kerri, L1 aRotter, Jerome, I1 aMulthaup, Michael1 aBakulski, Kelly1 aHorvath, Steven1 aTsao, Philip, S1 aAbsher, Devin, M1 aVokonas, Pantel1 aHirschhorn, Joel1 aFallin, Daniele1 aLiu, Chunyu1 aBandinelli, Stefania1 aBoerwinkle, Eric1 aDehghan, Abbas1 aSchwartz, Joel, D1 aPsaty, Bruce, M1 aFeinberg, Andrew, P1 aHou, Lifang1 aFerrucci, Luigi1 aSotoodehnia, Nona1 aMatullo, Giuseppe1 aPeters, Annette1 aFornage, Myriam1 aAssimes, Themistocles, L1 aWhitsel, Eric, A1 aLevy, Daniel1 aBaccarelli, Andrea, A uhttps://chs-nhlbi.org/node/850713143nas a2204261 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2019 eng d a1546-171800aA catalog of genetic loci associated with kidney function from analyses of a million individuals.0 acatalog of genetic loci associated with kidney function from ana c2019 06 a957-9720 v513 aChronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aInheritance Patterns10aKidney Function Tests10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRenal Insufficiency, Chronic10aUromodulin1 aWuttke, Matthias1 aLi, Yong1 aLi, Man1 aSieber, Karsten, B1 aFeitosa, Mary, F1 aGorski, Mathias1 aTin, Adrienne1 aWang, Lihua1 aChu, Audrey, Y1 aHoppmann, Anselm1 aKirsten, Holger1 aGiri, Ayush1 aChai, Jin-Fang1 aSveinbjornsson, Gardar1 aTayo, Bamidele, O1 aNutile, Teresa1 aFuchsberger, Christian1 aMarten, Jonathan1 aCocca, Massimiliano1 aGhasemi, Sahar1 aXu, Yizhe1 aHorn, Katrin1 aNoce, Damia1 avan der Most, Peter, J1 aSedaghat, Sanaz1 aYu, Zhi1 aAkiyama, Masato1 aAfaq, Saima1 aAhluwalia, Tarunveer, S1 aAlmgren, Peter1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoissel, Mathilde1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrenner, Hermann1 aBrumat, Marco1 aBurkhardt, Ralph1 aButterworth, Adam, S1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCanouil, Mickaël1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aChee, Miao-Ling1 aChee, Miao-Li1 aChen, Xu1 aCheng, Ching-Yu1 aCheng, Yurong1 aChristensen, Kaare1 aCifkova, Renata1 aCiullo, Marina1 aConcas, Maria, Pina1 aCook, James, P1 aCoresh, Josef1 aCorre, Tanguy1 aSala, Cinzia, Felicita1 aCusi, Daniele1 aDanesh, John1 aDaw, Warwick1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDegenhardt, Frauke1 aDelgado, Graciela1 aDemirkan, Ayse1 aDi Angelantonio, Emanuele1 aDittrich, Katalin1 aDivers, Jasmin1 aDorajoo, Rajkumar1 aEckardt, Kai-Uwe1 aEhret, Georg1 aElliott, Paul1 aEndlich, Karlhans1 aEvans, Michele, K1 aFelix, Janine, F1 aFoo, Valencia, Hui Xian1 aFranco, Oscar, H1 aFranke, Andre1 aFreedman, Barry, I1 aFreitag-Wolf, Sandra1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGansevoort, Ron, T1 aGao, He1 aGasparini, Paolo1 aGaziano, Michael1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGiulianini, Franco1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHartman, Catharina, A1 aHayward, Caroline1 aHellwege, Jacklyn, N1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHofer, Edith1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aIndridason, Olafur, S1 aIngelsson, Erik1 aIsing, Marcus1 aJaddoe, Vincent, W V1 aJakobsdottir, Johanna1 aJonas, Jost, B1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKanai, Masahiro1 aKastarinen, Mika1 aKerr, Shona, M1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKörner, Antje1 aKovacs, Peter1 aKraja, Aldi, T1 aKrajcoviechova, Alena1 aKramer, Holly1 aKrämer, Bernhard, K1 aKronenberg, Florian1 aKubo, Michiaki1 aKuhnel, Brigitte1 aKuokkanen, Mikko1 aKuusisto, Johanna1 aLa Bianca, Martina1 aLaakso, Markku1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLee, Jeannette, Jen-Mai1 aLehne, Benjamin1 aLehtimäki, Terho1 aLieb, Wolfgang1 aLim, Su-Chi1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Jun1 aLiu, Jianjun1 aLoeffler, Markus1 aLoos, Ruth, J F1 aLucae, Susanne1 aLukas, Mary, Ann1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMahajan, Anubha1 aMartin, Nicholas, G1 aMartins, Jade1 aMärz, Winfried1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMeisinger, Christa1 aMeitinger, Thomas1 aMelander, Olle1 aMetspalu, Andres1 aMikaelsdottir, Evgenia, K1 aMilaneschi, Yuri1 aMiliku, Kozeta1 aMishra, Pashupati, P1 aMohlke, Karen, L1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMychaleckyj, Josyf, C1 aNadkarni, Girish, N1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey1 aO'Donoghue, Michelle, L1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aOrho-Melander, Marju1 aOuwehand, Willem, H1 aPadmanabhan, Sandosh1 aPalmer, Nicholette, D1 aPalsson, Runolfur1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPerola, Markus1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPodgornaia, Anna, I1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPramstaller, Peter, P1 aPreuss, Michael, H1 aPrins, Bram, P1 aProvince, Michael, A1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRizzi, Federica1 aRoberts, David, J1 aRobino, Antonietta1 aRossing, Peter1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSalvi, Erika1 aSaum, Kai-Uwe1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSchöttker, Ben1 aSchulz, Christina-Alexandra1 aSchupf, Nicole1 aShaffer, Christian, M1 aShi, Yuan1 aSmith, Albert, V1 aSmith, Blair, H1 aSoranzo, Nicole1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStringham, Heather, M1 aStumvoll, Michael1 aSvensson, Per, O1 aSzymczak, Silke1 aTai, E-Shyong1 aTajuddin, Salman, M1 aTan, Nicholas, Y Q1 aTaylor, Kent, D1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomsen, Hauke1 aThorleifsson, Gudmar1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aTzoulaki, Ioanna1 aUitterlinden, André, G1 aVaccargiu, Simona1 avan Dam, Rob, M1 aHarst, Pim1 aDuijn, Cornelia, M1 aEdward, Digna, R Velez1 aVerweij, Niek1 aVogelezang, Suzanne1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWallentin, Lars1 aWang, Ya, Xing1 aWang, Chaolong1 aWaterworth, Dawn, M1 aBin Wei, Wen1 aWhite, Harvey1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWojczynski, Mary, K1 aWong, Charlene1 aWong, Tien-Yin1 aXu, Liang1 aYang, Qiong1 aYasuda, Masayuki1 aYerges-Armstrong, Laura, M1 aZhang, Weihua1 aZonderman, Alan, B1 aRotter, Jerome, I1 aBochud, Murielle1 aPsaty, Bruce, M1 aVitart, Veronique1 aWilson, James, G1 aDehghan, Abbas1 aParsa, Afshin1 aChasman, Daniel, I1 aHo, Kevin1 aMorris, Andrew, P1 aDevuyst, Olivier1 aAkilesh, Shreeram1 aPendergrass, Sarah, A1 aSim, Xueling1 aBöger, Carsten, A1 aOkada, Yukinori1 aEdwards, Todd, L1 aSnieder, Harold1 aStefansson, Kari1 aHung, Adriana, M1 aHeid, Iris, M1 aScholz, Markus1 aTeumer, Alexander1 aKöttgen, Anna1 aPattaro, Cristian1 aLifeLines Cohort Study1 aV. A. Million Veteran Program uhttps://chs-nhlbi.org/node/810904831nas a2201009 4500008004100000022001400041245014800055210006900203260001600272300001400288490000700302520194700309653000902256653002802265653003002293653001902323653002502342653004102367653002902408653002502437653002002462653003502482653001102517653001102528653001702539653003402556653001102590653001702601653000902618653001602627653002402643653001802667653001802685653002102703653002902724653003602753653002002789653001702809653002602826653001802852653001702870100002502887700002402912700002002936700002002956700001902976700002202995700002103017700001803038700001903056700002003075700001603095700001803111700001503129700002503144700002103169700001903190700001803209700002103227700002203248700002103270700002203291700001303313700001603326700001703342700001603359700002603375700001803401700001903419700002003438700001403458700001903472700002403491700002903515700002003544700001903564700002103583700002503604700001603629700002703645700002103672700002103693700002803714700002103742700002203763856003603785 2019 eng d a1941-722500aGenome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.0 aGenomeWide Association Study of Apparent TreatmentResistant Hype c2019 Nov 15 a1146-11530 v323 aBACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.
METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.
RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.
CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
10aAged10aAntihypertensive Agents10aBlack or African American10aBlood Pressure10aCase-Control Studies10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methyltransferase 3A10aDNA-Binding Proteins10aDrug Resistance10aDystrophin-Associated Proteins10aEurope10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMiddle Aged10aMyosin Heavy Chains10aMyosin Type V10aNeuropeptides10aPharmacogenetics10aPharmacogenomic Variants10aPolymorphism, Single Nucleotide10aRisk Assessment10aRisk Factors10aTranscription Factors10aUnited States10aWhite People1 aIrvin, Marguerite, R1 aSitlani, Colleen, M1 aFloyd, James, S1 aPsaty, Bruce, M1 aBis, Joshua, C1 aWiggins, Kerri, L1 aWhitsel, Eric, A1 aStürmer, Til1 aStewart, James1 aRaffield, Laura1 aSun, Fangui1 aLiu, Ching-Ti1 aXu, Hanfei1 aCupples, Adrienne, L1 aTanner, Rikki, M1 aRossing, Peter1 aSmith, Albert1 aZilhão, Nuno, R1 aLauner, Lenore, J1 aNoordam, Raymond1 aRotter, Jerome, I1 aYao, Jie1 aLi, Xiaohui1 aGuo, Xiuqing1 aLimdi, Nita1 aSundaresan, Aishwarya1 aLange, Leslie1 aCorrea, Adolfo1 aStott, David, J1 aFord, Ian1 aJukema, Wouter1 aGudnason, Vilmundur1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aPalmas, Walter1 aWarren, Helen, R1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aO'donnell, Christopher1 aHung, Adriana, M1 aEdwards, Todd, L1 aAhluwalia, Tarunveer, S1 aArnett, Donna, K1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/937202874nas a2200505 4500008004100000022001400041245013200055210006900187260001200256300001400268490000800282520125100290653004401541653002501585653002301610653003801633653003401671653001101705653005101716653004701767653002201814653002901836653003601865653003101901653001701932653003001949653001901979100002001998700001702018700002502035700001802060700001902078700002302097700001902120700002302139700002002162700002002182700002102202700002702223700002002250700001902270700002102289700002202310856003602332 2019 eng d a1532-653500aGenomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink.0 aGenomewide Association Study of StatinInduced Myopathy in Patien c2019 12 a1353-13610 v1063 aStatins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.
10aAdverse Drug Reaction Reporting Systems10aCase-Control Studies10aDatabases, Factual10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aLiver-Specific Organic Anion Transporter 110aMuscular Diseases10aPharmacogenomic Variants10aPolymorphism, Single Nucleotide10aReproducibility of Results10aRisk Factors10aSeverity of Illness Index10aUnited Kingdom1 aCarr, Daniel, F1 aFrancis, Ben1 aJorgensen, Andrea, L1 aZhang, Eunice1 aChinoy, Hector1 aHeckbert, Susan, R1 aBis, Joshua, C1 aBrody, Jennifer, A1 aFloyd, James, S1 aPsaty, Bruce, M1 aMolokhia, Mariam1 aLapeyre-Mestre, Maryse1 aConforti, Anita1 aAlfirevic, Ana1 avan Staa, Tjeerd1 aPirmohamed, Munir uhttps://chs-nhlbi.org/node/850810097nas a2203265 4500008004100000022001400041245010400055210006900159260001500228300000800243490000700251520106700258653001501325653001001340653003901350653000901389653002201398653003701420653001101457653002901468653001601497653002101513653002101534653004001555653001301595653001101608653001701619653003401636653001301670653002301683653001101706653002901717653002101746653001101767653000901778653002201787653003601809653001601845653002001861653002601881653002601907653001801933653001601951100002801967700002001995700002102015700001802036700002102054700002302075700002402098700002302122700001902145700001902164700002002183700002202203700002602225700002302251700001702274700002002291700002302311700002102334700001702355700002302372700002102395700001702416700001402433700002002447700002402467700002102491700002202512700002102534700002502555700002802580700001702608700002002625700002102645700001702666700002102683700002402704700001702728700001902745700002202764700002002786700001302806700001902819700002502838700001502863700002202878700002102900700001402921700001802935700002102953700001902974700001902993700002103012700002203033700002803055700001903083700002103102700001903123700002303142700001703165700002603182700002303208700002703231700002003258700001803278700001803296700001703314700001603331700001903347700001603366700002103382700002103403700001803424700001603442700002203458700002203480700002403502700001803526700002303544700002103567700002203588700001903610700002003629700002203649700002103671700002503692700002303717700002103740700002303761700002103784700001703805700002203822700001403844700002003858700002003878700002003898700002003918700001903938700001903957700002203976700002103998700002804019700002104047700002204068700002304090700002404113700002204137700001904159700002404178700001904202700002004221700001704241700001804258700002104276700002204297700002104319700002104340700002104361700002204382700002204404700001904426700002404445700002704469700002204496700002004518700002804538700002004566700002604586700002704612700001704639700002304656700002004679700002404699700001904723700002304742700001904765700002304784700002104807700001604828700002604844700001904870700001604889700002504905700002104930700002304951700001604974700002304990700002005013700001705033700001905050700002305069700002405092700001405116700002005130700002105150700002305171700002805194700002405222700002205246700002005268700002605288700002105314700002005335700002105355700001305376700001705389700001905406700001405425700002305439700002105462700002105483700002205504700001805526700001805544700001805562700001605580700002305596700002205619700002105641700002205662700001905684700001905703700001905722700002205741700002705763700002905790700002705819700002205846700001705868700001505885700003505900700002405935700002605959700001605985700002506001700001906026700001706045700001506062700001806077700002206095700002006117700002406137700002206161700002306183700002106206700001706227700001906244700002606263700002006289700001906309700002006328700001806348700002406366700001806390700002906408700002506437700001906462700002306481700002206504700002706526700002106553700002006574700001806594700002406612700002006636700002506656700002306681700002406704700002006728700002006748710002706768856003606795 2019 eng d a2041-172300aMulti-ancestry study of blood lipid levels identifies four loci interacting with physical activity.0 aMultiancestry study of blood lipid levels identifies four loci i c2019 01 22 a3760 v103 aMany genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aBrazil10aCalcium-Binding Proteins10aCholesterol10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aExercise10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHispanic Americans10aHumans10aLIM-Homeodomain Proteins10aLipid Metabolism10aLipids10aMale10aMembrane Proteins10aMicrotubule-Associated Proteins10aMiddle Aged10aMuscle Proteins10aNerve Tissue Proteins10aTranscription Factors10aTriglycerides10aYoung Adult1 aKilpeläinen, Tuomas, O1 aBentley, Amy, R1 aNoordam, Raymond1 aSung, Yun, Ju1 aSchwander, Karen1 aWinkler, Thomas, W1 aJakupović, Hermina1 aChasman, Daniel, I1 aManning, Alisa1 aNtalla, Ioanna1 aAschard, Hugues1 aBrown, Michael, R1 aFuentes, Lisa, de Las1 aFranceschini, Nora1 aGuo, Xiuqing1 aVojinovic, Dina1 aAslibekyan, Stella1 aFeitosa, Mary, F1 aKho, Minjung1 aMusani, Solomon, K1 aRichard, Melissa1 aWang, Heming1 aWang, Zhe1 aBartz, Traci, M1 aBielak, Lawrence, F1 aCampbell, Archie1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLi, Changwei1 aLohman, Kurt, K1 aMarten, Jonathan1 aSim, Xueling1 aSmith, Albert, V1 aTajuddin, Salman, M1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGraff, Mariaelisa1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aZhao, Jing Hua1 aKraja, Aldi, T1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRobino, Antonietta1 aRueedi, Rico1 aStringham, Heather, M1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVerweij, Niek1 aWare, Erin, B1 aWen, Wanqing1 aLi, Xiaoyin1 aYanek, Lisa, R1 aAmin, Najaf1 aArnett, Donna, K1 aBoerwinkle, Eric1 aBrumat, Marco1 aCade, Brian1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aConcas, Maria, Pina1 aConnell, John1 ade Mutsert, Renée1 ade Silva, Janaka1 ade Vries, Paul, S1 aDemirkan, Ayse1 aDing, Jingzhong1 aEaton, Charles, B1 aFaul, Jessica, D1 aFriedlander, Yechiel1 aGabriel, Kelley, P1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGu, Chi, Charles1 aGu, Dongfeng1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHunt, Steven, C1 aIkram, Arfan, M1 aJonas, Jost, B1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLeander, Karin1 aLemaitre, Rozenn, N1 aLewis, Cora, E1 aLiang, Jingjing1 aLiu, Jianjun1 aMägi, Reedik1 aManichaikul, Ani1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMurray, Alison, D1 aNalls, Mike, A1 aNang, Ei-Ei, Khaing1 aNelson, Christopher, P1 aNona, Sotoodehnia1 aNorris, Jill, M1 aNwuba, Chiamaka, Vivian1 aO'Connell, Jeff1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPorteous, David, J1 aPoveda, Alaitz1 aRaitakari, Olli, T1 aRich, Stephen, S1 aRisch, Neil1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchreiner, Pamela, J1 aScott, Robert, A1 aSidney, Stephen, S1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aSofer, Tamar1 aStarr, John, M1 aSternfeld, Barbara1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTsai, Michael, Y1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 avan der Ende, Yldau1 avan Heemst, Diana1 aVoortman, Trudy1 aWaldenberger, Melanie1 aWennberg, Patrik1 aWilson, Gregory1 aXiang, Yong-Bing1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aKato, Norihiro1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aShu, Xiao-Ou1 aHarst, Pim1 avan Vliet-Ostaptchouk, Jana, V1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWang, Ya, X1 aWareham, Nicholas, J1 aWeir, David, R1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aEvans, Michele, K1 aFranks, Paul, W1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aLiu, Yongmei1 aNorth, Kari, E1 aPereira, Alexandre, C1 aRidker, Paul, M1 aTai, Shyong, E1 avan Dam, Rob, M1 aFox, Ervin, R1 aKardia, Sharon, L R1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aProvince, Michael, A1 aRedline, Susan1 aDuijn, Cornelia, M1 aRotter, Jerome, I1 aKooperberg, Charles, B1 aGauderman, James1 aPsaty, Bruce, M1 aRice, Kenneth1 aMunroe, Patricia, B1 aFornage, Myriam1 aCupples, Adrienne, L1 aRotimi, Charles, N1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aLoos, Ruth, J F1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/797603191nas a2200373 4500008004100000022001400041245011600055210006900171260001200240300001300252490000700265520212000272653001002392653001602402653001102418653003402429653003102463653001102494653000902505653003702514653003302551653001602584653001402600653001602614100002202630700001802652700002002670700001802690700001802708700002102726700002202747700001202769856003602781 2019 eng d a1549-167600aNo causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study.0 aNo causal effects of serum urate levels on the risk of chronic k c2019 01 ae10027250 v163 aBACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).
METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.
CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.
10aAdult10aAge Factors10aFemale10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aMale10aMendelian Randomization Analysis10aRenal Insufficiency, Chronic10aSex Factors10aUric Acid10aYoung Adult1 aJordan, Daniel, M1 aChoi, Hyon, K1 aVerbanck, Marie1 aTopless, Ruth1 aWon, Hong-Hee1 aNadkarni, Girish1 aMerriman, Tony, R1 aDo, Ron uhttps://chs-nhlbi.org/node/804603270nas a2200601 4500008004100000022001400041245015200055210006900207260001500276300000900291490000700300520149000307653003001797653004301827653000901870653002201879653002201901653001201923653001901935653001101954653003401965653001301999653001102012653000902023653002602032653001202058653002802070653002602098653003602124653002702160100002202187700002002209700002502229700002502254700001902279700001602298700002402314700002002338700001902358700001902377700002002396700002002416700002202436700002202458700002302480700002202503700002202525700002202547700002402569700001802593700002102611856003602632 2020 eng d a1554-657800aAlzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene.0 aAlzheimer Disease PathologyAssociated Polymorphism in a Complex c2020 01 01 a3-210 v793 aWe found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.
10aAdaptor Protein Complex 210aAdaptor Protein Complex alpha Subunits10aAged10aAged, 80 and over10aAlzheimer Disease10aAutopsy10aCohort Studies10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMinisatellite Repeats10aMucin-610aNeurofibrillary Tangles10aPolymorphism, Genetic10aPolymorphism, Single Nucleotide10aTDP-43 Proteinopathies1 aKatsumata, Yuriko1 aFardo, David, W1 aBachstetter, Adam, D1 aArtiushin, Sergey, C1 aWang, Wang-Xia1 aWei, Angela1 aBrzezinski, Lena, J1 aNelson, Bela, G1 aHuang, Qingwei1 aAbner, Erin, L1 aAnderson, Sonya1 aPatel, Indumati1 aShaw, Benjamin, C1 aPrice, Douglas, A1 aNiedowicz, Dana, M1 aWilcock, Donna, W1 aJicha, Gregory, A1 aNeltner, Janna, H1 aVan Eldik, Linda, J1 aEstus, Steven1 aNelson, Peter, T uhttps://chs-nhlbi.org/node/839604581nas a2200541 4500008004100000022001400041245005500055210005400110260001500164300001200179490000800191520308300199653001003282653001103292653003303303653003803336653003403374653001103408653001603419653001103435653002003446653000903466653001603475653003603491100002403527700002303551700002403574700002503598700002603623700001503649700002503664700002203689700001903711700002303730700002203753700002103775700001603796700001903812700002303831700002203854700002003876700002003896700002503916700001903941700002003960700002303980856003604003 2020 eng d a2168-617300aAssociation of Genetic Variation With Keratoconus.0 aAssociation of Genetic Variation With Keratoconus c2020 02 01 a174-1810 v1383 aImportance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus.
Objective: To identify genetic susceptibility regions for keratoconus in the human genome.
Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019.
Main Outcomes and Measures: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.
Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8).
Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.
10aAdult10aFemale10aFuchs' Endothelial Dystrophy10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aKeratoconus10aLipase10aLogistic Models10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aMcComish, Bennet, J1 aSahebjada, Srujana1 aBykhovskaya, Yelena1 aWilloughby, Colin, E1 aRichardson, Andrea, J1 aTenen, Abi1 aCharlesworth, Jac, C1 aMacgregor, Stuart1 aMitchell, Paul1 aLucas, Sionne, E M1 aMills, Richard, A1 aMackey, David, A1 aLi, Xiaohui1 aWang, Jie, Jin1 aJensen, Richard, A1 aRotter, Jerome, I1 aTaylor, Kent, D1 aHewitt, Alex, W1 aRabinowitz, Yaron, S1 aBaird, Paul, N1 aCraig, Jamie, E1 aBurdon, Kathryn, P uhttps://chs-nhlbi.org/node/863104660nas a2200793 4500008004100000022001400041245013400055210006900189260001200258300001200270490000600282520241900288653001002707653002502717653001902742653001102761653002902772653003402801653001102835653000902846653001602855653001402871653004302885653001702928653001902945100001802964700002902982700001703011700002003028700001903048700002003067700002003087700002603107700002003133700001903153700001903172700002303191700001903214700002303233700002403256700001603280700002103296700002103317700002103338700001603359700001803375700001503393700002203408700001703430700002003447700002003467700002103487700002103508700002203529700002003551700001703571700001503588700001903603700001703622700001703639700002003656700002403676700002103700700002103721700002003742710004303762710002503805856003603830 2020 eng d a2213-261900aChronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.0 aChronic obstructive pulmonary disease and related phenotypes pol c2020 07 a696-7080 v83 aBACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.
METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.
FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.
INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.
FUNDING: US National Institutes of Health, Wellcome Trust.
10aAdult10aCase-Control Studies10aCohort Studies10aFemale10aForced Expiratory Volume10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPhenotype10aPulmonary Disease, Chronic Obstructive10aRisk Factors10aVital Capacity1 aMoll, Matthew1 aSakornsakolpat, Phuwanat1 aShrine, Nick1 aHobbs, Brian, D1 aDeMeo, Dawn, L1 aJohn, Catherine1 aGuyatt, Anna, L1 aMcGeachie, Michael, J1 aGharib, Sina, A1 aObeidat, Ma'en1 aLahousse, Lies1 aWijnant, Sara, R A1 aBrusselle, Guy1 aMeyers, Deborah, A1 aBleecker, Eugene, R1 aLi, Xingnan1 aTal-Singer, Ruth1 aManichaikul, Ani1 aRich, Stephen, S1 aWon, Sungho1 aKim, Woo, Jin1 aDo, Ah, Ra1 aWashko, George, R1 aBarr, Graham1 aPsaty, Bruce, M1 aBartz, Traci, M1 aHansel, Nadia, N1 aBarnes, Kathleen1 aHokanson, John, E1 aCrapo, James, D1 aLynch, David1 aBakke, Per1 aGulsvik, Amund1 aHall, Ian, P1 aWain, Louise1 aWeiss, Scott, T1 aSilverman, Edwin, K1 aDudbridge, Frank1 aTobin, Martin, D1 aCho, Michael, H1 aInternational COPD Genetics Consortium1 aSpiroMeta Consortium uhttps://chs-nhlbi.org/node/840004618nas a2200805 4500008004100000022001400041245019400055210006900249260000900318300001300327490000700340520222500347653001002572653002802582653002802610653001102638653004002649653001702689653003402706653001102740653002602751653003602777653002402813100001602837700001602853700002202869700001902891700002202910700002102932700001902953700001802972700002302990700002603013700001703039700002003056700002103076700002103097700002103118700002303139700002203162700002103184700001703205700002203222700001903244700002003263700001903283700002203302700002603324700002103350700002103371700002003392700002603412700002203438700002203460700002003482700002803502700001703530700001903547700001303566700002303579700001803602700002403620700002303644700001603667700002003683700001903703700003003722700002403752856003603776 2020 eng d a1932-620300aGenetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.0 aGenetic loci associated with prevalent and incident myocardial i c2020 ae02300350 v153 aBACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.
METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.
CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
10aAging10aCoronary Artery Disease10aCross-Sectional Studies10aEurope10aEuropean Continental Ancestry Group10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies1 aHahn, Julie1 aFu, Yi-Ping1 aBrown, Michael, R1 aBis, Joshua, C1 ade Vries, Paul, S1 aFeitosa, Mary, F1 aYanek, Lisa, R1 aWeiss, Stefan1 aGiulianini, Franco1 aSmith, Albert, Vernon1 aGuo, Xiuqing1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aChen, Yii-Der Ida1 aFranco, Oscar, H1 aGrove, Megan1 aHarris, Tamara, B1 aHofman, Albert1 aHwang, Shih-Jen1 aKral, Brian, G1 aLauner, Lenore, J1 aMarkus, Marcello, R P1 aRice, Kenneth, M1 aRich, Stephen, S1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aUitterlinden, André, G1 aVölker, Uwe1 aVölzke, Henry1 aYao, Jie1 aChasman, Daniel, I1 aDörr, Marcus1 aGudnason, Vilmundur1 aMathias, Rasika, A1 aPost, Wendy1 aPsaty, Bruce, M1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aMorrison, Alanna, C uhttps://chs-nhlbi.org/node/862504776nas a2201261 4500008004100000022001400041245010300055210006900158260001500227300000900242490000700251520104900258653001001307653002201317653000901339653002201348653005001370653002901420653002401449653001101473653002201484653001701506653003801523653003401561653001101595653005001606653000901656653000901665653001601674653003601690653004101726653004301767653004001810653004601850653002801896100001701924700001601941700001801957700001801975700001501993700001502008700001702023700001902040700001702059700003002076700002902106700002202135700002302157700001302180700002102193700001902214700001902233700001502252700002002267700001902287700002302306700002002329700002502349700002002374700002002394700002402414700002002438700002702458700002102485700002002506700001702526700001902543700002002562700001702582700001702599700002202616700002302638700002002661700002502681700002802706700002202734700002402756700001702780700002602797700002002823700002302843700003102866700002502897700001902922700002002941700002102961700002402982700001903006700002003025700002103045700002403066700002503090700002403115700002203139700002003161700002103181700002503202700002303227700002603250700002503276700002403301700001703325700002003342700002103362710006503383710003003448856003603478 2020 eng d a2041-172300aWhole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.0 aWhole genome sequence analysis of pulmonary function and COPD in c2020 10 14 a51820 v113 aChronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
10aAdult10aAfrican Americans10aAged10aAged, 80 and over10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aCalcium-Binding Proteins10aFeasibility Studies10aFemale10aFollow-Up Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aIntracellular Signaling Peptides and Proteins10aLung10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Inhibitors of Activated STAT10aPulmonary Disease, Chronic Obstructive10aRespiratory Physiological Phenomena10aSmall Ubiquitin-Related Modifier Proteins10aWhole Genome Sequencing1 aZhao, Xutong1 aQiao, Dandi1 aYang, Chaojie1 aKasela, Silva1 aKim, Wonji1 aMa, Yanlin1 aShrine, Nick1 aBatini, Chiara1 aSofer, Tamar1 aTaliun, Sarah, A Gagliano1 aSakornsakolpat, Phuwanat1 aBalte, Pallavi, P1 aProkopenko, Dmitry1 aYu, Bing1 aLange, Leslie, A1 aDupuis, Josée1 aCade, Brian, E1 aLee, Jiwon1 aGharib, Sina, A1 aDaya, Michelle1 aLaurie, Cecelia, A1 aRuczinski, Ingo1 aCupples, Adrienne, L1 aLoehr, Laura, R1 aBartz, Traci, M1 aMorrison, Alanna, C1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aWilson, James, G1 aTaylor, Kent, D1 aDurda, Peter1 aJohnson, Craig1 aCornell, Elaine1 aGuo, Xiuqing1 aLiu, Yongmei1 aTracy, Russell, P1 aArdlie, Kristin, G1 aAguet, Francois1 aVanDenBerg, David, J1 aPapanicolaou, George, J1 aRotter, Jerome, I1 aBarnes, Kathleen, C1 aJain, Deepti1 aNickerson, Deborah, A1 aMuzny, Donna, M1 aMetcalf, Ginger, A1 aDoddapaneni, Harshavardhan1 aDugan-Perez, Shannon1 aGupta, Namrata1 aGabriel, Stacey1 aRich, Stephen, S1 aO'Connor, George, T1 aRedline, Susan1 aReed, Robert, M1 aLaurie, Cathy, C1 aDaviglus, Martha, L1 aPreudhomme, Liana, K1 aBurkart, Kristin, M1 aKaplan, Robert, C1 aWain, Louise, V1 aTobin, Martin, D1 aLondon, Stephanie, J1 aLappalainen, Tuuli1 aOelsner, Elizabeth, C1 aAbecasis, Goncalo, R1 aSilverman, Edwin, K1 aBarr, Graham1 aCho, Michael, H1 aManichaikul, Ani1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Lung Working Group uhttps://chs-nhlbi.org/node/863904156nas a2200889 4500008004100000022001400041245009300055210006900148260001500217300000800232490000700240520170200247653001001949653001001959653001401969653003401983653001602017653001102033653003602044653003002080100001802110700001702128700002102145700001802166700001902184700001702203700002202220700001602242700002302258700002002281700001602301700002202317700001802339700002102357700002102378700001802399700002402417700002502441700002602466700002002492700001702512700001702529700002402546700001902570700001802589700002002607700002502627700001802652700001902670700001902689700002302708700001602731700002602747700002002773700002202793700002002815700002202835700002002857700002302877700002502900700001802925700002302943700002002966700001602986700001403002700002403016700002203040700002803062700002003090700002003110700001703130700002303147700002003170700002203190700001803212856003603230 2021 eng d a2158-318800aAssociation of low-frequency and rare coding variants with information processing speed.0 aAssociation of lowfrequency and rare coding variants with inform c2021 12 04 a6130 v113 aMeasures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
10aAdult10aAging10aCognition10aGenome-Wide Association Study10aGeroscience10aHumans10aPolymorphism, Single Nucleotide10aUbiquitin-Protein Ligases1 aBressler, Jan1 aDavies, Gail1 aSmith, Albert, V1 aSaba, Yasaman1 aBis, Joshua, C1 aJian, Xueqiu1 aHayward, Caroline1 aYanek, Lisa1 aSmith, Jennifer, A1 aMirza, Saira, S1 aWang, Ruiqi1 aAdams, Hieab, H H1 aBecker, Diane1 aBoerwinkle, Eric1 aCampbell, Archie1 aCox, Simon, R1 aEiriksdottir, Gudny1 aFawns-Ritchie, Chloe1 aGottesman, Rebecca, F1 aGrove, Megan, L1 aGuo, Xiuqing1 aHofer, Edith1 aKardia, Sharon, L R1 aKnol, Maria, J1 aKoini, Marisa1 aLopez, Oscar, L1 aMarioni, Riccardo, E1 aNyquist, Paul1 aPattie, Alison1 aPolasek, Ozren1 aPorteous, David, J1 aRudan, Igor1 aSatizabal, Claudia, L1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSidney, Stephen1 aSimino, Jeannette1 aSmith, Blair, H1 aTurner, Stephen, T1 avan der Lee, Sven, J1 aWare, Erin, B1 aWhitmer, Rachel, A1 aYaffe, Kristine1 aYang, Qiong1 aZhao, Wei1 aGudnason, Vilmundur1 aLauner, Lenore, J1 aFitzpatrick, Annette, L1 aPsaty, Bruce, M1 aFornage, Myriam1 aIkram, Arfan1 aDuijn, Cornelia, M1 aSeshadri, Sudha1 aMosley, Thomas, H1 aDeary, Ian, J uhttps://chs-nhlbi.org/node/898805600nas a2201549 4500008004100000022001400041245011600055210006900171260001500240300000900255490000700264520122500271653003501496653001901531653001601550653002001566653001401586653001101600653003801611653003401649653004501683653000901728653001101737653000901748653001401757100001801771700002201789700002901811700002101840700001901861700001601880700001201896700001901908700002101927700003301948700001901981700003202000700002602032700002202058700001902080700001902099700002302118700002102141700002102162700001802183700002702201700002202228700001802250700001802268700001802286700001902304700001802323700002502341700002102366700001902387700002202406700002002428700002102448700001202469700001502481700002102496700002102517700001902538700002202557700002202579700002002601700002102621700001902642700002002661700002202681700001902703700001602722700002002738700002002758700002402778700001802802700002202820700002102842700002202863700002402885700002102909700002702930700002202957700001502979700001302994700002703007700002203034700001503056700002503071700002003096700002503116700002403141700001703165700002503182700002003207700002103227700002003248700002103268700002003289700002303309700002203332700002003354700002003374700001903394700002003413700002303433700002203456700002303478700002303501700002203524700002403546700002603570700003503596700001903631700001703650700002403667700003003691700001403721700001703735700001503752700002003767700002603787700001703813700002203830700002203852700002103874700002203895700001903917710003503936710004303971856003604014 2021 eng d a2041-172300aEpigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.0 aEpigenomewide association study of serum urate reveals insights c2021 12 09 a71730 v123 aElevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
10aAmino Acid Transport System y+10aCohort Studies10aCpG Islands10aDNA Methylation10aEpigenome10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlucose Transport Proteins, Facilitative10aGout10aHumans10aMale10aUric Acid1 aTin, Adrienne1 aSchlosser, Pascal1 aMatias-Garcia, Pamela, R1 aThio, Chris, H L1 aJoehanes, Roby1 aLiu, Hongbo1 aYu, Zhi1 aWeihs, Antoine1 aHoppmann, Anselm1 aGrundner-Culemann, Franziska1 aMin, Josine, L1 aKuhns, Victoria, L Halperin1 aAdeyemo, Adebowale, A1 aAgyemang, Charles1 aArnlöv, Johan1 aAziz, Nasir, A1 aBaccarelli, Andrea1 aBochud, Murielle1 aBrenner, Hermann1 aBressler, Jan1 aBreteler, Monique, M B1 aCarmeli, Cristian1 aChaker, Layal1 aCoresh, Josef1 aCorre, Tanguy1 aCorrea, Adolfo1 aCox, Simon, R1 aDelgado, Graciela, E1 aEckardt, Kai-Uwe1 aEkici, Arif, B1 aEndlich, Karlhans1 aFloyd, James, S1 aFraszczyk, Eliza1 aGao, Xu1 aGào, Xīn1 aGelber, Allan, C1 aGhanbari, Mohsen1 aGhasemi, Sahar1 aGieger, Christian1 aGreenland, Philip1 aGrove, Megan, L1 aHarris, Sarah, E1 aHemani, Gibran1 aHenneman, Peter1 aHerder, Christian1 aHorvath, Steve1 aHou, Lifang1 aHurme, Mikko, A1 aHwang, Shih-Jen1 aKardia, Sharon, L R1 aKasela, Silva1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKronenberg, Florian1 aKuhnel, Brigitte1 aLadd-Acosta, Christine1 aLehtimäki, Terho1 aLind, Lars1 aLiu, Dan1 aLloyd-Jones, Donald, M1 aLorkowski, Stefan1 aLu, Ake, T1 aMarioni, Riccardo, E1 aMärz, Winfried1 aMcCartney, Daniel, L1 aMeeks, Karlijn, A C1 aMilani, Lili1 aMishra, Pashupati, P1 aNauck, Matthias1 aNowak, Christoph1 aPeters, Annette1 aProkisch, Holger1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRatliff, Scott, M1 aReiner, Alex, P1 aSchöttker, Ben1 aSchwartz, Joel1 aSedaghat, Sanaz1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStocker, Hannah, R1 aStringhini, Silvia1 aSundström, Johan1 aSwenson, Brenton, R1 avan Meurs, Joyce, B J1 avan Vliet-Ostaptchouk, Jana, V1 aVenema, Andrea1 aVölker, Uwe1 aWinkelmann, Juliane1 aWolffenbuttel, Bruce, H R1 aZhao, Wei1 aZheng, Yinan1 aLoh, Marie1 aSnieder, Harold1 aWaldenberger, Melanie1 aLevy, Daniel1 aAkilesh, Shreeram1 aWoodward, Owen, M1 aSusztak, Katalin1 aTeumer, Alexander1 aKöttgen, Anna1 aEstonian Biobank Research Team1 aGenetics of DNA Methylation Consortium uhttps://chs-nhlbi.org/node/900602490nas a2200481 4500008004100000022001400041245010000055210006900155260001500224300000900239490000700248520108200255653001501337653001401352653002401366653003701390653002201427653001701449653003801466653001801504653003401522653001101556653002701567653001801594653002001612653003601632653003101668653002801699100001501727700001501742700001501757700001801772700001601790700002401806700001301830700002401843700001401867700002401881700002001905700002201925700002501947856003601972 2021 eng d a2041-172300aIdentification of putative causal loci in whole-genome sequencing data via knockoff statistics.0 aIdentification of putative causal loci in wholegenome sequencing c2021 05 25 a31520 v123 aThe analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.
10aAlgorithms10aCausality10aComputer Simulation10aData Interpretation, Statistical10aDatasets as Topic10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMarkov Chains10aModels, Genetic10aPolymorphism, Single Nucleotide10aReproducibility of Results10aWhole Genome Sequencing1 aHe, Zihuai1 aLiu, Linxi1 aWang, Chen1 aLe Guen, Yann1 aLee, Justin1 aGogarten, Stephanie1 aLu, Fred1 aMontgomery, Stephen1 aTang, Hua1 aSilverman, Edwin, K1 aCho, Michael, H1 aGreicius, Michael1 aIonita-Laza, Iuliana uhttps://chs-nhlbi.org/node/877802976nas a2200265 4500008004100000022001400041245013700055210006900192260001200261300001300273490000700286520215200293653002202445653001602467653003402483653001102517653001402528653003602542653002802578100001702606700001502623700001702638700001902655856003602674 2021 eng d a1553-740400aRare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.0 aRare variants in the endocytic pathway are associated with Alzhe c2021 09 ae10097720 v173 aLate-onset Alzheimer's disease (LOAD) is the most common type of dementia causing irreversible brain damage to the elderly and presents a major public health challenge. Clinical research and genome-wide association studies have suggested a potential contribution of the endocytic pathway to AD, with an emphasis on common loci. However, the contribution of rare variants in this pathway to AD has not been thoroughly investigated. In this study, we focused on the effect of rare variants on AD by first applying a rare-variant gene-set burden analysis using genes in the endocytic pathway on over 3,000 individuals with European ancestry from three large whole-genome sequencing (WGS) studies. We identified significant associations of rare-variant burden within the endocytic pathway with AD, which were successfully replicated in independent datasets. We further demonstrated that this endocytic rare-variant enrichment is associated with neurofibrillary tangles (NFTs) and age-related phenotypes, increasing the risk of obtaining severer brain damage, earlier age-at-onset, and earlier age-of-death. Next, by aggregating rare variants within each gene, we sought to identify single endocytic genes associated with AD and NFTs. Careful examination using NFTs revealed one significantly associated gene, ANKRD13D. To identify functional associations, we integrated bulk RNA-Seq data from over 600 brain tissues and found two endocytic expression genes (eGenes), HLA-A and SLC26A7, that displayed significant influences on their gene expressions. Differential expressions between AD patients and controls of these three identified genes were further examined by incorporating scRNA-Seq data from 48 post-mortem brain samples and demonstrated distinct expression patterns across cell types. Taken together, our results demonstrated strong rare-variant effect in the endocytic pathway on AD risk and progression and functional effect of gene expression alteration in both bulk and single-cell resolution, which may bring more insight and serve as valuable resources for future AD genetic studies, clinical research, and therapeutic targeting.
10aAlzheimer Disease10aEndocytosis10aGenome-Wide Association Study10aHumans10aPhenotype10aPolymorphism, Single Nucleotide10aWhole Genome Sequencing1 aZhan, Lingyu1 aLi, Jiajin1 aJew, Brandon1 aSul, Jae, Hoon uhttps://chs-nhlbi.org/node/891805743nas a2201309 4500008004100000022001400041245011800055210006900173260001500242300001200257490000800269520205100277653001002328653000902338653003202347653002202379653001702401653001102418653001702429653002202446653003402468653001702502653001102519653000902530653001602539653005302555653001402608653002002622653003102642653001802673100001202691700002302703700002302726700001702749700001702766700001802783700001502801700003602816700002302852700002002875700001902895700002002914700001302934700001702947700001602964700002002980700002203000700002003022700001403042700002303056700002303079700002503102700002003127700001903147700002803166700002303194700001403217700002003231700002303251700001503274700002003289700002103309700001803330700002003348700002203368700001803390700001803408700002103426700002003447700002203467700002003489700002703509700002703536700002303563700001903586700002103605700002103626700002103647700002503668700001603693700002603709700002403735700002003759700001903779700001903798700001903817700002003836700002003856700002403876700002303900700002903923700001403952700002003966700002003986700002504006700002204031700002104053700002504074700002304099700001804122700001204140700002304152700002204175700002104197700002104218700002304239700002104262700002404283700002504307710006504332856003604397 2021 eng d a1537-660500aWhole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.0 aWholegenome sequencing association analysis of quantitative red c2021 05 06 a874-8930 v1083 aWhole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
10aAdult10aAged10aChromosomes, Human, Pair 1610aDatasets as Topic10aErythrocytes10aFemale10aGene Editing10aGenetic Variation10aGenome-Wide Association Study10aHEK293 Cells10aHumans10aMale10aMiddle Aged10aNational Heart, Lung, and Blood Institute (U.S.)10aPhenotype10aQuality Control10aReproducibility of Results10aUnited States1 aHu, Yao1 aStilp, Adrienne, M1 aMcHugh, Caitlin, P1 aRao, Shuquan1 aJain, Deepti1 aZheng, Xiuwen1 aLane, John1 ade Bellefon, Sébastian, Méric1 aRaffield, Laura, M1 aChen, Ming-Huei1 aYanek, Lisa, R1 aWheeler, Marsha1 aYao, Yao1 aRen, Chunyan1 aBroome, Jai1 aMoon, Jee-Young1 ade Vries, Paul, S1 aHobbs, Brian, D1 aSun, Quan1 aSurendran, Praveen1 aBrody, Jennifer, A1 aBlackwell, Thomas, W1 aChoquet, Helene1 aRyan, Kathleen1 aDuggirala, Ravindranath1 aHeard-Costa, Nancy1 aWang, Zhe1 aChami, Nathalie1 aPreuss, Michael, H1 aMin, Nancy1 aEkunwe, Lynette1 aLange, Leslie, A1 aCushman, Mary1 aFaraday, Nauder1 aCurran, Joanne, E1 aAlmasy, Laura1 aKundu, Kousik1 aSmith, Albert, V1 aGabriel, Stacey1 aRotter, Jerome, I1 aFornage, Myriam1 aLloyd-Jones, Donald, M1 aVasan, Ramachandran, S1 aSmith, Nicholas, L1 aNorth, Kari, E1 aBoerwinkle, Eric1 aBecker, Lewis, C1 aLewis, Joshua, P1 aAbecasis, Goncalo, R1 aHou, Lifang1 aO'Connell, Jeffrey, R1 aMorrison, Alanna, C1 aBeaty, Terri, H1 aKaplan, Robert1 aCorrea, Adolfo1 aBlangero, John1 aJorgenson, Eric1 aPsaty, Bruce, M1 aKooperberg, Charles1 aWalton, Russell, T1 aKleinstiver, Benjamin, P1 aTang, Hua1 aLoos, Ruth, J F1 aSoranzo, Nicole1 aButterworth, Adam, S1 aNickerson, Debbie1 aRich, Stephen, S1 aMitchell, Braxton, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aLi, Yun1 aMathias, Rasika, A1 aLettre, Guillaume1 aPankratz, Nathan1 aLaurie, Cathy, C1 aLaurie, Cecelia, A1 aBauer, Daniel, E1 aConomos, Matthew, P1 aReiner, Alexander, P1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/877905763nas a2201477 4500008004100000022001400041245012500055210006900180260001500249300001400264490000800278520153200286653001101818653001501829653002301844653003801867653001801905653003401923653001101957653001501968653005301983653001402036653003602050653001402086653001302100653004302113653002802156653001902184653001802203653002802221100002402249700002302273700002102296700002302317700002902340700002502369700002302394700001602417700002002433700002002453700002402473700001502497700002202512700001902534700002002553700002002573700002302593700002502616700002002641700001802661700001702679700002102696700002802717700001502745700002002760700002302780700002002803700001902823700002102842700001402863700002302877700002202900700002002922700001402942700002002956700001902976700001502995700002503010700001803035700002403053700002003077700002103097700001903118700002103137700002503158700001903183700002003202700002003222700001903242700001503261700001903276700002003295700002003315700002403335700001603359700002303375700002003398700001903418700002403437700001803461700002303479700002203502700002103524700001703545700001203562700002703574700002003601700002103621700002303642700002503665700002403690700001503714700002603729700002303755700001903778700002603797700002203823700002103845700002003866700002003886700002103906700002003927700002203947700002403969700002303993700001404016700002204030700002504052700002704077700001404104700002304118700002504141700001804166710006504184856003604249 2021 eng d a1537-660500aWhole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.0 aWholegenome sequencing in diverse subjects identifies genetic co c2021 10 07 a1836-18510 v1083 aMany common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
10aAsthma10aBiomarkers10aDermatitis, Atopic10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLeukocytes10aNational Heart, Lung, and Blood Institute (U.S.)10aPhenotype10aPolymorphism, Single Nucleotide10aPrognosis10aProteome10aPulmonary Disease, Chronic Obstructive10aQuantitative Trait Loci10aUnited Kingdom10aUnited States10aWhole Genome Sequencing1 aMikhaylova, Anna, V1 aMcHugh, Caitlin, P1 aPolfus, Linda, M1 aRaffield, Laura, M1 aBoorgula, Meher, Preethi1 aBlackwell, Thomas, W1 aBrody, Jennifer, A1 aBroome, Jai1 aChami, Nathalie1 aChen, Ming-Huei1 aConomos, Matthew, P1 aCox, Corey1 aCurran, Joanne, E1 aDaya, Michelle1 aEkunwe, Lynette1 aGlahn, David, C1 aHeard-Costa, Nancy1 aHighland, Heather, M1 aHobbs, Brian, D1 aIlboudo, Yann1 aJain, Deepti1 aLange, Leslie, A1 aMiller-Fleming, Tyne, W1 aMin, Nancy1 aMoon, Jee-Young1 aPreuss, Michael, H1 aRosen, Jonathon1 aRyan, Kathleen1 aSmith, Albert, V1 aSun, Quan1 aSurendran, Praveen1 ade Vries, Paul, S1 aWalter, Klaudia1 aWang, Zhe1 aWheeler, Marsha1 aYanek, Lisa, R1 aZhong, Xue1 aAbecasis, Goncalo, R1 aAlmasy, Laura1 aBarnes, Kathleen, C1 aBeaty, Terri, H1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aButterworth, Adam, S1 aChavan, Sameer1 aCho, Michael, H1 aChoquet, Helene1 aCorrea, Adolfo1 aCox, Nancy1 aDeMeo, Dawn, L1 aFaraday, Nauder1 aFornage, Myriam1 aGerszten, Robert, E1 aHou, Lifang1 aJohnson, Andrew, D1 aJorgenson, Eric1 aKaplan, Robert1 aKooperberg, Charles1 aKundu, Kousik1 aLaurie, Cecelia, A1 aLettre, Guillaume1 aLewis, Joshua, P1 aLi, Bingshan1 aLi, Yun1 aLloyd-Jones, Donald, M1 aLoos, Ruth, J F1 aManichaikul, Ani1 aMeyers, Deborah, A1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aNgo, Debby1 aNickerson, Deborah, A1 aNongmaithem, Suraj1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOrtega, Victor, E1 aPankratz, Nathan1 aPerry, James, A1 aPsaty, Bruce, M1 aRich, Stephen, S1 aSoranzo, Nicole1 aRotter, Jerome, I1 aSilverman, Edwin, K1 aSmith, Nicholas, L1 aTang, Hua1 aTracy, Russell, P1 aThornton, Timothy, A1 aVasan, Ramachandran, S1 aZein, Joe1 aMathias, Rasika, A1 aReiner, Alexander, P1 aAuer, Paul, L1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/891403432nas a2200457 4500008004100000022001400041245018200055210006900237260001300306300001200319490000700331520203700338653000902375653001702384653004602401653003202447653001502479653002802494653001102522653003402533653001802567653001102585653002502596653000902621100001702630700002302647700002002670700001902690700002502709700001802734700002202752700001802774700001802792700001902810700002602829700002002855700002002875700002202895700002102917856003602938 2022 eng d a2047-998000aCirculating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study.0 aCirculating Soluble CD163 Associations With Cardiovascular Outco c2022 Nov ae0243740 v113 aBackground Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near (top result rs62165726, =3.3×10),19 variants near chromosome 17 gene (rs55714927, =1.5×10), and 18 variants near chromosome 11 gene . These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 =7.1×10) in the region, and 3 variants (rs115391969 =4.3×10) near the chromosome 16 gene Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.
10aAged10aAntigens, CD10aAntigens, Differentiation, Myelomonocytic10aAsialoglycoprotein Receptor10aBiomarkers10aCardiovascular Diseases10aFemale10aGenome-Wide Association Study10aHeart Failure10aHumans10aLongitudinal Studies10aMale1 aDurda, Peter1 aRaffield, Laura, M1 aLange, Ethan, M1 aOlson, Nels, C1 aJenny, Nancy, Swords1 aCushman, Mary1 aDeichgraeber, Pia1 aGrarup, Niels1 aJonsson, Anna1 aHansen, Torben1 aMychaleckyj, Josyf, C1 aPsaty, Bruce, M1 aReiner, Alex, P1 aTracy, Russell, P1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/924506322nas a2201285 4500008004100000022001400041245007900055210006900134260001600203300001400219490000800233520251800241653003802759653003402797653001302831653001102844653003602855653002802891653001502919653002702934100002102961700001802982700002303000700002003023700002203043700002303065700002003088700002003108700002403128700002603152700001803178700002503196700001503221700002303236700002203259700002403281700002203305700002903327700002303356700002003379700002403399700002403423700002003447700001803467700001903485700002003504700001903524700002203543700001403565700003003579700002003609700002303629700002303652700002203675700001703697700002603714700002003740700002203760700001203782700002503794700001403819700001403833700002403847700002403871700002103895700002203916700002303938700002403961700002203985700001804007700002204025700002004047700002004067700002304087700002504110700001804135700002104153700001904174700001804193700002604211700002004237700002304257700002504280700002104305700002504326700002204351700002004373700003004393700002704423700001704450700002104467700002004488700002004508700002604528700002104554700001904575700002104594700001704615700001804632700002404650700002404674700002904698700002504727700003204752700002304784700002304807700002304830710014704853856003605000 2022 eng d a1524-453900aCross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.0 aCrossAncestry Investigation of Venous Thromboembolism Genomic Pr c2022 Oct 18 a1225-12420 v1463 aBACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.
METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.
RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.
CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.
10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenomics10aHumans10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aThrombosis10aVenous Thromboembolism1 aThibord, Florian1 aKlarin, Derek1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aLevin, Michael, G1 aChasman, Daniel, I1 aGoode, Ellen, L1 aHveem, Kristian1 aTeder-Laving, Maris1 aMartinez-Perez, Angel1 aAïssi, Dylan1 aDaian-Bacq, Delphine1 aIto, Kaoru1 aNatarajan, Pradeep1 aLutsey, Pamela, L1 aNadkarni, Girish, N1 ade Vries, Paul, S1 aCuellar-Partida, Gabriel1 aWolford, Brooke, N1 aPattee, Jack, W1 aKooperberg, Charles1 aBraekkan, Sigrid, K1 aLi-Gao, Ruifang1 aSaut, Noémie1 aSept, Corriene1 aGermain, Marine1 aJudy, Renae, L1 aWiggins, Kerri, L1 aKo, Darae1 aO'Donnell, Christopher, J1 aTaylor, Kent, D1 aGiulianini, Franco1 ade Andrade, Mariza1 aNøst, Therese, H1 aBoland, Anne1 aEmpana, Jean-Philippe1 aKoyama, Satoshi1 aGilliland, Thomas1 aDo, Ron1 aHuffman, Jennifer, E1 aWang, Xin1 aZhou, Wei1 aSoria, Jose, Manuel1 aSouto, Juan, Carlos1 aPankratz, Nathan1 aHaessler, Jeffery1 aHindberg, Kristian1 aRosendaal, Frits, R1 aTurman, Constance1 aOlaso, Robert1 aKember, Rachel, L1 aBartz, Traci, M1 aLynch, Julie, A1 aHeckbert, Susan, R1 aArmasu, Sebastian, M1 aBrumpton, Ben1 aSmadja, David, M1 aJouven, Xavier1 aKomuro, Issei1 aClapham, Katharine, R1 aLoos, Ruth, J F1 aWiller, Cristen, J1 aSabater-Lleal, Maria1 aPankow, James, S1 aReiner, Alexander, P1 aMorelli, Vania, M1 aRidker, Paul, M1 aVlieg, Astrid, van Hylcka1 aDeleuze, Jean-Francois1 aKraft, Peter1 aRader, Daniel, J1 aLee, Kyung, Min1 aPsaty, Bruce, M1 aSkogholt, Anne, Heidi1 aEmmerich, Joseph1 aSuchon, Pierre1 aRich, Stephen, S1 aVy, Ha, My T1 aTang, Weihong1 aJackson, Rebecca, D1 aHansen, John-Bjarne1 aMorange, Pierre-Emmanuel1 aKabrhel, Christopher1 aTrégouët, David-Alexandre1 aDamrauer, Scott, M1 aJohnson, Andrew, D1 aSmith, Nicholas, L1 aGlobal Biobank Meta-Analysis Initiative; Estonian Biobank Research Team; 23andMe Research Team; Biobank Japan; CHARGE Hemostasis Working Group uhttps://chs-nhlbi.org/node/919412282nas a2204021 4500008004100000022001400041245011000055210006900165260001600234300000800250490000600258520108400264653001501348653002201363653002701385653003401412653003101446653001101477653001101488100002301499700002101522700002201543700002001565700002001585700002201605700002301627700001801650700002101668700001901689700001901708700002101727700001801748700001901766700002301785700001701808700001201825700001901837700002401856700002101880700002701901700001601928700001901944700001901963700001301982700002001995700002002015700001902035700001902054700001802073700002002091700002402111700002302135700002102158700002902179700002602208700002902234700001802263700001802281700002102299700002102320700002202341700001802363700001702381700002402398700002002422700001902442700002002461700002102481700002302502700002402525700001702549700002002566700001802586700002002604700002502624700001802649700002602667700002002693700001702713700002702730700002602757700002002783700002502803700002302828700002202851700002802873700003002901700002602931700002502957700001902982700002803001700002003029700002003049700002203069700002003091700002703111700002203138700002603160700003203186700002303218700002303241700002803264700002203292700002103314700002003335700002303355700002403378700002403402700002903426700002203455700001703477700001703494700002103511700001703532700002403549700001803573700002003591700002003611700001403631700002603645700002303671700002703694700001703721700002003738700001903758700002103777700002003798700002403818700002503842700002503867700002003892700002003912700002103932700001203953700002603965700002003991700001704011700002104028700001604049700002004065700001804085700001604103700001904119700002104138700002304159700001804182700001904200700002104219700002004240700002104260700001904281700002204300700002804322700002304350700002204373700001704395700001204412700002004424700001904444700002204463700002604485700002204511700002204533700002304555700002104578700002104599700001804620700001904638700002604657700002304683700002104706700002104727700002204748700002204770700002204792700002104814700002004835700001404855700001704869700002004886700002404906700001904930700002004949700001504969700002004984700003105004700002305035700002605058700002205084700002805106700002105134700002105155700001905176700002005195700001805215700002205233700002905255700002405284700001905308700001905327700002505346700001905371700002105390700001905411700002405430700002005454700002305474700002105497700002105518700001905539700002405558700002005582700002005602700002005622700002105642700002005663700002605683700001805709700002005727700002105747700002305768700002205791700002505813700002205838700002805860700001905888700002005907700002105927700001905948700002105967700002105988700002106009700002706030700002406057700002306081700002606104700002006130700001906150700001806169700002606187700001806213700001806231700002106249700001906270700002306289700001906312700001906331700002106350700002506371700001906396700002706415700001806442700002006460700001706480700002106497700002006518700001806538700002606556700001906582700002406601700001506625700002206640700002106662700002106683700001306704700002106717700001806738700002206756700002306778700001706801700002006818700002306838700002306861700002006884700002706904700002006931700002506951700002506976700002607001700002107027700002107048700002007069700001907089700002207108700002107130700001807151700002507169700001607194700001907210700002407229700001907253700001807272700002807290700002207318700002307340700002207363700001907385700002007404700002107424700001607445700001907461700002807480700001707508700002807525700002007553700002207573700002607595700002407621700002507645700001507670700001807685700001707703700001907720700002007739700002107759700001907780700001507799700001707814700001907831700002507850700002007875700002307895700002007918700002107938700001207959700002007971700002107991700002308012700002108035700002408056700001908080700002208099700001808121710002708139710002708166710003108193856003608224 2022 eng d a2399-364200aDifferential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.0 aDifferential and shared genetic effects on kidney function betwe c2022 Jun 13 a5800 v53 aReduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
10aCreatinine10aDiabetes Mellitus10aDiabetic Nephropathies10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney1 aWinkler, Thomas, W1 aRasheed, Humaira1 aTeumer, Alexander1 aGorski, Mathias1 aRowan, Bryce, X1 aStanzick, Kira, J1 aThomas, Laurent, F1 aTin, Adrienne1 aHoppmann, Anselm1 aChu, Audrey, Y1 aTayo, Bamidele1 aThio, Chris, H L1 aCusi, Daniele1 aChai, Jin-Fang1 aSieber, Karsten, B1 aHorn, Katrin1 aLi, Man1 aScholz, Markus1 aCocca, Massimiliano1 aWuttke, Matthias1 avan der Most, Peter, J1 aYang, Qiong1 aGhasemi, Sahar1 aNutile, Teresa1 aLi, Yong1 aPontali, Giulia1 aGünther, Felix1 aDehghan, Abbas1 aCorrea, Adolfo1 aParsa, Afshin1 aFeresin, Agnese1 ade Vries, Aiko, P J1 aZonderman, Alan, B1 aSmith, Albert, V1 aOldehinkel, Albertine, J1 aDe Grandi, Alessandro1 aRosenkranz, Alexander, R1 aFranke, Andre1 aTeren, Andrej1 aMetspalu, Andres1 aHicks, Andrew, A1 aMorris, Andrew, P1 aTönjes, Anke1 aMorgan, Anna1 aPodgornaia, Anna, I1 aPeters, Annette1 aKörner, Antje1 aMahajan, Anubha1 aCampbell, Archie1 aFreedman, Barry, I1 aSpedicati, Beatrice1 aPonte, Belen1 aSchöttker, Ben1 aBrumpton, Ben1 aBanas, Bernhard1 aKrämer, Bernhard, K1 aJung, Bettina1 aÅsvold, Bjørn, Olav1 aSmith, Blair, H1 aNing, Boting1 aPenninx, Brenda, W J H1 aVanderwerff, Brett, R1 aPsaty, Bruce, M1 aKammerer, Candace, M1 aLangefeld, Carl, D1 aHayward, Caroline1 aSpracklen, Cassandra, N1 aRobinson-Cohen, Cassianne1 aHartman, Catharina, A1 aLindgren, Cecilia, M1 aWang, Chaolong1 aSabanayagam, Charumathi1 aHeng, Chew-Kiat1 aLanzani, Chiara1 aKhor, Chiea-Chuen1 aCheng, Ching-Yu1 aFuchsberger, Christian1 aGieger, Christian1 aShaffer, Christian, M1 aSchulz, Christina-Alexandra1 aWiller, Cristen, J1 aChasman, Daniel, I1 aGudbjartsson, Daniel, F1 aRuggiero, Daniela1 aToniolo, Daniela1 aCzamara, Darina1 aPorteous, David, J1 aWaterworth, Dawn, M1 aMascalzoni, Deborah1 aMook-Kanamori, Dennis, O1 aReilly, Dermot, F1 aDaw, Warwick1 aHofer, Edith1 aBoerwinkle, Eric1 aSalvi, Erika1 aBottinger, Erwin, P1 aTai, E-Shyong1 aCatamo, Eulalia1 aRizzi, Federica1 aGuo, Feng1 aRivadeneira, Fernando1 aGuilianini, Franco1 aSveinbjornsson, Gardar1 aEhret, Georg1 aWaeber, Gérard1 aBiino, Ginevra1 aGirotto, Giorgia1 aPistis, Giorgio1 aNadkarni, Girish, N1 aDelgado, Graciela, E1 aMontgomery, Grant, W1 aSnieder, Harold1 aCampbell, Harry1 aWhite, Harvey, D1 aGao, He1 aStringham, Heather, M1 aSchmidt, Helena1 aLi, Hengtong1 aBrenner, Hermann1 aHolm, Hilma1 aKirsten, Holgen1 aKramer, Holly1 aRudan, Igor1 aNolte, Ilja, M1 aTzoulaki, Ioanna1 aOlafsson, Isleifur1 aMartins, Jade1 aCook, James, P1 aWilson, James, F1 aHalbritter, Jan1 aFelix, Janine, F1 aDivers, Jasmin1 aKooner, Jaspal, S1 aLee, Jeannette, Jen-Mai1 aO'Connell, Jeffrey1 aRotter, Jerome, I1 aLiu, Jianjun1 aXu, Jie1 aThiery, Joachim1 aArnlöv, Johan1 aKuusisto, Johanna1 aJakobsdottir, Johanna1 aTremblay, Johanne1 aChambers, John, C1 aWhitfield, John, B1 aGaziano, John, M1 aMarten, Jonathan1 aCoresh, Josef1 aJonas, Jost, B1 aMychaleckyj, Josyf, C1 aChristensen, Kaare1 aEckardt, Kai-Uwe1 aMohlke, Karen, L1 aEndlich, Karlhans1 aDittrich, Katalin1 aRyan, Kathleen, A1 aRice, Kenneth, M1 aTaylor, Kent, D1 aHo, Kevin1 aNikus, Kjell1 aMatsuda, Koichi1 aStrauch, Konstantin1 aMiliku, Kozeta1 aHveem, Kristian1 aLind, Lars1 aWallentin, Lars1 aYerges-Armstrong, Laura, M1 aRaffield, Laura, M1 aPhillips, Lawrence, S1 aLauner, Lenore, J1 aLyytikäinen, Leo-Pekka1 aLange, Leslie, A1 aCitterio, Lorena1 aKlaric, Lucija1 aIkram, Arfan, M1 aIsing, Marcus1 aKleber, Marcus, E1 aFrancescatto, Margherita1 aConcas, Maria, Pina1 aCiullo, Marina1 aPiratsu, Mario1 aOrho-Melander, Marju1 aLaakso, Markku1 aLoeffler, Markus1 aPerola, Markus1 ade Borst, Martin, H1 aGögele, Martin1 aLa Bianca, Martina1 aLukas, Mary, Ann1 aFeitosa, Mary, F1 aBiggs, Mary, L1 aWojczynski, Mary, K1 aKavousi, Maryam1 aKanai, Masahiro1 aAkiyama, Masato1 aYasuda, Masayuki1 aNauck, Matthias1 aWaldenberger, Melanie1 aChee, Miao-Li1 aChee, Miao-Ling1 aBoehnke, Michael1 aPreuss, Michael, H1 aStumvoll, Michael1 aProvince, Michael, A1 aEvans, Michele, K1 aO'Donoghue, Michelle, L1 aKubo, Michiaki1 aKähönen, Mika1 aKastarinen, Mika1 aNalls, Mike, A1 aKuokkanen, Mikko1 aGhanbari, Mohsen1 aBochud, Murielle1 aJosyula, Navya, Shilpa1 aMartin, Nicholas, G1 aTan, Nicholas, Y Q1 aPalmer, Nicholette, D1 aPirastu, Nicola1 aSchupf, Nicole1 aVerweij, Niek1 aHutri-Kähönen, Nina1 aMononen, Nina1 aBansal, Nisha1 aDevuyst, Olivier1 aMelander, Olle1 aRaitakari, Olli, T1 aPolasek, Ozren1 aManunta, Paolo1 aGasparini, Paolo1 aMishra, Pashupati, P1 aSulem, Patrick1 aMagnusson, Patrik, K E1 aElliott, Paul1 aRidker, Paul, M1 aHamet, Pavel1 aSvensson, Per, O1 aJoshi, Peter, K1 aKovacs, Peter1 aPramstaller, Peter, P1 aRossing, Peter1 aVollenweider, Peter1 aHarst, Pim1 aDorajoo, Rajkumar1 aSim, Ralene, Z H1 aBurkhardt, Ralph1 aTao, Ran1 aNoordam, Raymond1 aMägi, Reedik1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aRueedi, Rico1 avan Dam, Rob, M1 aCarroll, Robert, J1 aGansevoort, Ron, T1 aLoos, Ruth, J F1 aFelicita, Sala, Cinzia1 aSedaghat, Sanaz1 aPadmanabhan, Sandosh1 aFreitag-Wolf, Sandra1 aPendergrass, Sarah, A1 aGraham, Sarah, E1 aGordon, Scott, D1 aHwang, Shih-Jen1 aKerr, Shona, M1 aVaccargiu, Simona1 aPatil, Snehal, B1 aHallan, Stein1 aBakker, Stephan, J L1 aLim, Su-Chi1 aLucae, Susanne1 aVogelezang, Suzanne1 aBergmann, Sven1 aCorre, Tanguy1 aAhluwalia, Tarunveer, S1 aLehtimäki, Terho1 aBoutin, Thibaud, S1 aMeitinger, Thomas1 aWong, Tien-Yin1 aBergler, Tobias1 aRabelink, Ton, J1 aEsko, Tõnu1 aHaller, Toomas1 aThorsteinsdottir, Unnur1 aVölker, Uwe1 aFoo, Valencia, Hui Xian1 aSalomaa, Veikko1 aVitart, Veronique1 aGiedraitis, Vilmantas1 aGudnason, Vilmundur1 aJaddoe, Vincent, W V1 aHuang, Wei1 aZhang, Weihua1 aBin Wei, Wen1 aKiess, Wieland1 aMärz, Winfried1 aKoenig, Wolfgang1 aLieb, Wolfgang1 aGào, Xīn1 aSim, Xueling1 aWang, Ya, Xing1 aFriedlander, Yechiel1 aTham, Yih-Chung1 aKamatani, Yoichiro1 aOkada, Yukinori1 aMilaneschi, Yuri1 aYu, Zhi1 aStark, Klaus, J1 aStefansson, Kari1 aBöger, Carsten, A1 aHung, Adriana, M1 aKronenberg, Florian1 aKöttgen, Anna1 aPattaro, Cristian1 aHeid, Iris, M1 aLifeLines Cohort Study1 aDiscovEHR/MyCode study1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/911202329nas a2200301 4500008004100000022001400041245010500055210006900160260001500229490000700244520139300251653001101644653003401655653001301689653003901702653002801741100001701769700001401786700001401800700001901814700001901833700002201852700002301874700001701897700001201914710006501926856003601991 2022 eng d a1477-405400aeSCAN: scan regulatory regions for aggregate association testing using whole-genome sequencing data.0 aeSCAN scan regulatory regions for aggregate association testing c2022 01 170 v233 aMultiple statistical methods for aggregate association testing have been developed for whole-genome sequencing (WGS) data. Many aggregate variants in a given genomic window and ignore existing knowledge to define test regions, resulting in many identified regions not clearly linked to genes, and thus, limiting biological understanding. Functional information from new technologies (such as Hi-C and its derivatives), which can help link enhancers to their effector genes, can be leveraged to predefine variant sets for aggregate testing in WGS data. Here, we propose the eSCAN (scan the enhancers) method for genome-wide assessment of enhancer regions in sequencing studies, combining the advantages of dynamic window selection in SCANG (SCAN the Genome), a previously developed method, with the advantages of incorporating putative regulatory regions from annotation. eSCAN, by searching in putative enhancers, increases statistical power and aids mechanistic interpretation, as demonstrated by extensive simulation studies. We also apply eSCAN for blood cell traits using NHLBI Trans-Omics for Precision Medicine WGS data. Results from real data analysis show that eSCAN is able to capture more significant signals, and these signals are of shorter length (indicating higher resolution fine-mapping capability) and drive association of larger regions detected by other methods.
10aGenome10aGenome-Wide Association Study10aGenomics10aRegulatory Sequences, Nucleic Acid10aWhole Genome Sequencing1 aYang, Yingxi1 aSun, Quan1 aHuang, Le1 aBroome, Jai, G1 aCorrea, Adolfo1 aReiner, Alexander1 aRaffield, Laura, M1 aYang, Yuchen1 aLi, Yun1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/911304304nas a2201045 4500008004100000022001400041245011400055210006900169260001300238300001400251490000700265520128500272653002201557653001101579653003401590653001101624653001401635653002801649100001401677700001401691700001701705700002201722700003201744700002401776700001801800700001501818700001401833700001401847700001601861700002101877700001801898700002401916700001901940700002501959700001901984700002102003700002202024700002302046700001902069700002402088700001902112700002502131700002202156700002202178700002802200700002302228700002302251700002502274700001702299700002102316700002402337700001902361700002102380700002002401700002102421700002202442700002002464700002302484700002002507700002502527700002202552700002402574700001702598700002602615700002602641700002402667700002002691700002302711700001902734700002502753700003402778700002102812700002102833700002302854700002002877700002202897700002702919700002102946700002102967700001902988700001403007700002203021700002303043700002303066700002003089700001603109710006503125710003203190856003603222 2022 eng d a1548-710500aA framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.0 aframework for detecting noncoding rarevariant associations of la c2022 Dec a1599-16110 v193 aLarge-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.
10aGenetic Variation10aGenome10aGenome-Wide Association Study10aHumans10aPhenotype10aWhole Genome Sequencing1 aLi, Zilin1 aLi, Xihao1 aZhou, Hufeng1 aGaynor, Sheila, M1 aSelvaraj, Margaret, Sunitha1 aArapoglou, Theodore1 aQuick, Corbin1 aLiu, Yaowu1 aChen, Han1 aSun, Ryan1 aDey, Rounak1 aArnett, Donna, K1 aAuer, Paul, L1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlackwell, Thomas, W1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aConomos, Matthew, P1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 ade Vries, Paul, S1 aDuggirala, Ravindranath1 aFranceschini, Nora1 aFreedman, Barry, I1 aGöring, Harald, H H1 aGuo, Xiuqing1 aKalyani, Rita, R1 aKooperberg, Charles1 aKral, Brian, G1 aLange, Leslie, A1 aLin, Bridget, M1 aManichaikul, Ani1 aManning, Alisa, K1 aMartin, Lisa, W1 aMathias, Rasika, A1 aMeigs, James, B1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRedline, Susan1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aRice, Kenneth, M1 aRich, Stephen, S1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aTaub, Margaret, A1 aVasan, Ramachandran, S1 aWeeks, Daniel, E1 aWilson, James, G1 aYanek, Lisa, R1 aZhao, Wei1 aRotter, Jerome, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aLin, Xihong1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/925301045nas a2200325 4500008004100000022001400041245014300055210006900198260001600267300001200283490000800295653002100303653002100324653001400345653003400359653004100393653001400434653001800448100002400466700002500490700001600515700002300531700002000554700002100574700002000595700002400615700002200639700002200661856003600683 2022 eng d a1524-457100aGenome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus.0 aGenome Wide Association Studies of VariantbyThiazide Interaction c2022 Jul 22 a277-2790 v13110aCholesterol, HDL10aCholesterol, LDL10aDiuretics10aGenome-Wide Association Study10aSodium Chloride Symporter Inhibitors10aThiazides10aTriglycerides1 aDownie, Carolina, G1 aHighland, Heather, M1 aLee, Moa, P1 aRaffield, Laura, M1 aPreuss, Michael1 aWhitsel, Eric, A1 aPsaty, Bruce, M1 aSitlani, Colleen, M1 aGraff, Mariaelisa1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/945205087nas a2201237 4500008004100000022001400041245010900055210006900164260001200233300001400245490000700259520156200266653002801828653003801856653003401894653001101928653003601939653001701975100002701992700001502019700002402034700002002058700002302078700001602101700002002117700001802137700001402155700001802169700001802187700002402205700002002229700002102249700002302270700001802293700002202311700002802333700002502361700002302386700002202409700002202431700002302453700002002476700001502496700001802511700001602529700001902545700002402564700002202588700002002610700001202630700002002642700002502662700001902687700002202706700002202728700002702750700002302777700002202800700001902822700002102841700001702862700002102879700001602900700002002916700002302936700002102959700002002980700002003000700002003020700001903040700002403059700001503083700002403098700002303122700002203145700002403167700002203191700001603213700001903229700002203248700002503270700002203295700002103317700002103338700002103359700001503380700002103395700002303416700002503439700002403464700002103488700002003509700002003529700002303549700002303572700001403595700001603609700002003625700003003645700002903675710003003704710003303734710001803767710002803785856003603813 2022 eng d a1546-170X00aLarge-scale genome-wide association study of coronary artery disease in genetically diverse populations.0 aLargescale genomewide association study of coronary artery disea c2022 08 a1679-16920 v283 aWe report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
10aCoronary Artery Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aTcheandjieu, Catherine1 aZhu, Xiang1 aHilliard, Austin, T1 aClarke, Shoa, L1 aNapolioni, Valerio1 aMa, Shining1 aLee, Kyung, Min1 aFang, Huaying1 aChen, Fei1 aLu, Yingchang1 aTsao, Noah, L1 aRaghavan, Sridharan1 aKoyama, Satoshi1 aGorman, Bryan, R1 aVujkovic, Marijana1 aKlarin, Derek1 aLevin, Michael, G1 aSinnott-Armstrong, Nasa1 aWojcik, Genevieve, L1 aPlomondon, Mary, E1 aMaddox, Thomas, M1 aWaldo, Stephen, W1 aBick, Alexander, G1 aPyarajan, Saiju1 aHuang, Jie1 aSong, Rebecca1 aHo, Yuk-Lam1 aBuyske, Steven1 aKooperberg, Charles1 aHaessler, Jeffrey1 aLoos, Ruth, J F1 aDo, Ron1 aVerbanck, Marie1 aChaudhary, Kumardeep1 aNorth, Kari, E1 aAvery, Christy, L1 aGraff, Mariaelisa1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aWilkens, Lynne, R1 aBis, Joshua, C1 aLeonard, Hampton1 aShen, Botong1 aLange, Leslie, A1 aGiri, Ayush1 aDikilitas, Ozan1 aKullo, Iftikhar, J1 aStanaway, Ian, B1 aJarvik, Gail, P1 aGordon, Adam, S1 aHebbring, Scott1 aNamjou, Bahram1 aKaufman, Kenneth, M1 aIto, Kaoru1 aIshigaki, Kazuyoshi1 aKamatani, Yoichiro1 aVerma, Shefali, S1 aRitchie, Marylyn, D1 aKember, Rachel, L1 aBaras, Aris1 aLotta, Luca, A1 aKathiresan, Sekar1 aHauser, Elizabeth, R1 aMiller, Donald, R1 aLee, Jennifer, S1 aSaleheen, Danish1 aReaven, Peter, D1 aCho, Kelly1 aGaziano, Michael1 aNatarajan, Pradeep1 aHuffman, Jennifer, E1 aVoight, Benjamin, F1 aRader, Daniel, J1 aChang, Kyong-Mi1 aLynch, Julie, A1 aDamrauer, Scott, M1 aWilson, Peter, W F1 aTang, Hua1 aSun, Yan, V1 aTsao, Philip, S1 aO'Donnell, Christopher, J1 aAssimes, Themistocles, L1 aRegeneron Genetics Center1 aCARDIoGRAMplusC4D Consortium1 aBiobank Japan1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/917613363nas a2204429 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2022 eng d a1546-171800aMulti-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.0 aMultiancestry genetic study of type 2 diabetes highlights the po c2022 May a560-5720 v543 aWe assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
10aDiabetes Mellitus, Type 210aEthnicity10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aZhang, Weihua1 aC Y Ng, Maggie1 aPetty, Lauren, E1 aKitajima, Hidetoshi1 aYu, Grace, Z1 aRüeger, Sina1 aSpeidel, Leo1 aKim, Young, Jin1 aHorikoshi, Momoko1 aMercader, Josep, M1 aTaliun, Daniel1 aMoon, Sanghoon1 aKwak, Soo-Heon1 aRobertson, Neil, R1 aRayner, Nigel, W1 aLoh, Marie1 aKim, Bong-Jo1 aChiou, Joshua1 aMiguel-Escalada, Irene1 aParolo, Pietro, Della Brio1 aLin, Kuang1 aBragg, Fiona1 aPreuss, Michael, H1 aTakeuchi, Fumihiko1 aNano, Jana1 aGuo, Xiuqing1 aLamri, Amel1 aNakatochi, Masahiro1 aScott, Robert, A1 aLee, Jung-Jin1 aHuerta-Chagoya, Alicia1 aGraff, Mariaelisa1 aChai, Jin-Fang1 aParra, Esteban, J1 aYao, Jie1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aSteinthorsdottir, Valgerdur1 aCook, James, P1 aKals, Mart1 aGrarup, Niels1 aSchmidt, Ellen, M1 aPan, Ian1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aAhmad, Meraj1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aLecoeur, Cécile1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aJensen, Richard, A1 aTajuddin, Salman1 aKabagambe, Edmond, K1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aFlanagan, Jack1 aAbaitua, Fernando1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAkiyama, Masato1 aAnand, Sonia, S1 aBertoni, Alain1 aBian, Zheng1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBrummett, Chad, M1 aBuchanan, Thomas, A1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFornage, Myriam1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aFuchsberger, Christian1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGoodarzi, Mark, O1 aGordon-Larsen, Penny1 aGorkin, David1 aGross, Myron1 aGuo, Yu1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKamatani, Yoichiro1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKohara, Katsuhiko1 aKriebel, Jennifer1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLigthart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLyssenko, Valeriya1 aMamakou, Vasiliki1 aMani, Radha, K1 aMeitinger, Thomas1 aMetspalu, Andres1 aMorris, Andrew, D1 aNadkarni, Girish, N1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNongmaithem, Suraj, S1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPorneala, Bianca1 aPrasad, Gauri1 aPreissl, Sebastian1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Kathryn1 aSabanayagam, Charumathi1 aSander, Maike1 aSandow, Kevin1 aSattar, Naveed1 aSchönherr, Sebastian1 aSchurmann, Claudia1 aShahriar, Mohammad1 aShi, Jinxiu1 aShin, Dong, Mun1 aShriner, Daniel1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aSuzuki, Ken1 aTakahashi, Atsushi1 aTaylor, Kent, D1 aThorand, Barbara1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTorres, Jason, M1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aVujkovic, Marijana1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWhitsel, Eric, A1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamauchi, Toshimasa1 aYengo, Loic1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZhang, Liang1 aZheng, Wei1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aHanis, Craig, L1 aPeyser, Patricia, A1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aZeggini, Eleftheria1 aYokota, Mitsuhiro1 aRich, Stephen, S1 aKooperberg, Charles1 aPankow, James, S1 aEngert, James, C1 aChen, Yii-Der Ida1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aKardia, Sharon, L R1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aGroop, Leif1 aMook-Kanamori, Dennis, O1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aBottinger, Erwin, P1 aDehghan, Abbas1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aPalmer, Colin, N A1 aLiu, Simin1 aAbecasis, Goncalo1 aKooner, Jaspal, S1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aFlorez, Jose, C1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aMägi, Reedik1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aMaeda, Shiro1 aKadowaki, Takashi1 aLee, Juyoung1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aMyers, Simon, R1 aFerrer, Jorge1 aGaulton, Kyle, J1 aMeigs, James, B1 aMohlke, Karen, L1 aGloyn, Anna, L1 aBowden, Donald, W1 aBelow, Jennifer, E1 aChambers, John, C1 aSim, Xueling1 aBoehnke, Michael1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aMorris, Andrew, P1 aFinnGen1 aeMERGE Consortium uhttps://chs-nhlbi.org/node/910403010nas a2200697 4500008004100000022001400041245012100055210006900176260001600245300000900261490000700270520097500277653001001252653003001262653003801292653003401330653001101364653001701375653003101392653001501423653001701438100002501455700002401480700002101504700001801525700002201543700001901565700001701584700001901601700002001620700001801640700002201658700001301680700001901693700002301712700001301735700002401748700002201772700001401794700002001808700001501828700003201843700002101875700002701896700002101923700002001944700001901964700001901983700002402002700002002026700002202046700002002068700002202088700002102110700002402131700002302155700001702178700001702195710006402212856003602276 2022 eng d a2041-172300aA multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood.0 amultiethnic polygenic risk score is associated with hypertension c2022 Jun 21 a35490 v133 aIn a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.
10aAdult10aDiabetes Mellitus, Type 210aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aMultifactorial Inheritance10aPrevalence10aRisk Factors1 aKurniansyah, Nuzulul1 aGoodman, Matthew, O1 aKelly, Tanika, N1 aElfassy, Tali1 aWiggins, Kerri, L1 aBis, Joshua, C1 aGuo, Xiuqing1 aPalmas, Walter1 aTaylor, Kent, D1 aLin, Henry, J1 aHaessler, Jeffrey1 aGao, Yan1 aShimbo, Daichi1 aSmith, Jennifer, A1 aYu, Bing1 aFeofanova, Elena, V1 aSmit, Roelof, A J1 aWang, Zhe1 aHwang, Shih-Jen1 aLiu, Simin1 aWassertheil-Smoller, Sylvia1 aManson, JoAnn, E1 aLloyd-Jones, Donald, M1 aRich, Stephen, S1 aLoos, Ruth, J F1 aRedline, Susan1 aCorrea, Adolfo1 aKooperberg, Charles1 aFornage, Myriam1 aKaplan, Robert, C1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aArnett, Donna, K1 aMorrison, Alanna, C1 aFranceschini, Nora1 aLevy, Daniel1 aSofer, Tamar1 aNHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/910015436nas a2205137 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2022 eng d a1546-171800aNew insights into the genetic etiology of Alzheimer's disease and related dementias.0 aNew insights into the genetic etiology of Alzheimers disease and c2022 Apr a412-4360 v543 aCharacterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
10aAlzheimer Disease10aCognitive Dysfunction10aGenome-Wide Association Study10aHumans10atau Proteins1 aBellenguez, Céline1 aKüçükali, Fahri1 aJansen, Iris, E1 aKleineidam, Luca1 aMoreno-Grau, Sonia1 aAmin, Najaf1 aNaj, Adam, C1 aCampos-Martin, Rafael1 aGrenier-Boley, Benjamin1 aAndrade, Victor1 aHolmans, Peter, A1 aBoland, Anne1 aDamotte, Vincent1 avan der Lee, Sven, J1 aCosta, Marcos, R1 aKuulasmaa, Teemu1 aYang, Qiong1 ade Rojas, Itziar1 aBis, Joshua, C1 aYaqub, Amber1 aProkic, Ivana1 aChapuis, Julien1 aAhmad, Shahzad1 aGiedraitis, Vilmantas1 aAarsland, Dag1 aGarcia-Gonzalez, Pablo1 aAbdelnour, Carla1 aAlarcón-Martín, Emilio1 aAlcolea, Daniel1 aAlegret, Montserrat1 aAlvarez, Ignacio1 aAlvarez, Victoria1 aArmstrong, Nicola, J1 aTsolaki, Anthoula1 aAntunez, Carmen1 aAppollonio, Ildebrando1 aArcaro, Marina1 aArchetti, Silvana1 aPastor, Alfonso, Arias1 aArosio, Beatrice1 aAthanasiu, Lavinia1 aBailly, Henri1 aBanaj, Nerisa1 aBaquero, Miquel1 aBarral, Sandra1 aBeiser, Alexa1 aPastor, Ana, Belén1 aBelow, Jennifer, E1 aBenchek, Penelope1 aBenussi, Luisa1 aBerr, Claudine1 aBesse, Céline1 aBessi, Valentina1 aBinetti, Giuliano1 aBizarro, Alessandra1 aBlesa, Rafael1 aBoada, Merce1 aBoerwinkle, Eric1 aBorroni, Barbara1 aBoschi, Silvia1 aBossù, Paola1 aBråthen, Geir1 aBressler, Jan1 aBresner, Catherine1 aBrodaty, Henry1 aBrookes, Keeley, J1 aBrusco, Luis, Ignacio1 aBuiza-Rueda, Dolores1 aBûrger, Katharina1 aBurholt, Vanessa1 aBush, William, S1 aCalero, Miguel1 aCantwell, Laura, B1 aChene, Geneviève1 aChung, Jaeyoon1 aCuccaro, Michael, L1 aCarracedo, Angel1 aCecchetti, Roberta1 aCervera-Carles, Laura1 aCharbonnier, Camille1 aChen, Hung-Hsin1 aChillotti, Caterina1 aCiccone, Simona1 aClaassen, Jurgen, A H R1 aClark, Christopher1 aConti, Elisa1 aCorma-Gómez, Anaïs1 aCostantini, Emanuele1 aCustodero, Carlo1 aDaian, Delphine1 aDalmasso, Maria, Carolina1 aDaniele, Antonio1 aDardiotis, Efthimios1 aDartigues, Jean-François1 ade Deyn, Peter, Paul1 aLopes, Katia, de Paiva1 ade Witte, Lot, D1 aDebette, Stephanie1 aDeckert, Jürgen1 aDel Ser, Teodoro1 aDenning, Nicola1 aDeStefano, Anita1 aDichgans, Martin1 aDiehl-Schmid, Janine1 aDiez-Fairen, Monica1 aRossi, Paolo, Dionigi1 aDjurovic, Srdjan1 aDuron, Emmanuelle1 aDüzel, Emrah1 aDufouil, Carole1 aEiriksdottir, Gudny1 aEngelborghs, Sebastiaan1 aEscott-Price, Valentina1 aEspinosa, Ana1 aEwers, Michael1 aFaber, Kelley, M1 aFabrizio, Tagliavini1 aNielsen, Sune, Fallgaard1 aFardo, David, W1 aFarotti, Lucia1 aFenoglio, Chiara1 aFernández-Fuertes, Marta1 aFerrari, Raffaele1 aFerreira, Catarina, B1 aFerri, Evelyn1 aFin, Bertrand1 aFischer, Peter1 aFladby, Tormod1 aFließbach, Klaus1 aFongang, Bernard1 aFornage, Myriam1 aFortea, Juan1 aForoud, Tatiana, M1 aFostinelli, Silvia1 aFox, Nick, C1 aFranco-Macías, Emlio1 aBullido, María, J1 aFrank-García, Ana1 aFroelich, Lutz1 aFulton-Howard, Brian1 aGalimberti, Daniela1 aGarcía-Alberca, Jose, Maria1 aGarcia-Gonzalez, Pablo1 aGarcia-Madrona, Sebastian1 aGarcia-Ribas, Guillermo1 aGhidoni, Roberta1 aGiegling, Ina1 aGiorgio, Giaccone1 aGoate, Alison, M1 aGoldhardt, Oliver1 aGomez-Fonseca, Duber1 aGonzález-Perez, Antonio1 aGraff, Caroline1 aGrande, Giulia1 aGreen, Emma1 aGrimmer, Timo1 aGrünblatt, Edna1 aGrunin, Michelle1 aGudnason, Vilmundur1 aGuetta-Baranes, Tamar1 aHaapasalo, Annakaisa1 aHadjigeorgiou, Georgios1 aHaines, Jonathan, L1 aHamilton-Nelson, Kara, L1 aHampel, Harald1 aHanon, Olivier1 aHardy, John1 aHartmann, Annette, M1 aHausner, Lucrezia1 aHarwood, Janet1 aHeilmann-Heimbach, Stefanie1 aHelisalmi, Seppo1 aHeneka, Michael, T1 aHernandez, Isabel1 aHerrmann, Martin, J1 aHoffmann, Per1 aHolmes, Clive1 aHolstege, Henne1 aVilas, Raquel, Huerto1 aHulsman, Marc1 aHumphrey, Jack1 aBiessels, Geert, Jan1 aJian, Xueqiu1 aJohansson, Charlotte1 aJun, Gyungah, R1 aKastumata, Yuriko1 aKauwe, John1 aKehoe, Patrick, G1 aKilander, Lena1 aStåhlbom, Anne, Kinhult1 aKivipelto, Miia1 aKoivisto, Anne1 aKornhuber, Johannes1 aKosmidis, Mary, H1 aKukull, Walter, A1 aKuksa, Pavel, P1 aKunkle, Brian, W1 aKuzma, Amanda, B1 aLage, Carmen1 aLaukka, Erika, J1 aLauner, Lenore1 aLauria, Alessandra1 aLee, Chien-Yueh1 aLehtisalo, Jenni1 aLerch, Ondrej1 aLleo, Alberto1 aLongstreth, William1 aLopez, Oscar1 ade Munain, Adolfo, Lopez1 aLove, Seth1 aLöwemark, Malin1 aLuckcuck, Lauren1 aLunetta, Kathryn, L1 aMa, Yiyi1 aMacías, Juan1 aMacLeod, Catherine, A1 aMaier, Wolfgang1 aMangialasche, Francesca1 aSpallazzi, Marco1 aMarquié, Marta1 aMarshall, Rachel1 aMartin, Eden, R1 aMontes, Angel, Martín1 aRodríguez, Carmen, Martínez1 aMasullo, Carlo1 aMayeux, Richard1 aMead, Simon1 aMecocci, Patrizia1 aMedina, Miguel1 aMeggy, Alun1 aMehrabian, Shima1 aMendoza, Silvia1 aMenéndez-González, Manuel1 aMir, Pablo1 aMoebus, Susanne1 aMol, Merel1 aMolina-Porcel, Laura1 aMontrreal, Laura1 aMorelli, Laura1 aMoreno, Fermin1 aMorgan, Kevin1 aMosley, Thomas1 aNöthen, Markus, M1 aMuchnik, Carolina1 aMukherjee, Shubhabrata1 aNacmias, Benedetta1 aNgandu, Tiia1 aNicolas, Gaël1 aNordestgaard, Børge, G1 aOlaso, Robert1 aOrellana, Adelina1 aOrsini, Michela1 aOrtega, Gemma1 aPadovani, Alessandro1 aPaolo, Caffarra1 aPapenberg, Goran1 aParnetti, Lucilla1 aPasquier, Florence1 aPastor, Pau1 aPeloso, Gina1 aPérez-Cordón, Alba1 aPérez-Tur, Jordi1 aPericard, Pierre1 aPeters, Oliver1 aPijnenburg, Yolande, A L1 aPineda, Juan, A1 aPiñol-Ripoll, Gerard1 aPisanu, Claudia1 aPolak, Thomas1 aPopp, Julius1 aPosthuma, Danielle1 aPriller, Josef1 aPuerta, Raquel1 aQuenez, Olivier1 aQuintela, Inés1 aThomassen, Jesper, Qvist1 aRábano, Alberto1 aRainero, Innocenzo1 aRajabli, Farid1 aRamakers, Inez1 aReal, Luis, M1 aReinders, Marcel, J T1 aReitz, Christiane1 aReyes-Dumeyer, Dolly1 aRidge, Perry1 aRiedel-Heller, Steffi1 aRiederer, Peter1 aRoberto, Natalia1 aRodriguez-Rodriguez, Eloy1 aRongve, Arvid1 aAllende, Irene, Rosas1 aRosende-Roca, Maitée1 aRoyo, Jose, Luis1 aRubino, Elisa1 aRujescu, Dan1 aSáez, María, Eugenia1 aSakka, Paraskevi1 aSaltvedt, Ingvild1 aSanabria, Ángela1 aSánchez-Arjona, María, Bernal1 aSanchez-Garcia, Florentino1 aJuan, Pascual, Sánchez1 aSánchez-Valle, Raquel1 aSando, Sigrid, B1 aSarnowski, Chloe1 aSatizabal, Claudia, L1 aScamosci, Michela1 aScarmeas, Nikolaos1 aScarpini, Elio1 aScheltens, Philip1 aScherbaum, Norbert1 aScherer, Martin1 aSchmid, Matthias1 aSchneider, Anja1 aSchott, Jonathan, M1 aSelbæk, Geir1 aSeripa, Davide1 aSerrano, Manuel1 aSha, Jin1 aShadrin, Alexey, A1 aSkrobot, Olivia1 aSlifer, Susan1 aSnijders, Gijsje, J L1 aSoininen, Hilkka1 aSolfrizzi, Vincenzo1 aSolomon, Alina1 aSong, Yeunjoo1 aSorbi, Sandro1 aSotolongo-Grau, Oscar1 aSpalletta, Gianfranco1 aSpottke, Annika1 aSquassina, Alessio1 aStordal, Eystein1 aTartan, Juan, Pablo1 aTarraga, Lluis1 aTesí, Niccolo1 aThalamuthu, Anbupalam1 aThomas, Tegos1 aTosto, Giuseppe1 aTraykov, Latchezar1 aTremolizzo, Lucio1 aTybjærg-Hansen, Anne1 aUitterlinden, Andre1 aUllgren, Abbe1 aUlstein, Ingun1 aValero, Sergi1 aValladares, Otto1 aVan Broeckhoven, Christine1 aVance, Jeffery1 aVardarajan, Badri, N1 avan der Lugt, Aad1 aVan Dongen, Jasper1 avan Rooij, Jeroen1 avan Swieten, John1 aVandenberghe, Rik1 aVerhey, Frans1 aVidal, Jean-Sébastien1 aVogelgsang, Jonathan1 aVyhnalek, Martin1 aWagner, Michael1 aWallon, David1 aSan Wang, Li-1 aWang, Ruiqi1 aWeinhold, Leonie1 aWiltfang, Jens1 aWindle, Gill1 aWoods, Bob1 aYannakoulia, Mary1 aZare, Habil1 aZhao, Yi1 aZhang, Xiaoling1 aZhu, Congcong1 aZulaica, Miren1 aFarrer, Lindsay, A1 aPsaty, Bruce, M1 aGhanbari, Mohsen1 aRaj, Towfique1 aSachdev, Perminder1 aMather, Karen1 aJessen, Frank1 aIkram, Arfan, M1 ade Mendonça, Alexandre1 aHort, Jakub1 aTsolaki, Magda1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aWilliams, Julie1 aFrikke-Schmidt, Ruth1 aClarimon, Jordi1 aDeleuze, Jean-Francois1 aRossi, Giacomina1 aSeshadri, Sudha1 aAndreassen, Ole, A1 aIngelsson, Martin1 aHiltunen, Mikko1 aSleegers, Kristel1 aSchellenberg, Gerard, D1 aDuijn, Cornelia, M1 aSims, Rebecca1 avan der Flier, Wiesje, M1 aRuiz, Agustin1 aRamirez, Alfredo1 aLambert, Jean-Charles1 aEADB1 aGR@ACE1 aDEGESCO1 aEADI1 aGERAD1 aDemgene1 aFinnGen1 aADGC1 aCHARGE uhttps://chs-nhlbi.org/node/903502763nas a2200481 4500008004100000022001400041245012500055210006900180260001500249300000800264490000600272520128200278653003801560653003401598653001101632653002101643653003101664653003601695100002001731700002101751700002801772700002501800700002301825700001701848700001801865700002001883700001301903700001401916700001901930700002701949700002101976700002001997700002002017700002202037700002102059700002402080700002002104700001702124700001902141700001702160710006802177856003602245 2022 eng d a2399-364200aNon-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations.0 aNonlinear machine learning models incorporating SNPs and PRS imp c2022 08 22 a8560 v53 aPolygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22% for height, 27% for HDL cholesterol, 43% for body mass index, 50% for sleep duration, 58% for systolic blood pressure, 64% for total cholesterol, 66% for triglycerides, 77% for LDL cholesterol, and 100% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.
10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMachine Learning10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide1 aElgart, Michael1 aLyons, Genevieve1 aRomero-Brufau, Santiago1 aKurniansyah, Nuzulul1 aBrody, Jennifer, A1 aGuo, Xiuqing1 aLin, Henry, J1 aRaffield, Laura1 aGao, Yan1 aChen, Han1 ade Vries, Paul1 aLloyd-Jones, Donald, M1 aLange, Leslie, A1 aPeloso, Gina, M1 aFornage, Myriam1 aRotter, Jerome, I1 aRich, Stephen, S1 aMorrison, Alanna, C1 aPsaty, Bruce, M1 aLevy, Daniel1 aRedline, Susan1 aSofer, Tamar1 aNHLBI’s Trans-Omics in Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/916108881nas a2202605 4500008004100000022001400041245012200055210006900177260001500246300001000261490000800271520141300279653001201692653001801704653002501722653002601747653002301773653003001796653001001826653003801836653002201874653002501896653003401921653001101955653002101966653001101987653001001998653003402008653003102042653002402073653001402097653003602111100001802147700001902165700002102184700002002205700001802225700003202243700001702275700001702292700003102309700003002340700002102370700002102391700002302412700001602435700002802451700002902479700001802508700002102526700002402547700001902571700001902590700002102609700002502630700002102655700002202676700002102698700002302719700001902742700001902761700001902780700002702799700001702826700002002843700002102863700002002884700002002904700001902924700002902943700002402972700001902996700002503015700002203040700001703062700002203079700002303101700002403124700002803148700002203176700002403198700002103222700002003243700002003263700002303283700002103306700003103327700002803358700001803386700002203404700002203426700002103448700002303469700003903492700002203531700002103553700001803574700001903592700001703611700001903628700001503647700002003662700001903682700001403701700002603715700001703741700002103758700002503779700002603804700002003830700002003850700002403870700001803894700002103912700001903933700001703952700001703969700002003986700002504006700002404031700002204055700002004077700001904097700002104116700001504137700001704152700001804169700002104187700002404208700002104232700001704253700002004270700002204290700002304312700002004335700002804355700003604383700002304419700002504442700002004467700002004487700002204507700001904529700002604548700002304574700001504597700002104612700002204633700002004655700002904675700002404704700002004728700002104748700002204769700002604791700002504817700001904842700002304861700002604884700002104910700002104931700001904952700002104971700002404992700001905016700002005035700002005055700001405075700001405089700001905103700002505122700003105147700002105178700001905199700002405218700002305242700001705265700001905282700001705301700001605318700002105334700001805355700002305373700001905396700002205415700002005437700001905457700002005476700002105496700002105517700002205538700002305560700002405583700002105607700002005628700002705648700003005675700001905705700001605724700001805740700002105758700002105779700002105800700001905821700001905840700002205859700002105881700002205902700002105924700002205945700002305967700002305990700002306013700001906036700002006055710006106075710006506136710003806201856003606239 2022 eng d a1537-660500aRare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.0 aRare coding variants in 35 genes associate with circulating lipi c2022 01 06 a81-960 v1093 aLarge-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
10aAlleles10aBlood Glucose10aCase-Control Studies10aComputational Biology10aDatabases, Genetic10aDiabetes Mellitus, Type 210aExome10aGenetic Predisposition to Disease10aGenetic Variation10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aLipids10aLiver10aMolecular Sequence Annotation10aMultifactorial Inheritance10aOpen Reading Frames10aPhenotype10aPolymorphism, Single Nucleotide1 aHindy, George1 aDornbos, Peter1 aChaffin, Mark, D1 aLiu, Dajiang, J1 aWang, Minxian1 aSelvaraj, Margaret, Sunitha1 aZhang, David1 aPark, Joseph1 aAguilar-Salinas, Carlos, A1 aAntonacci-Fulton, Lucinda1 aArdissino, Diego1 aArnett, Donna, K1 aAslibekyan, Stella1 aAtzmon, Gil1 aBallantyne, Christie, M1 aBarajas-Olmos, Francisco1 aBarzilai, Nir1 aBecker, Lewis, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBottinger, Erwin1 aBowden, Donald, W1 aBown, Matthew, J1 aBrody, Jennifer, A1 aBroome, Jai, G1 aBurtt, Noel, P1 aCade, Brian, E1 aCenteno-Cruz, Federico1 aChan, Edmund1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aCheng, Ching-Yu1 aChoi, Won, Jung1 aChowdhury, Raj1 aContreras-Cubas, Cecilia1 aCórdova, Emilio, J1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDanesh, John1 ade Vries, Paul, S1 aDeFronzo, Ralph, A1 aDoddapaneni, Harsha1 aDuggirala, Ravindranath1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aFlorez, Jose, C1 aFornage, Myriam1 aFreedman, Barry, I1 aFuster, Valentin1 aGaray-Sevilla, Ma, Eugenia1 aGarcía-Ortiz, Humberto1 aGermer, Soren1 aGibbs, Richard, A1 aGieger, Christian1 aGlaser, Benjamin1 aGonzalez, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGraff, Mariaelisa1 aGraham, Sarah, E1 aGrarup, Niels1 aGroop, Leif, C1 aGuo, Xiuqing1 aGupta, Namrata1 aHan, Sohee1 aHanis, Craig, L1 aHansen, Torben1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aIrvin, Marguerite, R1 aIslas-Andrade, Sergio1 aJarvik, Gail, P1 aKang, Hyun, Min1 aKardia, Sharon, L R1 aKelly, Tanika1 aKenny, Eimear, E1 aKhan, Alyna, T1 aKim, Bong-Jo1 aKim, Ryan, W1 aKim, Young, Jin1 aKoistinen, Heikki, A1 aKooperberg, Charles1 aKuusisto, Johanna1 aKwak, Soo, Heon1 aLaakso, Markku1 aLange, Leslie, A1 aLee, Jiwon1 aLee, Juyoung1 aLee, Seonwook1 aLehman, Donna, M1 aLemaitre, Rozenn, N1 aLinneberg, Allan1 aLiu, Jianjun1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aLyssenko, Valeriya1 aMa, Ronald, C W1 aMartin, Lisa, Warsinger1 aMartínez-Hernández, Angélica1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMcPherson, Ruth1 aMeigs, James, B1 aMeitinger, Thomas1 aMelander, Olle1 aMendoza-Caamal, Elvia1 aMetcalf, Ginger, A1 aMi, Xuenan1 aMohlke, Karen, L1 aMontasser, May, E1 aMoon, Jee-Young1 aMoreno-Macias, Hortensia1 aMorrison, Alanna, C1 aMuzny, Donna, M1 aNelson, Sarah, C1 aNilsson, Peter, M1 aO'Connell, Jeffrey, R1 aOrho-Melander, Marju1 aOrozco, Lorena1 aPalmer, Colin, N A1 aPalmer, Nicholette, D1 aPark, Cheol, Joo1 aPark, Kyong, Soo1 aPedersen, Oluf1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPost, Wendy, S1 aPreuss, Michael1 aPsaty, Bruce, M1 aQi, Qibin1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRevilla-Monsalve, Cristina1 aRich, Stephen, S1 aSamani, Nilesh1 aSchunkert, Heribert1 aSchurmann, Claudia1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSim, Xueling1 aSladek, Rob1 aSmall, Kerrin, S1 aSo, Wing, Yee1 aStilp, Adrienne, M1 aTai, Shyong, E1 aTam, Claudia, H T1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aThameem, Farook1 aTomlinson, Brian1 aTsai, Michael, Y1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 avan Dam, Rob, M1 aVasan, Ramachandran, S1 aMartinez, Karine, A Viaud1 aWang, Fei, Fei1 aWang, Xuzhi1 aWatkins, Hugh1 aWeeks, Daniel, E1 aWilson, James, G1 aWitte, Daniel, R1 aWong, Tien-Yin1 aYanek, Lisa, R1 aKathiresan, Sekar1 aRader, Daniel, J1 aRotter, Jerome, I1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aFlannick, Jason, A1 aKhera, Amit, V1 aPeloso, Gina, M1 aAMP-T2D-GENES, Myocardial Infarction Genetics Consortium1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aNHLBI TOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/897504203nas a2200697 4500008004100000022001400041245011000055210006900165260000900234300001100243490000700254520220700261653001902468653002202487653003402509653001102543653001202554653002802566100001402594700002102608700002002629700002102649700002002670700001902690700001902709700002302728700002002751700001502771700002802786700002402814700002402838700001802862700002702880700002102907700002302928700001902951700002102970700002102991700001903012700001903031700002303050700002303073700001703096700002103113700002103134700002203155700002403177700002203201700001903223700002403242700001903266700002103285700002503306700002303331700002403354700002403378700002503402700002203427700002003449856003603469 2022 eng d a1664-239200aThe Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.0 aValue of Rare Genetic Variation in the Prediction of Common Obes c2022 a8638930 v133 aPolygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.
10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aHumans10aObesity10aWhole Genome Sequencing1 aWang, Zhe1 aChoi, Shing, Wan1 aChami, Nathalie1 aBoerwinkle, Eric1 aFornage, Myriam1 aRedline, Susan1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aKim, Wonji1 aMcDonald, Merry-Lynn, N1 aRegan, Elizabeth, A1 aSilverman, Edwin, K1 aLiu, Ching-Ti1 aVasan, Ramachandran, S1 aKalyani, Rita, R1 aMathias, Rasika, A1 aYanek, Lisa, R1 aArnett, Donna, K1 aJustice, Anne, E1 aNorth, Kari, E1 aKaplan, Robert1 aHeckbert, Susan, R1 ade Andrade, Mariza1 aGuo, Xiuqing1 aLange, Leslie, A1 aRich, Stephen, S1 aRotter, Jerome, I1 aEllinor, Patrick, T1 aLubitz, Steven, A1 aBlangero, John1 aShoemaker, Benjamin1 aDarbar, Dawood1 aGladwin, Mark, T1 aAlbert, Christine, M1 aChasman, Daniel, I1 aJackson, Rebecca, D1 aKooperberg, Charles1 aReiner, Alexander, P1 aO'Reilly, Paul, F1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/910903611nas a2200889 4500008004100000022001400041245012300055210006900178260001600247300000900263490000700272520111000279653001601389653003401405653001101439653002801450100002301478700002301501700001701524700002701541700001801568700001301586700002401599700002301623700001501646700001901661700002301680700001301703700002401716700002001740700001301760700001901773700002001792700002201812700001801834700002001852700001301872700001701885700001501902700002001917700001901937700001901956700001801975700002101993700001902014700002002033700002202053700002002075700002202095700002102117700002002138700002502158700002402183700002002207700002002227700002102247700002202268700001402290700002202304700002102326700002502347700002502372700002102397700002302418700002302441700002602464700002402490700001202514700002802526700002702554700002102581700002402602700002102626700001802647700002002665856003602685 2022 eng d a2041-172300aWhole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.0 aWhole genome sequencing identifies structural variants contribut c2022 Dec 08 a75920 v133 aGenome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
10aBlood Cells10aGenome-Wide Association Study10aHumans10aWhole Genome Sequencing1 aWheeler, Marsha, M1 aStilp, Adrienne, M1 aRao, Shuquan1 aHalldorsson, Bjarni, V1 aBeyter, Doruk1 aWen, Jia1 aMihkaylova, Anna, V1 aMcHugh, Caitlin, P1 aLane, John1 aJiang, Min-Zhi1 aRaffield, Laura, M1 aJun, Goo1 aSedlazeck, Fritz, J1 aMetcalf, Ginger1 aYao, Yao1 aBis, Joshua, B1 aChami, Nathalie1 ade Vries, Paul, S1 aDesai, Pinkal1 aFloyd, James, S1 aGao, Yan1 aKammers, Kai1 aKim, Wonji1 aMoon, Jee-Young1 aRatan, Aakrosh1 aYanek, Lisa, R1 aAlmasy, Laura1 aBecker, Lewis, C1 aBlangero, John1 aCho, Michael, H1 aCurran, Joanne, E1 aFornage, Myriam1 aKaplan, Robert, C1 aLewis, Joshua, P1 aLoos, Ruth, J F1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPreuss, Michael1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRotter, Jerome, I1 aTang, Hua1 aTracy, Russell, P1 aBoerwinkle, Eric1 aAbecasis, Goncalo, R1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aJohnson, Andrew, D1 aMathias, Rasika, A1 aNickerson, Deborah, A1 aConomos, Matthew, P1 aLi, Yun1 aÞorsteinsdottir, Unnur1 aMagnússon, Magnús, K1 aStefansson, Kari1 aPankratz, Nathan, D1 aBauer, Daniel, E1 aAuer, Paul, L1 aReiner, Alex, P uhttps://chs-nhlbi.org/node/926106073nas a2201597 4500008004100000022001400041245008800055210006900143260001300212300001200225490000800237520158400245653001201829653001201841653002501853653003401878653001801912653002901930653001101959653000901970653001301979653003001992100002502022700002802047700002902075700002202104700001902126700001902145700001702164700001802181700001702199700001302216700002202229700001902251700002602270700002602296700002302322700001902345700002002364700001702384700002202401700003102423700001902454700002302473700002602496700002102522700002102543700002402564700002002588700002102608700002002629700002002649700001602669700002702685700001902712700001902731700002002750700001902770700002302789700002402812700001802836700001602854700002602870700002302896700002202919700002002941700001902961700002702980700001903007700002103026700002403047700002403071700001403095700002203109700001503131700001903146700002303165700002303188700002203211700002103233700002503254700001903279700002303298700001903321700002203340700001903362700002303381700001303404700002303417700002203440700002103462700002203483700002303505700002103528700002303549700001803572700001903590700002203609700002103631700002803652700002203680700001903702700002203721700002003743700001703763700001403780700001603794700002203810700001803832700002303850700001803873700002403891700002403915700001903939700001803958700002203976700002403998700001504022700002104037700001804058700002304076700002304099700002504122700002504147700002104172700001804193700002504211700002304236700002204259700002104281700002504302700002304327700002404350710006504374856003604439 2023 eng d a1476-468700aAberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.0 aAberrant activation of TCL1A promotes stem cell expansion in clo c2023 Apr a755-7630 v6163 aMutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
10aAlleles10aAnimals10aClonal Hematopoiesis10aGenome-Wide Association Study10aHematopoiesis10aHematopoietic Stem Cells10aHumans10aMice10aMutation10aPromoter Regions, Genetic1 aWeinstock, Joshua, S1 aGopakumar, Jayakrishnan1 aBurugula, Bala, Bharathi1 aUddin, Md, Mesbah1 aJahn, Nikolaus1 aBelk, Julia, A1 aBouzid, Hind1 aDaniel, Bence1 aMiao, Zhuang1 aLy, Nghi1 aMack, Taralynn, M1 aLuna, Sofia, E1 aProthro, Katherine, P1 aMitchell, Shaneice, R1 aLaurie, Cecelia, A1 aBroome, Jai, G1 aTaylor, Kent, D1 aGuo, Xiuqing1 aSinner, Moritz, F1 avon Falkenhausen, Aenne, S1 aKääb, Stefan1 aShuldiner, Alan, R1 aO'Connell, Jeffrey, R1 aLewis, Joshua, P1 aBoerwinkle, Eric1 aBarnes, Kathleen, C1 aChami, Nathalie1 aKenny, Eimear, E1 aLoos, Ruth, J F1 aFornage, Myriam1 aHou, Lifang1 aLloyd-Jones, Donald, M1 aRedline, Susan1 aCade, Brian, E1 aPsaty, Bruce, M1 aBis, Joshua, C1 aBrody, Jennifer, A1 aSilverman, Edwin, K1 aYun, Jeong, H1 aQiao, Dandi1 aPalmer, Nicholette, D1 aFreedman, Barry, I1 aBowden, Donald, W1 aCho, Michael, H1 aDeMeo, Dawn, L1 aVasan, Ramachandran, S1 aYanek, Lisa, R1 aBecker, Lewis, C1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aHe, Jiang1 aRienstra, Michiel1 aHarst, Pim1 aKaplan, Robert1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aArnett, Donna, K1 aIrvin, Marguerite, R1 aTiwari, Hemant1 aCutler, Michael, J1 aKnight, Stacey1 aMuhlestein, Brent1 aCorrea, Adolfo1 aRaffield, Laura, M1 aGao, Yan1 ade Andrade, Mariza1 aRotter, Jerome, I1 aRich, Stephen, S1 aTracy, Russell, P1 aKonkle, Barbara, A1 aJohnsen, Jill, M1 aWheeler, Marsha, M1 aSmith, Gustav1 aMelander, Olle1 aNilsson, Peter, M1 aCuster, Brian, S1 aDuggirala, Ravindranath1 aCurran, Joanne, E1 aBlangero, John1 aMcGarvey, Stephen1 aWilliams, Keoki1 aXiao, Shujie1 aYang, Mao1 aGu, Charles1 aChen, Yii-Der Ida1 aLee, Wen-Jane1 aMarcus, Gregory, M1 aKane, John, P1 aPullinger, Clive, R1 aShoemaker, Benjamin1 aDarbar, Dawood1 aRoden, Dan, M1 aAlbert, Christine1 aKooperberg, Charles1 aZhou, Ying1 aManson, JoAnn, E1 aDesai, Pinkal1 aJohnson, Andrew, D1 aMathias, Rasika, A1 aBlackwell, Thomas, W1 aAbecasis, Goncalo, R1 aSmith, Albert, V1 aKang, Hyun, M1 aSatpathy, Ansuman, T1 aNatarajan, Pradeep1 aKitzman, Jacob, O1 aWhitsel, Eric, A1 aReiner, Alexander, P1 aBick, Alexander, G1 aJaiswal, Siddhartha1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/938703124nas a2200769 4500008004100000022001400041245010100055210006900156260001600225300000900241490000700250520097600257653001901233653001401252653001101266653003801277653003401315653001101349653000901360653003101369653002201400653001701422100002501439700002401464700001901488700002001507700002101527700001901548700002201567700002501589700001801614700001801632700001701650700001901667700001801686700002001704700001301724700001801737700002301755700002301778700001301801700001501814700003201829700002101861700001801882700002201900700001401922700001601936700002701952700002401979700002002003700002402023700001902047700002002066700002102086700002102107700002102128700002202149700001902171700002502190700002302215700001702238700002202255700002402277700001702301856003602318 2023 eng d a2041-172300aEvaluating the use of blood pressure polygenic risk scores across race/ethnic background groups.0 aEvaluating the use of blood pressure polygenic risk scores acros c2023 Jun 02 a32020 v143 aWe assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.
10aBlood Pressure10aEthnicity10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMultifactorial Inheritance10aPopulation Health10aRisk Factors1 aKurniansyah, Nuzulul1 aGoodman, Matthew, O1 aKhan, Alyna, T1 aWang, Jiongming1 aFeofanova, Elena1 aBis, Joshua, C1 aWiggins, Kerri, L1 aHuffman, Jennifer, E1 aKelly, Tanika1 aElfassy, Tali1 aGuo, Xiuqing1 aPalmas, Walter1 aLin, Henry, J1 aHwang, Shih-Jen1 aGao, Yan1 aYoung, Kendra1 aKinney, Gregory, L1 aSmith, Jennifer, A1 aYu, Bing1 aLiu, Simin1 aWassertheil-Smoller, Sylvia1 aManson, JoAnn, E1 aZhu, Xiaofeng1 aChen, Yii-Der Ida1 aLee, I-Te1 aGu, Charles1 aLloyd-Jones, Donald, M1 aZöllner, Sebastian1 aFornage, Myriam1 aKooperberg, Charles1 aCorrea, Adolfo1 aPsaty, Bruce, M1 aArnett, Donna, K1 aIsasi, Carmen, R1 aRich, Stephen, S1 aKaplan, Robert, C1 aRedline, Susan1 aMitchell, Braxton, D1 aFranceschini, Nora1 aLevy, Daniel1 aRotter, Jerome, I1 aMorrison, Alanna, C1 aSofer, Tamar uhttps://chs-nhlbi.org/node/937905138nas a2201357 4500008004100000022001400041245012700055210006900182260001600251300000900267490000700276520124600283653002501529653002701554653001501581653002801596653002401624653003401648653001101682653001701693100002201710700002201732700002601754700001901780700001301799700001801812700002201830700001901852700002001871700002901891700002701920700002401947700001801971700001601989700002202005700001302027700002102040700002002061700001902081700002602100700002402126700001902150700002702169700002002196700002602216700002202242700001902264700002302283700002102306700001902327700001902346700002102365700002702386700002402413700002702437700001502464700002302479700001702502700001902519700002302538700002402561700001702585700003202602700002102634700002502655700002402680700001702704700002302721700002602744700002502770700001802795700002102813700001402834700002402848700002402872700001802896700002902914700001902943700002502962700001802987700002103005700002103026700002203047700001903069700002203088700001703110700002103127700001803148700002203166700001903188700002903207700002803236700002503264700002003289700002203309700002903331700002203360700002303382700001503405700002303420700001803443700002103461700001903482700002203501700001803523700002403541700001803565700002103583700002403604700002203628700002003650700002203670700002803692700002403720856003603744 2023 eng d a2041-172300aGenetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.0 aGenetic architecture of spatial electrical biomarkers for cardia c2023 Mar 14 a14110 v143 aThe 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
10aArrhythmias, Cardiac10aAtrioventricular Block10aBiomarkers10aCardiovascular Diseases10aElectrocardiography10aGenome-Wide Association Study10aHumans10aRisk Factors1 aYoung, William, J1 aHaessler, Jeffrey1 aBenjamins, Jan-Walter1 aRepetto, Linda1 aYao, Jie1 aIsaacs, Aaron1 aHarper, Andrew, R1 aRamirez, Julia1 aGarnier, Sophie1 aVan Duijvenboden, Stefan1 aBaldassari, Antoine, R1 aConcas, Maria, Pina1 aDuong, ThuyVy1 aFoco, Luisa1 aIsaksen, Jonas, L1 aMei, Hao1 aNoordam, Raymond1 aNursyifa, Casia1 aRichmond, Anne1 aSantolalla, Meddly, L1 aSitlani, Colleen, M1 aSoroush, Negin1 aThériault, Sébastien1 aTrompet, Stella1 aAeschbacher, Stefanie1 aAhmadizar, Fariba1 aAlonso, Alvaro1 aBrody, Jennifer, A1 aCampbell, Archie1 aCorrea, Adolfo1 aDarbar, Dawood1 aDe Luca, Antonio1 aDeleuze, Jean-Francois1 aEllervik, Christina1 aFuchsberger, Christian1 aGoel, Anuj1 aGrace, Christopher1 aGuo, Xiuqing1 aHansen, Torben1 aHeckbert, Susan, R1 aJackson, Rebecca, D1 aKors, Jan, A1 aLima-Costa, Maria, Fernanda1 aLinneberg, Allan1 aMacfarlane, Peter, W1 aMorrison, Alanna, C1 aNavarro, Pau1 aPorteous, David, J1 aPramstaller, Peter, P1 aReiner, Alexander, P1 aRisch, Lorenz1 aSchotten, Ulrich1 aShen, Xia1 aSinagra, Gianfranco1 aSoliman, Elsayed, Z1 aStoll, Monika1 aTarazona-Santos, Eduardo1 aTinker, Andrew1 aTrajanoska, Katerina1 aVillard, Eric1 aWarren, Helen, R1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aArking, Dan, E1 aAvery, Christy, L1 aConen, David1 aGirotto, Giorgia1 aGrarup, Niels1 aHayward, Caroline1 aJukema, Wouter1 aMook-Kanamori, Dennis, O1 aOlesen, Morten, Salling1 aPadmanabhan, Sandosh1 aPsaty, Bruce, M1 aPattaro, Cristian1 aRibeiro, Antonio, Luiz P1 aRotter, Jerome, I1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aWilson, James, G1 aOrini, Michele1 aCharron, Philippe1 aWatkins, Hugh1 aKooperberg, Charles1 aLin, Henry, J1 aWilson, James, F1 aKanters, Jørgen, K1 aSotoodehnia, Nona1 aMifsud, Borbala1 aLambiase, Pier, D1 aTereshchenko, Larisa, G1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/932203311nas a2200829 4500008004100000022001400041245009300055210006900148260001300217300001400230490000700244520101000251653001701261653001801278653003401296653002301330653001101353653001401364653002301378100002501401700001501426700002001441700001701461700002001478700001701498700001801515700002101533700001901554700002101573700002301594700002101617700002301638700001701661700001701678700002401695700001501719700002301734700002001757700001701777700002401794700002101818700002001839700001701859700002601876700002201902700002301924700002501947700002601972700001601998700002102014700002402035700002302059700001702082700002302099700002702122700001902149700002102168700002202189700002402211700002302235700002002258700001902278700002002297700001502317700001202332700001802344700002302362700002502385700001702410700001802427856003602445 2023 eng d a1546-171800aMosaic chromosomal alterations in blood across ancestries using whole-genome sequencing.0 aMosaic chromosomal alterations in blood across ancestries using c2023 Nov a1912-19190 v553 aMegabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.
10aBlack People10aGenome, Human10aGenome-Wide Association Study10aHispanic or Latino10aHumans10aMosaicism10aPrecision Medicine1 aJakubek, Yasminka, A1 aZhou, Ying1 aStilp, Adrienne1 aBacon, Jason1 aWong, Justin, W1 aOzcan, Zuhal1 aArnett, Donna1 aBarnes, Kathleen1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aCarson, April, P1 aChasman, Daniel, I1 aChen, Jiawen1 aCho, Michael1 aConomos, Matthew, P1 aCox, Nancy1 aDoyle, Margaret, F1 aFornage, Myriam1 aGuo, Xiuqing1 aKardia, Sharon, L R1 aLewis, Joshua, P1 aLoos, Ruth, J F1 aMa, Xiaolong1 aMachiela, Mitchell, J1 aMack, Taralynn, M1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aMychaleckyj, Josyf, C1 aNorth, Kari1 aPankratz, Nathan1 aPeyser, Patricia, A1 aPreuss, Michael, H1 aPsaty, Bruce1 aRaffield, Laura, M1 aVasan, Ramachandran, S1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSilverman, Edwin, K1 aSmith, Jennifer, A1 aSmith, Aaron, P1 aTaub, Margaret1 aTaylor, Kent, D1 aYun, Jeong1 aLi, Yun1 aDesai, Pinkal1 aBick, Alexander, G1 aReiner, Alexander, P1 aScheet, Paul1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/953804817nas a2201309 4500008004100000022001400041245012100055210006900176260001300245300001200258490000700270520111100277653001201388653002301400653003801423653003401461653001101495653003601506653001601542653001801558100001501576700001801591700002201609700002001631700002501651700003001676700001501706700002101721700002501742700002801767700002101795700002801816700002401844700001701868700002101885700002401906700001901930700001901949700002901968700002301997700001902020700002102039700002102060700001902081700002202100700001902122700002602141700001702167700002802184700002102212700002402233700002002257700001702277700002102294700002202315700001402337700002002351700002202371700002002393700002002413700002002433700002502453700002102478700002102499700001902520700002402539700002102563700002102584700002202605700002402627700001402651700001702665700002002682700002402702700002002726700001702746700002502763700002102788700001802809700002202827700001702849700001902866700002602885700002102911700002402932700002002956700002202976700002302998700003403021700002103055700002203076700002303098700002403121700002103145700001603166700002303182700001403205700002003219700002203239700001903261700002103280700001903301700001903320700002103339700002203360700001403382700002103396700001603417700001803433700002003451856003603471 2023 eng d a1546-171800aMulti-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.0 aMultiancestry transcriptomewide association analyses yield insig c2023 Feb a291-3000 v553 aMost transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.
10aBiology10aDrug Repositioning10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aTobacco Use10aTranscriptome1 aChen, Fang1 aWang, Xingyan1 aJang, Seon-Kyeong1 aQuach, Bryan, C1 aWeissenkampen, Dylan1 aKhunsriraksakul, Chachrit1 aYang, Lina1 aSauteraud, Renan1 aAlbert, Christine, M1 aAllred, Nicholette, D D1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBarr, Graham1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoorgula, Meher, Preethi1 aChasman, Daniel, I1 aChavan, Sameer1 aChen, Yii-der, I1 aChuang, Lee-Ming1 aCorrea, Adolfo1 aCurran, Joanne, E1 aDavid, Sean, P1 aFuentes, Lisa, de Las1 aDeka, Ranjan1 aDuggirala, Ravindranath1 aFaul, Jessica, D1 aGarrett, Melanie, E1 aGharib, Sina, A1 aGuo, Xiuqing1 aHall, Michael, E1 aHawley, Nicola, L1 aHe, Jiang1 aHobbs, Brian, D1 aHokanson, John, E1 aHsiung, Chao, A1 aHwang, Shih-Jen1 aHyde, Thomas, M1 aIrvin, Marguerite, R1 aJaffe, Andrew, E1 aJohnson, Eric, O1 aKaplan, Robert1 aKardia, Sharon, L R1 aKaufman, Joel, D1 aKelly, Tanika, N1 aKleinman, Joel, E1 aKooperberg, Charles1 aLee, I-Te1 aLevy, Daniel1 aLutz, Sharon, M1 aManichaikul, Ani, W1 aMartin, Lisa, W1 aMarx, Olivia1 aMcGarvey, Stephen, T1 aMinster, Ryan, L1 aMoll, Matthew1 aMoussa, Karine, A1 aNaseri, Take1 aNorth, Kari, E1 aOelsner, Elizabeth, C1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRafaels, Nicholas1 aRaffield, Laura, M1 aReupena, Muagututi'a, Sefuiva1 aRich, Stephen, S1 aRotter, Jerome, I1 aSchwartz, David, A1 aShadyab, Aladdin, H1 aSheu, Wayne, H-H1 aSims, Mario1 aSmith, Jennifer, A1 aSun, Xiao1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aWatson, Harold1 aWeeks, Daniel, E1 aWeir, David, R1 aYanek, Lisa, R1 aYoung, Kendra, A1 aYoung, Kristin, L1 aZhao, Wei1 aHancock, Dana, B1 aJiang, Bibo1 aVrieze, Scott1 aLiu, Dajiang, J uhttps://chs-nhlbi.org/node/941203951nas a2200925 4500008004100000022001400041245013100055210006900186260001300255300001200268490000700280520122300287653002101510653003401531653001101565653001401576653002801590100001401618700001801632700001701650700002201667700001501689700001401704700003201718700001401750700001601764700002101780700002401801700001901825700001901844700002101863700002201884700002301906700001901929700001901948700002501967700002201992700002202014700002802036700002302064700002502087700001702112700002202129700002102151700002402172700001902196700002102215700002102236700002002257700002502277700002502302700002202327700002402349700001702373700002602390700002602416700002402442700002002466700002302486700001902509700002502528700003402553700002102587700002102608700002402629700002302653700002002676700002702696700002302723700002102746700001902767700001402786700002202800700002302822700002002845700001402865700001602879710009402895856003602989 2023 eng d a1546-171800aPowerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.0 aPowerful scalable and resourceefficient metaanalysis of rare var c2023 Jan a154-1640 v553 aMeta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.
10aExome Sequencing10aGenome-Wide Association Study10aLipids10aPhenotype10aWhole Genome Sequencing1 aLi, Xihao1 aQuick, Corbin1 aZhou, Hufeng1 aGaynor, Sheila, M1 aLiu, Yaowu1 aChen, Han1 aSelvaraj, Margaret, Sunitha1 aSun, Ryan1 aDey, Rounak1 aArnett, Donna, K1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 ade Vries, Paul, S1 aDuggirala, Ravindranath1 aFreedman, Barry, I1 aGöring, Harald, H H1 aGuo, Xiuqing1 aHaessler, Jeffrey1 aKalyani, Rita, R1 aKooperberg, Charles1 aKral, Brian, G1 aLange, Leslie, A1 aManichaikul, Ani1 aMartin, Lisa, W1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRedline, Susan1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aRice, Kenneth, M1 aRich, Stephen, S1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aWiller, Cristen, J1 aWilson, James, G1 aYanek, Lisa, R1 aZhao, Wei1 aRotter, Jerome, I1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aLi, Zilin1 aLin, Xihong1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/923902589nas a2200457 4500008004100000022001400041245008600055210006900141260001600210300000900226490000700235520126900242653001401511653003401525653001101559653001501570653003601585653002801621100002401649700002201673700001701695700002201712700001401734700002001748700001401768700002101782700002101803700001401824700001401838700002201852700002401874700002401898700002101922700001801943700002501961700002001986700002202006700001302028710005402041856003602095 2023 eng d a2041-172300aWhole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations.0 aWholeGenome Sequencing Analysis of Human Metabolome in MultiEthn c2023 May 30 a31110 v143 aCirculating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.
10aEthnicity10aGenome-Wide Association Study10aHumans10aMetabolome10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aFeofanova, Elena, V1 aBrown, Michael, R1 aAlkis, Taryn1 aManuel, Astrid, M1 aLi, Xihao1 aTahir, Usman, A1 aLi, Zilin1 aMendez, Kevin, M1 aKelly, Rachel, S1 aQi, Qibin1 aChen, Han1 aLarson, Martin, G1 aLemaitre, Rozenn, N1 aMorrison, Alanna, C1 aGrieser, Charles1 aWong, Kari, E1 aGersztern, Robert, E1 aZhao, Zhongming1 aLasky-Su, Jessica1 aYu, Bing1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) uhttps://chs-nhlbi.org/node/937604874nas a2201033 4500008004100000022001400041245014100055210006900196260001600265300000700281490000700288520197200295653000902267653001402276653003402290653001102324653001102335653001402346653001502360653003602375100001302411700002202424700001502446700001502461700001902476700001702495700001602512700001702528700002402545700001602569700001602585700002302601700001702624700002102641700002502662700002102687700001802708700002302726700002202749700002702771700002002798700002002818700001402838700002602852700001902878700002302897700002202920700001802942700002302960700002102983700001803004700002203022700001903044700001903063700002703082700002603109700002203135700001603157700001903173700002403192700002203216700002503238700002203263700001903285700002303304700001803327700002003345700002103365700002303386700002403409700002603433700002303459700002203482700002103504700002303525700002403548700001903572700002203591700002003613700001803633700002303651700001903674700002803693700002003721700001803741700002303759700002203782856003603804 2024 eng d a1758-919300aMulti-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.0 aMultiomics and pathway analyses of genomewide associations impli c2024 Jan 20 a140 v163 aBACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.
METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.
RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.
CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.
10aAged10aCognition10aGenome-Wide Association Study10aHumans10aMemory10aMicroRNAs10aMultiomics10aPolymorphism, Single Nucleotide1 aMei, Hao1 aSimino, Jeannette1 aLi, Lianna1 aJiang, Fan1 aBis, Joshua, C1 aDavies, Gail1 aHill, David1 aXia, Charley1 aGudnason, Vilmundur1 aYang, Qiong1 aLahti, Jari1 aSmith, Jennifer, A1 aKirin, Mirna1 aDe Jager, Philip1 aArmstrong, Nicola, J1 aGhanbari, Mohsen1 aKolcic, Ivana1 aMoran, Christopher1 aTeumer, Alexander1 aSargurupremraj, Murali1 aMahmud, Shamsed1 aFornage, Myriam1 aZhao, Wei1 aSatizabal, Claudia, L1 aPolasek, Ozren1 aRäikkönen, Katri1 aLiewald, David, C1 aHomuth, Georg1 aCallisaya, Michele1 aMather, Karen, A1 aWindham, Gwen1 aZemunik, Tatijana1 aPalotie, Aarno1 aPattie, Alison1 avan der Auwera, Sandra1 aThalamuthu, Anbupalam1 aKnopman, David, S1 aRudan, Igor1 aStarr, John, M1 aWittfeld, Katharina1 aKochan, Nicole, A1 aGriswold, Michael, E1 aVitart, Veronique1 aBrodaty, Henry1 aGottesman, Rebecca1 aCox, Simon, R1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aChasman, Daniel, I1 aGrodstein, Francine1 aSachdev, Perminder, S1 aSrikanth, Velandai1 aHayward, Caroline1 aWilson, James, F1 aEriksson, Johan, G1 aKardia, Sharon, L R1 aGrabe, Hans, J1 aBennett, David, A1 aIkram, Arfan, M1 aDeary, Ian, J1 aDuijn, Cornelia, M1 aLauner, Lenore1 aFitzpatrick, Annette, L1 aSeshadri, Sudha1 aBressler, Jan1 aDebette, Stephanie1 aMosley, Thomas, H uhttps://chs-nhlbi.org/node/957807235nas a2202173 4500008004100000022001400041245020700055210006900262260001600331300000800347490000700355520114400362653001401506653002601520653001101546653003801557653003401595653001101629653001101640653000901651653003601660653002201696653001701718100001901735700001701754700001601771700002101787700002401808700001601832700002001848700001301868700002101881700002001902700001901922700001201941700001801953700001901971700002401990700001502014700001902029700002002048700002602068700001802094700001902112700002002131700002102151700001802172700002102190700001702211700002102228700002002249700001902269700002302288700002102311700001902332700001302351700002002364700002002384700002102404700002202425700002202447700002102469700002202490700002102512700001602533700002302549700002102572700002802593700001802621700001702639700002602656700002202682700001802704700002502722700002102747700001602768700002602784700002002810700002102830700001902851700002002870700002302890700002002913700002102933700002302954700001902977700002202996700001903018700001803037700002603055700001803081700002503099700002103124700002003145700002103165700001903186700002203205700001703227700002003244700001703264700002103281700002803302700002703330700002403357700002003381700002103401700002503422700001803447700002503465700002903490700002603519700002003545700002003565700001703585700001903602700002103621700002003642700002303662700002903685700002703714700001903741700002003760700001903780700002303799700001903822700002003841700002103861700002303882700002303905700002103928700002203949700002103971700001903992700002004011700002204031700001604053700002804069700002004097700002304117700002004140700001604160700002004176700002004196700002104216700002004237700002204257700001904279700002704298700002104325700001804346700002004364700002204384700001804406700002004424700002004444700002104464700002304485700002204508700001804530700002704548700002204575700001704597700001904614700001904633700001704652700002304669700001904692700002104711700002304732700001904755700001904774700001704793700001904810700002104829700002804850700002104878700002204899700002304921700001804944700001904962700002204981700002205003856003605025 2024 eng d a2041-172300aX-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.0 aXchromosome and kidney function evidence from a multitrait genet c2024 Jan 18 a5860 v153 aX-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
10aAndrogens10aChromosomes, Human, X10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aKidney10aMale10aPolymorphism, Single Nucleotide10aResponse Elements10aTetraspanins1 aScholz, Markus1 aHorn, Katrin1 aPott, Janne1 aWuttke, Matthias1 aKühnapfel, Andreas1 aNasr, Kamal1 aKirsten, Holger1 aLi, Yong1 aHoppmann, Anselm1 aGorski, Mathias1 aGhasemi, Sahar1 aLi, Man1 aTin, Adrienne1 aChai, Jin-Fang1 aCocca, Massimiliano1 aWang, Judy1 aNutile, Teresa1 aAkiyama, Masato1 aÅsvold, Bjørn, Olav1 aBansal, Nisha1 aBiggs, Mary, L1 aBoutin, Thibaud1 aBrenner, Hermann1 aBrumpton, Ben1 aBurkhardt, Ralph1 aCai, Jianwen1 aCampbell, Archie1 aCampbell, Harry1 aChalmers, John1 aChasman, Daniel, I1 aChee, Miao, Ling1 aChee, Miao, Li1 aChen, Xu1 aCheng, Ching-Yu1 aCifkova, Renata1 aDaviglus, Martha1 aDelgado, Graciela1 aDittrich, Katalin1 aEdwards, Todd, L1 aEndlich, Karlhans1 aGaziano, Michael1 aGiri, Ayush1 aGiulianini, Franco1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aHallan, Stein1 aHamet, Pavel1 aHartman, Catharina, A1 aHayward, Caroline1 aHeid, Iris, M1 aHellwege, Jacklyn, N1 aHolleczek, Bernd1 aHolm, Hilma1 aHutri-Kähönen, Nina1 aHveem, Kristian1 aIsermann, Berend1 aJonas, Jost, B1 aJoshi, Peter, K1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKastarinen, Mika1 aKhor, Chiea, Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKörner, Antje1 aKovacs, Peter1 aKrajcoviechova, Alena1 aKramer, Holly1 aKrämer, Bernhard, K1 aKuokkanen, Mikko1 aKähönen, Mika1 aLange, Leslie, A1 aLash, James, P1 aLehtimäki, Terho1 aLi, Hengtong1 aLin, Bridget, M1 aLiu, Jianjun1 aLoeffler, Markus1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMartin, Nicholas, G1 aMatsuda, Koichi1 aMilaneschi, Yuri1 aMishra, Pashupati, P1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMychaleckyj, Josyf, C1 aMärz, Winfried1 aNauck, Matthias1 aNikus, Kjell1 aNolte, Ilja, M1 aNoordam, Raymond1 aOkada, Yukinori1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPirastu, Nicola1 aPolasek, Ozren1 aPorteous, David, J1 aPoulain, Tanja1 aPsaty, Bruce, M1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRasheed, Humaira1 aReilly, Dermot, F1 aRice, Kenneth, M1 aRichmond, Anne1 aRidker, Paul, M1 aRotter, Jerome, I1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSchneiderman, Neil1 aSchöttker, Ben1 aSims, Mario1 aSnieder, Harold1 aStark, Klaus, J1 aStefansson, Kari1 aStocker, Hannah1 aStumvoll, Michael1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSvensson, Per, O1 aTai, E-Shyong1 aTaylor, Kent, D1 aTayo, Bamidele, O1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomas, Laurent, F1 aTremblay, Johanne1 aTönjes, Anke1 avan der Most, Peter, J1 aVitart, Veronique1 aVölker, Uwe1 aWang, Ya, Xing1 aWang, Chaolong1 aBin Wei, Wen1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWinkler, Thomas, W1 aWong, Tien-Yin1 aWoodward, Mark1 aSim, Xueling1 aChu, Audrey, Y1 aFeitosa, Mary, F1 aThorsteinsdottir, Unnur1 aHung, Adriana, M1 aTeumer, Alexander1 aFranceschini, Nora1 aParsa, Afshin1 aKöttgen, Anna1 aSchlosser, Pascal1 aPattaro, Cristian uhttps://chs-nhlbi.org/node/9579