02839nas a2200469 4500008004100000022001400041245014000055210006900195260001300264300001000277490000700287520146600294653002201760653001601782653000901798653002201807653002201829653001401851653001901865653002501884653002301909653003001932653004001962653001102002653001302013653001102026653002502037653000902062653002902071653003202100653002402132653001702156653001602173100001702189700002802206700002002234700002102254700001602275700002002291700002202311856003602333 2008 eng d a0003-994200aEnhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study.0 aEnhanced risk for Alzheimer disease in persons with type 2 diabe c2008 Jan a89-930 v653 a
BACKGROUND: Diabetes and the apolipoprotein E epsilon4 allele (APOE epsilon4) increase the risk for Alzheimer disease (AD). We hypothesize that APOE epsilon4 may modify the risk for AD in individuals with diabetes.
OBJECTIVE: To examine the joint effect of type 2 diabetes and APOE epsilon4 on the risk of AD, AD with vascular dementia (mixed AD), and vascular dementia without AD.
DESIGN: The Cardiovascular Health Study (CHS) Cognition Study (1992-2000) is a prospective study designed to identify all existing and new cases of dementia among study participants. Diagnoses were made according to international criteria for dementia and subtypes. There were 2547 dementia-free participants in the CHS Cognition Study cohort with complete information on APOE epsilon4 and type 2 diabetes status; among these, 411 new cases of dementia developed. Risk of dementia was estimated with a Cox proportional hazard model adjusted for age and other demographic and cardiovascular risk factors.
RESULTS: Compared with those who had neither type 2 diabetes nor APOE epsilon4, those with both factors had a significantly higher risk of AD (hazard ratio, 4.58; 95% confidence interval, 2.18-9.65) and mixed AD (hazard ratio, 3.89; 95% confidence interval, 1.46-10.40).
CONCLUSION: These data suggest that having both diabetes and APOE epsilon4 increases the risk of dementia, especially for AD and mixed AD.
10aAfrican Americans10aAge Factors10aAged10aAlzheimer Disease10aApolipoprotein E410aCognition10aCohort Studies10aConfidence Intervals10aDementia, Vascular10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGenotype10aHumans10aLongitudinal Studies10aMale10aNeuropsychological Tests10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSex Factors1 aIrie, Fumiko1 aFitzpatrick, Annette, L1 aLopez, Oscar, L1 aKuller, Lewis, H1 aPeila, Rita1 aNewman, Anne, B1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/100904313nas 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/109803209nas 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 4500008004100000022001400041245010000055210006900155260001300224300001100237490000700248520080700255653001601062653002001078653001401098653001601112653002301128653004001151653003801191653003401229653001101263653001201274653003601286100002801322700002301350700002101373700001901394700002501413700002101438700002301459700002501482700001801507700001801525700002301543700002201566700002301588700001101611700003101622700001801653700003201671700002601703700002301729700002101752700002001773700002101793700002201814700002301836700001901859700001801878700001801896700001801914700002301932700002801955700001501983700002501998700001602023700002102039700002102060700002102081700002502102700001902127700002602146700001602172700001902188700001902207700002102226700001602247700001902263700001602282700002202298700002402320700002602344700001902370700002402389700001902413700001802432700002002450700002002470700001602490700002302506700002202529700001902551700002102570700002502591700002002616700002002636700002602656700002202682700002002704700002502724700002302749700002602772700002502798700002202823700002102845700002602866700002302892700002302915700002302938700002402961700002002985700002103005700001703026700002403043700002003067700002603087700001903113700002103132700001903153700002103172700002103193700002603214700002303240700002103263700002403284700001903308700002203327700003003349700001603379700002503395700002503420700002103445700002403466700002003490700002003510700002803530700003503558700002203593700001903615700002103634700001903655700001803674700001803692700001803710700002403728700001603752700001803768700001803786700002003804700002403824700002203848700002303870700002603893700002203919700003003941700002103971700002003992700002304012700001204035700001804047700002104065700001904086700002204105700002304127700001504150700002204165700002104187700002304208700002804231700002704259700002404286700002204310700002804332700002204360700002204382700002204404700002204426700002104448700002804469700002104497700001704518700001904535700001804554700001604572700001604588700002204604700001504626700002104641700001904662700002204681700001704703700002304720700002204743700001604765700002104781700001904802700001904821700002204840700002304862700002004885700002304905700001804928700002004946700002004966700001804986700002205004700001705026700002005043700002005063700002205083700002005105700002205125700002105147700002205168700002205190700001705212700002305229700002305252700002105275700002005296700001905316700001705335700001805352700002405370700002205394700001905416700002205435700002205457700001905479700001705498700002405515700002505539700002105564700002205585700001905607700002005626700001605646700002105662700002005683700003005703700002305733700001605756700001605772700002105788700002005809700001905829700001905848700002705867700002205894700001905916700001805935700002005953700002005973700002105993700002606014700001906040700001906059700002306078700001806101700002006119700002106139700002506160700001806185700002006203700002606223700002006249700001906269700002206288700002406310700002006334700001906354700002406373700001706397700002006414700001606434700002306450700001706473700001806490700002406508700002406532700002406556700002406580700002206604700001906626700001806645700002206663700002606685700002406711700001906735700001906754700002706773700002206800700002206822700002406844700002206868700002506890700002206915700002106937700002106958700001906979700002306998700002107021700002807042700001707070700001907087700001607106700002107122700001907143700002007162700001907182700002407201700002307225700001907248700002007267700002507287700002107312700002407333700001907357700002007376700002007396700002207416700002507438700001907463700002107482700002307503700002307526700002407549700002407573700002507597700002407622700002207646700002207668700002207690700002007712700001407732700001907746700002207765700002607787700002207813700002207835700001707857700002007874700001807894700002707912700001907939700001907958700001807977700002707995700001708022700001908039700002208058700002108080700002408101700002408125700001908149700002308168700002008191700002608211700002408237700002008261700001908281700001608300700002208316700002408338700002308362700002408385700002308409700001708432700002408449700001908473700002108492700002008513700002508533700001808558700002108576700002008597700002508617700002508642700002508667700001908692700002008711700002308731700002908754700002308783700002008806700002108826700001908847700002308866700002108889700002208910700002108932700002608953700002008979700002408999700002309023700002309046700002209069700002509091700002809116700002509144700001909169700002109188700002109209700001909230700002209249700002409271700002009295700002009315710001009335710002509345856003609370 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/123709616nas 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/122104063nas 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/117005209nas 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/124305807nas 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/121704951nas 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/115604048nas 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/115912698nas 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/123411930nas 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/117906326nas 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/118303858nas a2200685 4500008004100000022001400041245008900055210006900144260001600213300001200229490000800241520195200249653003902201653001602240653000902256653002202265653001502287653002402302653001902326653002002345653001902365653002402384653001102408653004002419653001102459653002202470653001802492653001102510653001702521653001402538653002602552653000902578653001602587653003202603653001702635653001602652653001202668653001802680100002402698700001902722700001202741700002202753700002402775700002202799700002402821700002502845700001702870700002302887700002002910700002402930700002002954700002202974700002202996700002703018700002003045700002403065700002403089700002303113856003603136 2010 eng d a1538-367900aValidation of an atrial fibrillation risk algorithm in whites and African Americans.0 aValidation of an atrial fibrillation risk algorithm in whites an c2010 Nov 22 a1909-170 v1703 aBACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.
METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.
RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.
CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.
10aAfrican Continental Ancestry Group10aAge Factors10aAged10aAged, 80 and over10aAlgorithms10aAtrial Fibrillation10aBlood Pressure10aBody Mass Index10aCohort Studies10aElectrocardiography10aEurope10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aHeart Failure10aHumans10aHypertension10aIncidence10aKaplan-Meier Estimate10aMale10aMiddle Aged10aProportional Hazards Models10aRisk Factors10aSex Factors10aSystole10aUnited States1 aSchnabel, Renate, B1 aAspelund, Thor1 aLi, Guo1 aSullivan, Lisa, M1 aSuchy-Dicey, Astrid1 aHarris, Tamara, B1 aPencina, Michael, J1 aD'Agostino, Ralph, B1 aLevy, Daniel1 aKannel, William, B1 aWang, Thomas, J1 aKronmal, Richard, A1 aWolf, Philip, A1 aBurke, Gregory, L1 aLauner, Lenore, J1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aHeckbert, Susan, R uhttps://chs-nhlbi.org/node/124703513nas a2200541 4500008004100000022001400041245011000055210006900165260001300234300001100247490000700258520187400265653001202139653002002151653002802171653001902199653001102218653003802229653001302267653001102280653001702291653000902308653002102317653003602338653003402374100002302408700002902431700002302460700002002483700001802503700001602521700001802537700002602555700002202581700002402603700002202627700002602649700002002675700002002695700002302715700002002738700002402758700001702782710007602799710002802875710003202903856003602935 2011 eng d a1524-456300aAssociation of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals.0 aAssociation of hypertension drug target genes with blood pressur c2011 May a903-100 v573 aWe previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29,136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34,433) and the Women's Genome Health Study (n=23,019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10(-10)), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10(-10)), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10(-4)). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10(-6)), as well as diastolic blood pressure (P=5.0×10(-8)) and hypertension (P=3.7×10(-7)). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10(-5)). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.
10aAlleles10aAngiotensinogen10aAntihypertensive Agents10aBlood Pressure10aFemale10aGenetic Predisposition to Disease10aGenotype10aHumans10aHypertension10aMale10aPharmacogenetics10aPolymorphism, Single Nucleotide10aReceptors, Adrenergic, beta-11 aJohnson, Andrew, D1 aNewton-Cheh, Christopher1 aChasman, Daniel, I1 aEhret, Georg, B1 aJohnson, Toby1 aRose, Lynda1 aRice, Kenneth1 aVerwoert, Germaine, C1 aLauner, Lenore, J1 aGudnason, Vilmundur1 aLarson, Martin, G1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aCaulfield, Mark1 aDuijn, Cornelia, M1 aRidker, Paul, M1 aMunroe, Patricia, B1 aLevy, Daniel1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium1 aGlobal BPgen Consortium1 aWomen's Genome Health Study uhttps://chs-nhlbi.org/node/128205938nas a2201621 4500008004100000022001400041245004200055210004100097260001300138300001100151490000700162520145500169653003901624653001601663653004001679653001701719653003801736653001101774653002301785653002801808100002301836700002001859700001801879700002001897700001901917700002001936700002701956700002601983700002202009700002202031700001802053700002202071700001202093700002602105700002002131700002302151700002102174700001802195700001902213700002002232700002202252700001802274700001502292700002102307700001702328700002302345700002202368700002302390700001802413700001902431700002002450700002402470700002202494700002202516700002302538700002502561700001902586700002302605700002102628700002002649700002002669700002102689700002502710700001902735700002402754700002002778700002202798700002302820700001902843700002402862700002002886700002002906700002102926700002302947700002002970700002002990700001703010700002303027700002703050700002203077700001903099700001903118700002803137700001803165700001803183700002103201700002503222700002103247700002603268700002103294700002503315700002203340700002403362700002003386700002203406700002103428700001903449700002003468700001903488700002203507700001803529700002003547700002203567700002403589700002403613700002403637700001703661700001903678700001703697700002403714700002103738700001603759700001903775700001803794700001803812700001803830700002003848700001803868700002403886700002103910700002603931700002203957700002503979700002004004700002204024700002604046700002504072700002504097700001604122700001804138700001904156700002504175700002104200700002104221700001604242710002204258856003604280 2011 eng d a1533-345000aCUBN is a gene locus for albuminuria.0 aCUBN is a gene locus for albuminuria c2011 Mar a555-700 v223 aIdentification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
10aAfrican Continental Ancestry Group10aAlbuminuria10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aHumans10aMutation, Missense10aReceptors, Cell Surface1 aBöger, Carsten, A1 aChen, Ming-Huei1 aTin, Adrienne1 aOlden, Matthias1 aKöttgen, Anna1 ade Boer, Ian, H1 aFuchsberger, Christian1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 aTeumer, Alexander1 aLiu, Ching-Ti1 aGlazer, Nicole, L1 aLi, Man1 aO'Connell, Jeffrey, R1 aTanaka, Toshiko1 aPeralta, Carmen, A1 aKutalik, Zoltán1 aLuan, Jian'an1 aZhao, Jing Hua1 aHwang, Shih-Jen1 aAkylbekova, Ermeg1 aKramer, Holly1 aHarst, Pim1 aSmith, Albert, V1 aLohman, Kurt1 ade Andrade, Mariza1 aHayward, Caroline1 aKollerits, Barbara1 aTönjes, Anke1 aAspelund, Thor1 aIngelsson, Erik1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aShuldiner, Alan, R1 aMitchell, Braxton, D1 aArking, Dan, E1 aFranceschini, Nora1 aBoerwinkle, Eric1 aEgan, Josephine1 aHernandez, Dena1 aReilly, Muredach1 aTownsend, Raymond, R1 aLumley, Thomas1 aSiscovick, David, S1 aPsaty, Bruce, M1 aKestenbaum, Bryan1 aHaritunians, Talin1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aMooser, Vincent1 aWaterworth, Dawn1 aJohnson, Andrew, D1 aFlorez, Jose, C1 aMeigs, James, B1 aLu, Xiaoning1 aTurner, Stephen, T1 aAtkinson, Elizabeth, J1 aLeak, Tennille, S1 aAasarød, Knut1 aSkorpen, Frank1 aSyvänen, Ann-Christine1 aIllig, Thomas1 aBaumert, Jens1 aKoenig, Wolfgang1 aKrämer, Bernhard, K1 aDevuyst, Olivier1 aMychaleckyj, Josyf, C1 aMinelli, Cosetta1 aBakker, Stephan, J L1 aKedenko, Lyudmyla1 aPaulweber, Bernhard1 aCoassin, Stefan1 aEndlich, Karlhans1 aKroemer, Heyo, K1 aBiffar, Reiner1 aStracke, Sylvia1 aVölzke, Henry1 aStumvoll, Michael1 aMägi, Reedik1 aCampbell, Harry1 aVitart, Veronique1 aHastie, Nicholas, D1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPolasek, Ozren1 aCurhan, Gary1 aKronenberg, Florian1 aProkopenko, Inga1 aRudan, Igor1 aArnlöv, Johan1 aHallan, Stein1 aNavis, Gerjan1 aParsa, Afshin1 aFerrucci, Luigi1 aCoresh, Josef1 aShlipak, Michael, G1 aBull, Shelley, B1 aPaterson, Nicholas, J1 aWichmann, H-Erich1 aWareham, Nicholas, J1 aLoos, Ruth, J F1 aRotter, Jerome, I1 aPramstaller, Peter, P1 aCupples, Adrienne, L1 aBeckmann, Jacques, S1 aYang, Qiong1 aHeid, Iris, M1 aRettig, Rainer1 aDreisbach, Albert, W1 aBochud, Murielle1 aFox, Caroline, S1 aKao, W, H L1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/127104780nas a2200553 4500008004100000022001400041245014300055210006900198260001300267300001200280490000800292520317000300653000903470653002203479653001203501653001003513653003503523653001003558653001103568653002203579653003203601653001303633653001103646653001703657653003103674653000903705653001603714653001403730653003003744653002403774653002103798653002103819100002003840700002103860700001903881700002403900700002003924700002603944700001803970700002403988700002004012700002304032700002204055700002304077700002204100700002204122710004604144856003604190 2011 eng d a1460-215600aGenetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.0 aGenetic variants of the NOTCH3 gene in the elderly and magnetic c2011 Nov a3384-970 v1343 aCerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.
10aAged10aAged, 80 and over10aAlleles10aBrain10aCerebral Small Vessel Diseases10aExons10aFemale10aFollow-Up Studies10aGenetic Association Studies10aGenotype10aHumans10aHypertension10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPhenotype10aPromoter Regions, Genetic10aProspective Studies10aReceptor, Notch310aReceptors, Notch1 aSchmidt, Helena1 aZeginigg, Marion1 aWiltgen, Marco1 aFreudenberger, Paul1 aPetrovic, Katja1 aCavalieri, Margherita1 aGider, Pierre1 aEnzinger, Christian1 aFornage, Myriam1 aDebette, Stephanie1 aRotter, Jerome, I1 aIkram, Mohammad, A1 aLauner, Lenore, J1 aSchmidt, Reinhold1 aCHARGE consortium Neurology working group uhttps://chs-nhlbi.org/node/134307169nas 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/129803421nas 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/130705459nas 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/126707422nas 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/609205536nas 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/608807748nas a2202497 4500008004100000022001400041245011400055210006900169260001600238300001000254490000700264520075000271653001601021653001801037653002501055653001601080653001501096653002301111653003201134653004001166653002601206653001101232653001701243653003401260653001101294653001301305653001401318653003601332653001301368100001901381700002101400700002301421700001601444700002101460700001901481700001901500700001701519700001901536700001901555700001601574700002301590700002801613700002401641700001701665700002401682700002001706700001801726700002101744700002601765700001801791700001901809700001801828700002501846700001901871700002501890700002501915700002501940700001801965700002101983700002402004700001802028700002002046700002402066700002002090700002502110700001802135700002402153700001702177700001702194700001802211700001902229700001802248700002702266700002502293700001802318700002402336700002002360700002302380700002402403700001902427700002002446700002002466700002102486700002302507700002102530700002202551700001902573700002602592700001402618700001902632700002402651700001602675700002202691700002102713700001902734700002002753700002602773700002302799700001902822700002402841700001802865700002102883700001802904700002102922700001602943700001602959700001702975700002102992700002203013700001703035700002003052700002303072700002703095700001903122700002403141700003003165700002303195700002203218700002203240700001803262700002003280700001703300700002003317700002003337700003103357700001903388700002103407700002003428700002303448700002403471700002003495700002103515700001903536700002103555700002003576700002303596700001903619700002203638700001603660700001703676700002103693700002003714700002203734700002303756700002003779700002003799700002103819700001903840700002703859700002303886700002103909700002603930700001603956700001903972700002103991700002104012700002604033700001404059700001804073700002004091700002204111700002304133700002204156700002404178700002304202700002204225700002004247700002504267700002304292700002104315700003404336700002304370700002104393700003004414700002004444700003104464700002204495700001604517700002504533700001904558700002104577700002304598700002104621700002004642700002304662700002404685700002204709700001704731700002104748700002204769700002104791700002504812700001904837700002004856700001804876700002404894700002004918700002104938700002704959700002804986700001705014700002805031700002305059700001905082700001705101700002405118700002105142700002405163710002705187856003605214 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 4500008004100000022001400041245008200055210006900137260001600206300001000222490000700232520088500239653001501124653001001139653000901149653002201158653003701180653002401217653001001241653002101251653004001272653001101312653001701323653003801340653003401378653001101412653001101423653002001434653000901454653001601463653003601479653001701515653001601532100002401548700002401572700002501596700002201621700002401643700002101667700001901688700003001707700002201737700002201759700001901781700001901800700001801819700001901837700002201856700001801878700001801896700002201914700001701936700002001953700002301973700002301996700002202019700002102041700002602062700002202088700001702110700002202127700002202149700002302171700002202194700002202216700002302238700002202261700001902283700001702302700001902319700002002338700001902358700002102377700001702398700002402415700002402439700001202463700002602475700001902501700002002520700001902540700002002559700001702579700002302596700002302619700002202642700001402664700002202678700001702700700002102717700001802738700001902756700002002775700002102795700002102816700002002837700002202857700002002879700002202899700003002921700002002951700002202971700001802993700002803011700002603039700002203065700002203087700002003109700001703129700002303146700001903169700002203188700002603210700002203236700001903258700001903277700001803296700002303314700002303337700002403360700002403384700001903408856003603427 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/138321848nas a2207177 4500008004100000022001400041245015100055210006900206260000900275300001300284490000600297520178200303653001602085653002202101653003702123653002102160653003002181653004002211653001102251653002002262653003802282653003402320653002702354653001102381653002302392653000902415653003602424653003602460653002002496100001802516700002502534700002202559700002102581700001402602700002102616700002002637700001802657700002002675700002802695700002702723700002002750700002202770700001802792700001802810700002002828700002002848700001702868700001102885700002202896700002102918700001602939700001302955700002402968700003102992700002603023700002203049700001903071700002203090700001803112700001903130700002303149700002403172700002003196700001903216700002503235700002403260700001703284700002403301700001903325700002103344700002003365700002303385700002003408700002203428700002003450700001403470700001903484700002003503700002603523700002003549700002303569700001903592700002003611700002503631700002103656700002303677700002303700700002203723700002203745700002303767700002403790700002103814700001903835700002003854700001703874700001703891700001803908700002203926700002003948700001903968700002103987700002104008700002604029700002004055700002104075700002104096700002004117700001704137700001804154700001904172700002404191700002404215700001904239700002204258700002104280700002304301700002804324700002504352700001704377700001704394700002404411700002404435700002004459700002004479700001604499700001904515700002004534700002004554700002004574700002304594700002504617700002104642700002204663700002404685700002404709700002404733700002004757700002004777700002404797700002004821700001904841700002004860700002404880700002004904700003204924700002004956700001904976700002404995700001905019700002405038700002505062700002405087700002105111700002105132700001605153700001705169700002305186700002505209700002405234700002305258700002305281700001605304700001705320700002005337700002105357700002305378700002305401700001905424700002105443700002505464700003405489700002105523700002405544700001905568700002705587700002105614700002205635700001905657700002105676700002605697700002305723700002205746700002105768700002905789700001905818700002205837700001805859700001605877700001905893700002705912700002205939700001805961700002205979700002206001700001506023700002106038700002306059700002306082700001806105700002006123700001706143700002206160700002306182700001206205700002306217700002506240700002306265700001806288700002206306700002406328700002106352700001906373700001906392700002306411700002006434700002606454700001706480700002406497700002106521700002306542700002006565700002306585700002406608700001906632700002406651700001806675700002506693700001906718700002306737700002006760700002406780700002606804700001206830700001806842700002106860700001706881700002206898700002006920700002606940700002106966700003506987700002207022700002307044700002007067700002507087700002407112700002107136700002407157700001907181700002007200700001907220700002107239700002207260700001907282700002107301700002007322700001907342700002207361700002307383700001607406700002007422700002207442700002307464700002407487700001707511700002507528700002507553700002307578700002007601700001807621700002607639700001907665700001907684700001607703700001607719700002807735700002107763700001807784700002207802700002307824700002107847700002107868700002107889700002207910700002007932700002107952700002207973700002507995700001808020700002008038700001808058700001708076700001908093700002408112700001808136700001508154700001908169700001608188700003508204700001808239700002508257700001908282700002008301700001308321700002308334700001808357700002008375700002508395700002708420700002208447700002408469700002008493700001908513700002008532700002108552700001908573700002108592700002308613700002408636700002208660700001808682700002708700700002208727700001808749700001908767700002308786700002308809700002008832700001808852700001908870700002308889700002308912700002808935700002108963700002708984700001709011700002209028700002309050700001809073700002009091700002109111700001909132700001609151700002809167700002209195700002009217700002009237700002209257700002409279700001609303700001409319700002109333700001909354700002509373700001909398700002109417700002009438700001809458700002309476700002109499700002209520700002409542700002109566700001209587700001909599700002109618700003609639700002309675700002009698700002309718700001809741700001709759700002509776700002209801700001909823700002409842700001709866700001609883700002309899700002209922700002009944700001909964700002309983700002710006700001910033700001910052700002310071700002110094700001810115700002510133700002110158700001810179700002010197700002610217700002110243700002210264700002210286700001810308700002210326700001710348700001710365700002210382700002210404700002410426700002510450700002110475700001910496700002210515700002310537700001610560700001510576700001910591700002810610700001810638700002810656700002110684700001810705700002710723700002210750700002310772700002010795700002110815700001910836700001710855700001810872700001910890700002310909700002910932700002310961700002010984700002211004700001811026700001911044700002511063700002311088700002011111700002711131700002111158700002411179700002011203700002511223700001911248700002211267700001911289700002311308700001811331700002611349700001511375700002011390700001711410700002011427700001811447700002011465700002011485700002811505700002011533700002211553700002011575700002411595700001911619700002211638700002711660700002311687700001711710700002011727700002411747700001711771700001911788700002711807700002011834700002011854700001911874700002011893700002111913700002511934700002611959700002111985700002612006700002312032700002912055700002412084700002012108700001912128700002312147700001912170700002112189700002512210700001912235700001612254700001612270700001912286700001612305700002012321700002012341700001812361700001612379700001712395700002312412700003012435700002112465700002112486700002112507700001812528700002112546700002312567700002212590700001712612700002012629700002212649700001912671700001712690700002012707700002012727700001912747700002012766700001712786700002012803700002112823700003012844700002412874700002612898700002512924700001912949700001812968700002412986700001913010700001713029700001813046700002313064700002213087700002213109700002313131700002113154700002213175700002013197700001813217700001913235700001913254700002613273700001613299700001813315700002813333700002213361700002413383700002213407700002313429700002213452700001913474700002013493700002313513700002213536700002213558700002013580700002413600700002313624700002513647700001813672700002213690700002113712700002313733700002413756700002913780700002413809700002013833700001813853700001813871700002113889700002713910700002213937700002313959700001613982700002413998700002214022700002114044700002414065700002214089700001814111700002214129700002514151700002014176700002314196700002414219700002214243700002414265700002514289700002514314700002014339700002114359700002214380710002414402710002114426710002314447710002214470710002314492710002114515710002914536710002514565710002414590710002014614856003614634 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/137803560nas a2200709 4500008004100000022001400041245008800055210006900143260000900212300001100221490000600232520160600238653001001844653001201854653002101866653001901887653003401906653001001940653001101950653001901961653001301980653001301993653001002006653001102016653000902027653004402036653003602080653001602116653001602132653002702148100002002175700001302195700002402208700002302232700001902255700002002274700001702294700002302311700002502334700002002359700002402379700002202403700002202425700001902447700002202466700001702488700001702505700001902522700002002541700002002561700002102581700002602602700002402628700002102652700002402673700002302697700002102720700003002741700002202771700002102793856003602814 2013 eng d a1932-620300aBest practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium.0 aBest practices and joint calling of the HumanExome BeadChip the c2013 ae680950 v83 aGenotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.
10aAging10aAlleles10aCluster Analysis10aCohort Studies10aContinental Population Groups10aExome10aFemale10aGene Frequency10aGenomics10aGenotype10aHeart10aHumans10aMale10aOligonucleotide Array Sequence Analysis10aPolymorphism, Single Nucleotide10aSample Size10aSelf Report10aSequence Analysis, DNA1 aGrove, Megan, L1 aYu, Bing1 aCochran, Barbara, J1 aHaritunians, Talin1 aBis, Joshua, C1 aTaylor, Kent, D1 aHansen, Mark1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aFornage, Myriam1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aKathiresan, Sekar1 aKraaij, Robert1 aLauner, Lenore, J1 aLevy, Daniel1 aLiu, Yongmei1 aMosley, Thomas1 aPeloso, Gina, M1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRivadeneira, Fernando1 aSiscovick, David, S1 aSmith, Albert, V1 aUitterlinden, Andre1 aDuijn, Cornelia, M1 aWilson, James, G1 aO'Donnell, Christopher, J1 aRotter, Jerome, I1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/606707440nas 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/628804387nas 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/602709406nas 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/607505039nas 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/607004413nas 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 4500008004100000022001400041245012800055210006900183260001300252300001100265490000700276520087200283653001801155653001601173653002001189653002501209653004001234653003801274653003401312653001301346653001101359653002701370653001201397653001401409653003601423653002801459653002001487100002101507700002301528700001801551700001801569700002101587700002101608700002101629700001901650700003001669700001801699700001601717700001501733700002101748700002201769700002101791700001801812700002301830700002201853700002301875700002301898700002001921700003101941700001601972700002001988700001802008700001602026700001902042700002302061700002502084700001502109700001802124700001602142700003102158700001702189700002402206700001802230700002002248700001502268700002402283700002502307700001902332700001902351700001802370700002202388700002202410700002002432700002302452700002102475700002002496700002102516700001202537700002102549700002202570700002802592700003002620700002002650700001902670700002502689700002402714700001902738700002502757700002002782700001902802700001702821700002002838700002602858700002502884700001702909700002202926700001902948700002002967700003502987700002403022700002203046700001903068700001803087700002703105700002003132700002303152700002603175700002003201700001703221700002503238700002103263700002403284700002003308700002303328700002103351700002403372700002103396700002403417700001803441700002003459700001703479700002103496700001803517700001903535700002003554700002003574700002303594700002003617700001703637700002003654700002103674700002103695700002203716700002403738700002203762700001403784700002803798700002203826700002603848700002103874700002403895700001803919700001703937700001903954700002103973700002203994700002104016700002304037700001604060700002004076700002204096700001504118700001804133700001904151700002104170700001904191700001804210700002004228700002204248700002304270700001904293700002404312700002204336700001504358700002204373700001704395700002004412700002304432700002304455700002204478700002504500700001904525700001704544700002004561700002404581700002204605700002204627700002104649700001704670700002504687700002004712700002604732700002404758700002004782700001904802700001804821700002204839700001904861700001604880700001904896700002304915700001904938700001904957700002004976700002004996700001905016700001805035700002605053700002105079700002105100700002605121700002005147700002005167700002605187700001605213700002205229700002605251700002105277700001805298700002005316700001905336700002205355700002405377700001805401700002305419700001905442700001905461700002005480700002505500700001705525700002605542700002305568700002105591700002205612700001805634700002605652700002105678700003205699700001905731700003005750700002605780700002305806700001905829700001905848700002205867700002005889700001905909700002105928700001905949700002305968700002805991700003006019700003006049700001706079700002006096700002506116700002206141700002306163700002106186700002306207700002306230700002406253700002506277700001806302700002506320700002206345700002306367700002006390700002206410700002206432700002006454700002006474700002206494700002806516700002106544700002106565700001706586700001906603700002106622700002006643700001806663700002706681700002406708700003706732700002706769700001506796700001906811700002206830700002506852700002406877700002106901700002206922700002406944700002106968700001906989700002907008700002407037700002007061700002007081700001707101700002507118700002007143700001107163700002107174700002007195700002007215700002007235700002207255700002007277700002907297700002407326700002107350700001807371700002307389700002807412700002007440700001507460700002407475700002507499700002507524700001807549700002207567700002107589700002507610700002907635700001907664700002107683700002307704700002007727700002107747700002207768700001907790700002207809700001807831700001807849700002207867700001907889700002307908700002107931700002607952700001807978700002007996700002408016700003208040700002308072700002808095700002308123700002308146700002708169700002408196700002508220700002208245700001708267700001908284700002208303700002808325700001908353700002008372700002008392856003608412 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/615205590nas 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/629104067nas a2200793 4500008004100000022001400041245014300055210006900198260001600267300001200283490000600295520178900301653002202090653001602112653000902128653002202137653002402159653001902183653002202202653004002224653001102264653001802275653001102293653001702304653001202321653001402333653000902347653001602356653002602372653001602398653003202414653002002446653001202466653001802478100001902496700002202515700001902537700002502556700002402581700002102605700002202626700002202648700002102670700002602691700002402717700002202741700002802763700002702791700002202818700002402840700002202864700002202886700002402908700002202932700002202954700002202976700001902998700001703017700002403034700001903058700001803077700002203095700002403117700002503141700002403166700002303190700002403213856003603237 2013 eng d a2047-998000aSimple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium.0 aSimple risk model predicts incidence of atrial fibrillation in a c2013 Mar 18 ae0001020 v23 aBACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.
METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.
CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.
10aAfrican Americans10aAge Factors10aAged10aAged, 80 and over10aAtrial Fibrillation10aCohort Studies10aDiabetes Mellitus10aEuropean Continental Ancestry Group10aFemale10aHeart Failure10aHumans10aHypertension10aIceland10aIncidence10aMale10aMiddle Aged10aMyocardial Infarction10aNetherlands10aProportional Hazards Models10aRisk Assessment10aSmoking10aUnited States1 aAlonso, Alvaro1 aKrijthe, Bouwe, P1 aAspelund, Thor1 aStepas, Katherine, A1 aPencina, Michael, J1 aMoser, Carlee, B1 aSinner, Moritz, F1 aSotoodehnia, Nona1 aFontes, João, D1 aJanssens, Cecile, J W1 aKronmal, Richard, A1 aMagnani, Jared, W1 aWitteman, Jacqueline, C1 aChamberlain, Alanna, M1 aLubitz, Steven, A1 aSchnabel, Renate, B1 aAgarwal, Sunil, K1 aMcManus, David, D1 aEllinor, Patrick, T1 aLarson, Martin, G1 aBurke, Gregory, L1 aLauner, Lenore, J1 aHofman, Albert1 aLevy, Daniel1 aGottdiener, John, S1 aKääb, Stefan1 aCouper, David1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aStricker, Bruno, H C1 aGudnason, Vilmundur1 aHeckbert, Susan, R1 aBenjamin, Emelia, J uhttps://chs-nhlbi.org/node/587805943nas a2201657 4500008004100000022001400041245014100055210006900196260001600265300001100281490000700292520126000299653005101559653001001610653003901620653000901659653001201668653001201680653002101692653002101713653001901734653002101753653004001774653001101814653001901825653003201844653001701876653002201893653001101915653001801926653000901944653000901953653002301962653003601985653001602021653001402037653002702051653001602078653001802094100002002112700001802132700001902150700001902169700002402188700002402212700002302236700002502259700002002284700002002304700001802324700002602342700002102368700001702389700002502406700002102431700001702452700001702469700001802486700002102504700002002525700001802545700001902563700002302582700001602605700001902621700002502640700002402665700002202689700002202711700002602733700002402759700002502783700002602808700002102834700001902855700002802874700002202902700002002924700002602944700002502970700002502995700001903020700002103039700002303060700001803083700001803101700002003119700002403139700001903163700002503182700002003207700001803227700002903245700002003274700001503294700002103309700002203330700002303352700001903375700002203394700001603416700002103432700002403453700002003477700001803497700002103515700001903536700001503555700002103570700002203591700001903613700002503632700002103657700001903678700001603697700002403713700002203737700002103759700001703780700001903797700002503816700002203841700001903863700001803882700002303900700001703923700002403940700002103964700002303985700002404008700002104032700002004053700002204073700003004095700001804125700002104143700002204164700002504186710003804211856003604249 2014 eng d a1537-660500aAssociation of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.0 aAssociation of lowfrequency and rare codingsequence variants wit c2014 Feb 06 a223-320 v943 aLow-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAdult10aAfrican Continental Ancestry Group10aAged10aAlleles10aAnimals10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Association Studies10aGenetic Code10aGenetic Variation10aHumans10aLinear Models10aMale10aMice10aMice, Inbred C57BL10aMicrotubule-Associated Proteins10aMiddle Aged10aPhenotype10aSequence Analysis, DNA10aSubtilisins10aTriglycerides1 aPeloso, Gina, M1 aAuer, Paul, L1 aBis, Joshua, C1 aVoorman, Arend1 aMorrison, Alanna, C1 aStitziel, Nathan, O1 aBrody, Jennifer, A1 aKhetarpal, Sumeet, A1 aCrosby, Jacy, R1 aFornage, Myriam1 aIsaacs, Aaron1 aJakobsdottir, Johanna1 aFeitosa, Mary, F1 aDavies, Gail1 aHuffman, Jennifer, E1 aManichaikul, Ani1 aDavis, Brian1 aLohman, Kurt1 aJoon, Aron, Y1 aSmith, Albert, V1 aGrove, Megan, L1 aZanoni, Paolo1 aRedon, Valeska1 aDemissie, Serkalem1 aLawson, Kim1 aPeters, Ulrike1 aCarlson, Christopher1 aJackson, Rebecca, D1 aRyckman, Kelli, K1 aMackey, Rachel, H1 aRobinson, Jennifer, G1 aSiscovick, David, S1 aSchreiner, Pamela, J1 aMychaleckyj, Josyf, C1 aPankow, James, S1 aHofman, Albert1 aUitterlinden, André, G1 aHarris, Tamara, B1 aTaylor, Kent, D1 aStafford, Jeanette, M1 aReynolds, Lindsay, M1 aMarioni, Riccardo, E1 aDehghan, Abbas1 aFranco, Oscar, H1 aPatel, Aniruddh, P1 aLu, Yingchang1 aHindy, George1 aGottesman, Omri1 aBottinger, Erwin, P1 aMelander, Olle1 aOrho-Melander, Marju1 aLoos, Ruth, J F1 aDuga, Stefano1 aMerlini, Piera, Angelica1 aFarrall, Martin1 aGoel, Anuj1 aAsselta, Rosanna1 aGirelli, Domenico1 aMartinelli, Nicola1 aShah, Svati, H1 aKraus, William, E1 aLi, Mingyao1 aRader, Daniel, J1 aReilly, Muredach, P1 aMcPherson, Ruth1 aWatkins, Hugh1 aArdissino, Diego1 aZhang, Qunyuan1 aWang, Judy1 aTsai, Michael, Y1 aTaylor, Herman, A1 aCorrea, Adolfo1 aGriswold, Michael, E1 aLange, Leslie, A1 aStarr, John, M1 aRudan, Igor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aOrdovas, Jose, M1 aLevy, Daniel1 aChen, Y-D, Ida1 aReiner, Alexander, P1 aHayward, Caroline1 aPolasek, Ozren1 aDeary, Ian, J1 aBorecki, Ingrid, B1 aLiu, Yongmei1 aGudnason, Vilmundur1 aWilson, James, G1 aDuijn, Cornelia, M1 aKooperberg, Charles1 aRich, Stephen, S1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aO'Donnell, Christopher, J1 aRice, Kenneth1 aBoerwinkle, Eric1 aKathiresan, Sekar1 aCupples, Adrienne, L1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659004368nas a2200805 4500008004100000022001400041245016100055210006900216260001300285300001200298490000700310520202900317653000902346653002402355653001502379653002302394653001102417653001102428653001102439653001402450653000902464653003102473653002202504653003002526653002002556653001702576653001802593100002202611700002502633700002102658700002202679700001902701700002202720700002102742700002602763700002402789700002202813700002802835700002702863700002202890700002402912700002702936700002002963700002202983700002203005700002103027700001703048700002203065700002203087700002203109700001903131700001703150700002403167700001903191700001803210700002203228700001903250700002803269700002203297700002003319700002403339700002403363700002503387700002403412700002303436700002403459700002403483700001903507856003603526 2014 eng d a1532-209200aB-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies.0 aBtype natriuretic peptide and Creactive protein in the predictio c2014 Oct a1426-330 v163 aAIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
10aAged10aAtrial Fibrillation10aBiomarkers10aC-Reactive Protein10aEurope10aFemale10aHumans10aIncidence10aMale10aNatriuretic Peptide, Brain10aPeptide Fragments10aPredictive Value of Tests10aRisk Assessment10aRisk Factors10aUnited States1 aSinner, Moritz, F1 aStepas, Katherine, A1 aMoser, Carlee, B1 aKrijthe, Bouwe, P1 aAspelund, Thor1 aSotoodehnia, Nona1 aFontes, João, D1 aJanssens, Cecile, J W1 aKronmal, Richard, A1 aMagnani, Jared, W1 aWitteman, Jacqueline, C1 aChamberlain, Alanna, M1 aLubitz, Steven, A1 aSchnabel, Renate, B1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aAgarwal, Sunil, K1 aMcManus, David, D1 aFranco, Oscar, H1 aYin, Xiaoyan1 aLarson, Martin, G1 aBurke, Gregory, L1 aLauner, Lenore, J1 aHofman, Albert1 aLevy, Daniel1 aGottdiener, John, S1 aKääb, Stefan1 aCouper, David1 aHarris, Tamara, B1 aAstor, Brad, C1 aBallantyne, Christie, M1 aHoogeveen, Ron, C1 aArai, Andrew, E1 aSoliman, Elsayed, Z1 aEllinor, Patrick, T1 aStricker, Bruno, H C1 aGudnason, Vilmundur1 aHeckbert, Susan, R1 aPencina, Michael, J1 aBenjamin, Emelia, J1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/660103125nas 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/660703970nas 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/656305870nas a2201489 4500008004100000022001400041245013500055210006900190260001600259300001000275490000700285520175700292653001502049653001002064653001602074653000902090653001902099653001902118653001102137653001602148653001602164100002202180700001402202700001902216700002302235700002002258700001702278700001702295700002002312700002002332700002102352700002602373700003102399700001702430700001502447700002002462700001802482700002302500700001502523700001802538700002202556700002602578700001802604700002802622700001902650700001702669700001702686700002702703700001802730700001902748700001602767700002102783700002102804700001902825700002402844700002002868700002102888700002202909700002202931700002002953700001902973700001902992700002303011700002003034700001803054700002103072700002203093700002203115700001203137700001703149700001503166700002403181700001803205700002303223700002703246700002303273700002003296700002203316700002303338700001803361700002603379700001903405700001803424700002103442700002403463700002103487700002803508700002203536700003003558700002703588700003203615700001703647700001903664700001803683700002003701700001403721700002103735700002003756700002603776700001603802700002303818700002203841700002003863700001703883700002003900700002003920700001903940700002003959700001903979700001803998700001504016700002504031700002004056700002004076700002004096700002404116700001704140700001904157700002004176700002204196700002304218700003004241700002604271700002004297710002704317856003604344 2014 eng d a1537-660500aGene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.0 aGeneage interactions in blood pressure regulation a largescale i c2014 Jul 03 a24-380 v953 aAlthough age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.
10aAdolescent10aAdult10aAge Factors10aAged10aBlood Pressure10aCohort Studies10aHumans10aMiddle Aged10aYoung Adult1 aSimino, Jeannette1 aShi, Gang1 aBis, Joshua, C1 aChasman, Daniel, I1 aEhret, Georg, B1 aGu, Xiangjun1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aSijbrands, Eric1 aSmith, Albert, V1 aVerwoert, Germaine, C1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aChen, Peng1 aCheng, Ching-Yu1 aCorre, Tanguy1 ade Boer, Rudolf, A1 aGoel, Anuj1 aJohnson, Toby1 aKhor, Chiea-Chuen1 aLluís-Ganella, Carla1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aSim, Xueling1 aSõber, Siim1 avan der Most, Peter, J1 aVerweij, Niek1 aZhao, Jing Hua1 aAmin, Najaf1 aBoerwinkle, Eric1 aBouchard, Claude1 aDehghan, Abbas1 aEiriksdottir, Gudny1 aElosua, Roberto1 aFranco, Oscar, H1 aGieger, Christian1 aHarris, Tamara, B1 aHercberg, Serge1 aHofman, Albert1 aJames, Alan, L1 aJohnson, Andrew, D1 aKähönen, Mika1 aKhaw, Kay-Tee1 aKutalik, Zoltán1 aLarson, Martin, G1 aLauner, Lenore, J1 aLi, Guo1 aLiu, Jianjun1 aLiu, Kiang1 aMorrison, Alanna, C1 aNavis, Gerjan1 aOng, Rick Twee-Hee1 aPapanicolau, George, J1 aPenninx, Brenda, W1 aPsaty, Bruce, M1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRice, Kenneth1 aRivadeneira, Fernando1 aRose, Lynda, M1 aSanna, Serena1 aScott, Robert, A1 aSiscovick, David, S1 aStolk, Ronald, P1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Klauw, Melanie, M1 aVasan, Ramachandran, S1 aVithana, Eranga, Nishanthie1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Hugh1 aYoung, Terri, L1 aAung, Tin1 aBochud, Murielle1 aFarrall, Martin1 aHartman, Catharina, A1 aLaan, Maris1 aLakatta, Edward, G1 aLehtimäki, Terho1 aLoos, Ruth, J F1 aLucas, Gavin1 aMeneton, Pierre1 aPalmer, Lyle, J1 aRettig, Rainer1 aSnieder, Harold1 aTai, Shyong, E1 aTeo, Yik-Ying1 aHarst, Pim1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aWong, Tien, Yin1 aFornage, Myriam1 aGudnason, Vilmundur1 aLevy, Daniel1 aPalmas, Walter1 aRidker, Paul, M1 aRotter, Jerome, I1 aDuijn, Cornelia, M1 aWitteman, Jacqueline, C M1 aChakravarti, Aravinda1 aRao, Dabeeru, C1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/659910059nas a2203157 4500008004100000022001400041245012200055210006900177260001300246300001100259490000700270520116100277653001001438653000901448653002501457653002201482653002701504653002401531653001101555653003801566653003401604653001301638653002101651653001101672653002101683653000901704653001601713653001501729653003601744100001901780700001901799700001601818700001501834700002401849700002401873700002201897700002501919700002001944700001801964700002301982700001902005700002802024700002502052700002202077700001902099700002302118700001802141700003002159700002502189700001902214700002602233700001902259700001802278700002502296700002102321700001902342700001902361700002802380700002102408700001802429700002202447700002202469700001702491700001802508700002002526700002102546700002302567700002302590700001802613700002302631700002002654700002502674700002302699700002302722700002602745700001802771700002202789700002502811700002302836700002502859700002102884700002202905700002202927700002302949700001902972700001902991700001703010700002003027700002003047700002103067700002503088700001803113700002303131700002203154700002403176700002003200700001803220700002203238700003903260700001703299700002103316700002203337700002303359700002003382700002203402700001803424700001903442700002003461700001903481700001803500700002003518700001603538700002803554700002103582700001803603700002303621700002003644700002103664700002203685700003003707700001703737700001703754700002203771700002103793700002403814700002103838700002403859700002203883700001603905700002203921700002203943700002103965700001903986700001904005700001904024700001804043700002404061700001904085700002304104700002204127700002004149700001904169700002204188700002204210700002004232700002004252700001804272700002204290700002604312700002304338700001704361700003104378700002704409700001804436700002404454700001804478700002304496700002004519700002704539700002404566700003004590700001704620700002004637700002004657700001904677700002104696700002404717700002404741700002504765700002304790700002604813700002604839700002704865700002604892700001604918700002204934700002004956700001904976700002504995700001805020700002705038700002405065700001805089700002905107700002805136700002005164700002205184700002105206700001905227700001705246700002805263700003005291700002205321700002005343700001905363700002505382700002305407700002105430700001705451700002405468700001705492700002605509700001705535700002005552700002405572700001905596700001505615700002205630700002805652700001905680700002005699700001805719700002305737700002205760700001905782700001905801700001705820700002605837700002405863700002305887700002405910700002005934700002205954700002405976700002506000700002306025700002006048700002006068700002106088700002106109700001606130700001806146700002606164700002606190700002506216700002406241700001806265700001706283700002306300700002406323700002406347700002006371700002006391700002206411700001806433700002406451700002306475700002106498700002106519700002306540700002106563700001706584700002306601700001906624700002606643700002506669700001806694700002506712700002906737710002006766710002206786710001406808710002206822710002106844856003606865 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/654408236nas 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 4500008004100000022001400041245010000055210006900155260001300224300001100237490000700248520092000255653001901175653002301194653002201217653002901239653001701268653003801285653001801323653003401341653001101375653001801386653002701404653003601431653001401467653002801481653003101509653001501540653001901555100001801574700002601592700002001618700002001638700002301658700001601681700002301697700002601720700001501746700002101761700002001782700002301802700001901825700002501844700002201869700002601891700002501917700001901942700001801961700001901979700002001998700002202018700001802040700002002058700001702078700002402095700003102119700001902150700001902169700002002188700001502208700001802223700002202241700002002263700002002283700001202303700001902315700001602334700002102350700001902371700002202390700001902412700002402431700001602455700001702471700001902488700002002507700002402527700002002551700001802571700001802589700002102607700002702628700001702655700001702672700002702689700001902716700002202735700001702757700002002774700002102794700001802815700001902833700001902852700002002871700002602891700001902917700001902936700002402955700002402979700002203003700001303025700002203038700002003060700002103080700001903101700001903120700001803139700002003157700002003177700001703197700002503214700002803239700002003267700002303287700002203310700001503332700001803347700002303365700001603388700002603404700001703430700001603447700001703463700001903480700002303499700001903522700002003541700002403561700002003585700002103605700002103626700002103647700002203668700001903690700002003709700002103729700002203750700001903772700002003791700002003811700002203831700001803853700002803871700002403899700001703923700002803940700002403968700002103992700001904013700001904032700002204051700001804073700002204091700001904113700001804132700002304150700002504173700002004198700001904218700002404237700001904261700001604280700001904296700002204315700001804337700001904355700001704374700002704391700002104418700001504439700002304454700002204477700002404499700001704523700002504540700002104565700001704586700001904603700002204622700001704644700002404661700002504685700001704710700002204727700001904749700001704768700002204785700002104807700002504828856003604853 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/658205294nas 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/660404102nas 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/629704953nas a2201105 4500008004100000022001400041245009300055210006900148260001500217300001200232490000700244520183400251653001002085653000902095653002202104653003702126653002402163653002302187653003102210653001102241653004002252653001102292653002002303653003802323653002502361653001102386653001002397653000902407653001602416653003602432653002602468100002202494700002402516700001902540700001902559700002002578700001202598700002202610700002302632700001802655700002202673700001802695700001902713700002102732700003002753700001902783700002202802700001902824700002302843700001702866700002402883700001402907700002102921700002202942700001902964700001902983700001903002700002203021700001903043700002203062700002503084700002203109700002203131700002203153700002003175700002003195700001903215700002203234700002603256700002303282700002203305700002003327700002003347700002403367700002303391700002803414700002603442700001703468700001903485700002403504700002203528700002403550700002203574700002003596700001603616700002503632700002303657700002203680700002303702700001903725700001903744700002403763700002403787856003603811 2014 eng d a1558-359700aNovel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.0 aNovel genetic markers associate with atrial fibrillation risk in c2014 Apr 1 a1200-100 v633 aOBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factors1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aLin, Honghuang1 aArking, Dan, E1 aTrompet, Stella1 aLi, Guo1 aKrijthe, Bouwe, P1 aChasman, Daniel, I1 aBarnard, John1 aKleber, Marcus, E1 aDörr, Marcus1 aOzaki, Kouichi1 aSmith, Albert, V1 aMüller-Nurasyid, Martina1 aWalter, Stefan1 aAgarwal, Sunil, K1 aBis, Joshua, C1 aBrody, Jennifer, A1 aChen, Lin, Y1 aEverett, Brendan, M1 aFord, Ian1 aFranco, Oscar, H1 aHarris, Tamara, B1 aHofman, Albert1 aKääb, Stefan1 aMahida, Saagar1 aKathiresan, Sekar1 aKubo, Michiaki1 aLauner, Lenore, J1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aMcKnight, Barbara1 aMcManus, David, D1 aPeters, Annette1 aPsaty, Bruce, M1 aRose, Lynda, M1 aRotter, Jerome, I1 aSilbernagel, Guenther1 aSmith, Jonathan, D1 aSotoodehnia, Nona1 aStott, David, J1 aTaylor, Kent, D1 aTomaschitz, Andreas1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aMurabito, Joanne, M1 aSinner, Moritz, F1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aMärz, Winfried1 aChung, Mina1 aAlbert, Christine, M1 aStricker, Bruno, H1 aTanaka, Toshihiro1 aHeckbert, Susan, R1 aJukema, Wouter1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/682004219nas 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/622003472nas 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/681505255nas 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/687504127nas 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/655009013nas a2202797 4500008004100000022001400041245011400055210006900169260000900238300000900247490000600256520115900262653003901421653001801460653003001478653004001508653001001548653001201558653003201570653001701602653003801619653002201657653003701679653002601716653001101742653001201753653001801765653004401783653003601827100002101863700001901884700002101903700001601924700002301940700002301963700001801986700002502004700002402029700002202053700002002075700001502095700002502110700001302135700001802148700003102166700001802197700002102215700001102236700002602247700002502273700002002298700001902318700001702337700002302354700002002377700002302397700002302420700001702443700001602460700001802476700002602494700002102520700002002541700001202561700002002573700002102593700002402614700001902638700002502657700002502682700002302707700002102730700002102751700002202772700002302794700002502817700002002842700002002862700002302882700001602905700002402921700001402945700002302959700002502982700002103007700002303028700002203051700001903073700001703092700001903109700002003128700001903148700002203167700001903189700002003208700002403228700002203252700002503274700002303299700002203322700002303344700002403367700001503391700002003406700002003426700002303446700001403469700002103483700001703504700001803521700002303539700002303562700002503585700002303610700002403633700001903657700002403676700001903700700002203719700002003741700001403761700001803775700001703793700001703810700001603827700001703843700002503860700002103885700002203906700002203928700002003950700002203970700002003992700002704012700001704039700002304056700002104079700002004100700001904120700002604139700001804165700001904183700002104202700002004223700001404243700002004257700002004277700002704297700002304324700002004347700002804367700001804395700002304413700002304436700002704459700001704486700002104503700002704524700001804551700001904569700001904588700002104607700001904628700002004647700002504667700001904692700002004711700002204731700002004753700002304773700002004796700002004816700002104836700002104857700002204878700001704900700002604917700001904943700002404962700002204986700002005008700002005028700002105048700002005069700002205089700002405111700002005135700002205155700002605177700002205203700001905225700002405244700002405268700002205292700001705314700001905331700003005350700002305380700002505403700002105428700001905449700002505468700002105493700002005514700001605534700002505550700002005575700002805595700001705623700001805640700001805658700002405676700001905700700002305719700002305742700001905765700002005784700001905804700002305823700002505846700002405871700002105895700002005916700002005936700002005956700002105976700002505997700002406022700001906046700002206065700002006087700002106107700002206128710002906150856003606179 2015 eng d a2041-172300aLow-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.0 aLowfrequency and rare exome chip variants associate with fasting c2015 a58970 v63 aFasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
10aAfrican Continental Ancestry Group10aBlood Glucose10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aExome10aFasting10aGenetic Association Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGlucagon-Like Peptide-1 Receptor10aGlucose-6-Phosphatase10aHumans10aInsulin10aMutation Rate10aOligonucleotide Array Sequence Analysis10aPolymorphism, Single Nucleotide1 aWessel, Jennifer1 aChu, Audrey, Y1 aWillems, Sara, M1 aWang, Shuai1 aYaghootkar, Hanieh1 aBrody, Jennifer, A1 aDauriz, Marco1 aHivert, Marie-France1 aRaghavan, Sridharan1 aLipovich, Leonard1 aHidalgo, Bertha1 aFox, Keolu1 aHuffman, Jennifer, E1 aAn, Ping1 aLu, Yingchang1 aRasmussen-Torvik, Laura, J1 aGrarup, Niels1 aEhm, Margaret, G1 aLi, Li1 aBaldridge, Abigail, S1 aStančáková, Alena1 aAbrol, Ravinder1 aBesse, Céline1 aBoland, Anne1 aBork-Jensen, Jette1 aFornage, Myriam1 aFreitag, Daniel, F1 aGarcia, Melissa, E1 aGuo, Xiuqing1 aHara, Kazuo1 aIsaacs, Aaron1 aJakobsdottir, Johanna1 aLange, Leslie, A1 aLayton, Jill, C1 aLi, Man1 aZhao, Jing, Hua1 aMeidtner, Karina1 aMorrison, Alanna, C1 aNalls, Mike, A1 aPeters, Marjolein, J1 aSabater-Lleal, Maria1 aSchurmann, Claudia1 aSilveira, Angela1 aSmith, Albert, V1 aSoutham, Lorraine1 aStoiber, Marcus, H1 aStrawbridge, Rona, J1 aTaylor, Kent, D1 aVarga, Tibor, V1 aAllin, Kristine, H1 aAmin, Najaf1 aAponte, Jennifer, L1 aAung, Tin1 aBarbieri, Caterina1 aBihlmeyer, Nathan, A1 aBoehnke, Michael1 aBombieri, Cristina1 aBowden, Donald, W1 aBurns, Sean, M1 aChen, Yuning1 aChen, Yii-DerI1 aCheng, Ching-Yu1 aCorrea, Adolfo1 aCzajkowski, Jacek1 aDehghan, Abbas1 aEhret, Georg, B1 aEiriksdottir, Gudny1 aEscher, Stefan, A1 aFarmaki, Aliki-Eleni1 aFrånberg, Mattias1 aGambaro, Giovanni1 aGiulianini, Franco1 aGoddard, William, A1 aGoel, Anuj1 aGottesman, Omri1 aGrove, Megan, L1 aGustafsson, Stefan1 aHai, Yang1 aHallmans, Göran1 aHeo, Jiyoung1 aHoffmann, Per1 aIkram, Mohammad, K1 aJensen, Richard, A1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKaraleftheri, Maria1 aKhor, Chiea, C1 aKirkpatrick, Andrea1 aKraja, Aldi, T1 aKuusisto, Johanna1 aLange, Ethan, M1 aLee, I, T1 aLee, Wen-Jane1 aLeong, Aaron1 aLiao, Jiemin1 aLiu, Chunyu1 aLiu, Yongmei1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aMalerba, Giovanni1 aMamakou, Vasiliki1 aMarouli, Eirini1 aMaruthur, Nisa, M1 aMatchan, Angela1 aMcKean-Cowdin, Roberta1 aMcLeod, Olga1 aMetcalf, Ginger, A1 aMohlke, Karen, L1 aMuzny, Donna, M1 aNtalla, Ioanna1 aPalmer, Nicholette, D1 aPasko, Dorota1 aPeter, Andreas1 aRayner, Nigel, W1 aRenstrom, Frida1 aRice, Ken1 aSala, Cinzia, F1 aSennblad, Bengt1 aSerafetinidis, Ioannis1 aSmith, Jennifer, A1 aSoranzo, Nicole1 aSpeliotes, Elizabeth, K1 aStahl, Eli, A1 aStirrups, Kathleen1 aTentolouris, Nikos1 aThanopoulou, Anastasia1 aTorres, Mina1 aTraglia, Michela1 aTsafantakis, Emmanouil1 aJavad, Sundas1 aYanek, Lisa, R1 aZengini, Eleni1 aBecker, Diane, M1 aBis, Joshua, C1 aBrown, James, B1 aCupples, Adrienne, L1 aHansen, Torben1 aIngelsson, Erik1 aKarter, Andrew, J1 aLorenzo, Carlos1 aMathias, Rasika, A1 aNorris, Jill, M1 aPeloso, Gina, M1 aSheu, Wayne, H-H1 aToniolo, Daniela1 aVaidya, Dhananjay1 aVarma, Rohit1 aWagenknecht, Lynne, E1 aBoeing, Heiner1 aBottinger, Erwin, P1 aDedoussis, George1 aDeloukas, Panos1 aFerrannini, Ele1 aFranco, Oscar, H1 aFranks, Paul, W1 aGibbs, Richard, A1 aGudnason, Vilmundur1 aHamsten, Anders1 aHarris, Tamara, B1 aHattersley, Andrew, T1 aHayward, Caroline1 aHofman, Albert1 aJansson, Jan-Håkan1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLevy, Daniel1 aOostra, Ben, A1 aO'Donnell, Christopher, J1 aO'Rahilly, Stephen1 aPadmanabhan, Sandosh1 aPankow, James, S1 aPolasek, Ozren1 aProvince, Michael, A1 aRich, Stephen, S1 aRidker, Paul, M1 aRudan, Igor1 aSchulze, Matthias, B1 aSmith, Blair, H1 aUitterlinden, André, G1 aWalker, Mark1 aWatkins, Hugh1 aWong, Tien, Y1 aZeggini, Eleftheria1 aLaakso, Markku1 aBorecki, Ingrid, B1 aChasman, Daniel, I1 aPedersen, Oluf1 aPsaty, Bruce, M1 aTai, Shyong, E1 aDuijn, Cornelia, M1 aWareham, Nicholas, J1 aWaterworth, Dawn, M1 aBoerwinkle, Eric1 aKao, Linda, W H1 aFlorez, Jose, C1 aLoos, Ruth, J F1 aWilson, James, G1 aFrayling, Timothy, M1 aSiscovick, David, S1 aDupuis, Josée1 aRotter, Jerome, I1 aMeigs, James, B1 aScott, Robert, A1 aGoodarzi, Mark, O1 aEPIC-InterAct Consortium uhttps://chs-nhlbi.org/node/668606153nas 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/668304741nas 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/686107420nas a2202053 4500008004100000022001400041245005000055210004800105260001600153300001200169490000700181520170000188100001501888700002401903700001801927700001801945700001701963700002401980700001802004700002402022700002202046700002202068700002202090700002102112700002202133700002802155700001902183700002002202700001902222700001802241700002002259700003002279700002102309700001802330700002202348700002202370700002602392700001802418700001902436700002202455700002502477700002302502700001602525700002502541700002502566700001902591700001802610700001902628700001702647700002402664700002002688700002102708700002602729700001702755700002502772700002502797700002602822700002402848700002002872700001402892700002202906700002202928700001702950700002102967700002302988700002103011700002403032700001903056700002003075700002003095700002103115700002003136700002003156700001803176700002503194700002203219700001703241700002303258700001703281700002203298700001703320700001903337700002503356700001503381700002203396700002103418700002003439700001903459700001603478700001803494700001903512700001903531700002103550700001903571700002403590700002303614700001803637700002003655700002003675700002003695700001803715700002503733700002603758700001903784700002303803700002503826700001703851700002503868700002203893700002303915700002403938700002403962700002203986700002504008700002404033700002204057700002304079700002404102700002404126700002004150700003204170700002104202700002404223700002004247700002304267700001704290700002804307700002804335700002304363700001904386700002204405700002304427700002204450700001704472700002604489700003204515700002104547700002004568700002804588700001504616700002304631700002404654700002004678700002004698700001604718700002104734700002704755700002804782700002304810700002004833700001904853700001804872700002204890700002104912700002504933700001904958700002104977700001904998700001905017700002405036700002205060700002305082700002305105700002905128700002105157700002205178700002005200700001605220700002905236700001805265700002205283700002505305856003605330 2016 eng d a1558-359700a52 Genetic Loci Influencing Myocardial Mass.0 a52 Genetic Loci Influencing Myocardial Mass c2016 Sep 27 a1435-480 v683 aBACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.
OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.
METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.
RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.
CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
1 aHarst, Pim1 avan Setten, Jessica1 aVerweij, Niek1 aVogler, Georg1 aFranke, Lude1 aMaurano, Matthew, T1 aWang, Xinchen1 aLeach, Irene, Mateo1 aEijgelsheim, Mark1 aSotoodehnia, Nona1 aHayward, Caroline1 aSorice, Rossella1 aMeirelles, Osorio1 aLyytikäinen, Leo-Pekka1 aPolasek, Ozren1 aTanaka, Toshiko1 aArking, Dan, E1 aUlivi, Sheila1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aSmith, Albert, V1 aDörr, Marcus1 aKerr, Kathleen, F1 aMagnani, Jared, W1 aM, Fabiola, del Greco1 aZhang, Weihua1 aNolte, Ilja, M1 aSilva, Claudia, T1 aPadmanabhan, Sandosh1 aTragante, Vinicius1 aEsko, Tõnu1 aAbecasis, Goncalo, R1 aAdriaens, Michiel, E1 aAndersen, Karl1 aBarnett, Phil1 aBis, Joshua, C1 aBodmer, Rolf1 aBuckley, Brendan, M1 aCampbell, Harry1 aCannon, Megan, V1 aChakravarti, Aravinda1 aChen, Lin, Y1 aDelitala, Alessandro1 aDevereux, Richard, B1 aDoevendans, Pieter, A1 aDominiczak, Anna, F1 aFerrucci, Luigi1 aFord, Ian1 aGieger, Christian1 aHarris, Tamara, B1 aHaugen, Eric1 aHeinig, Matthias1 aHernandez, Dena, G1 aHillege, Hans, L1 aHirschhorn, Joel, N1 aHofman, Albert1 aHubner, Norbert1 aHwang, Shih-Jen1 aIorio, Annamaria1 aKähönen, Mika1 aKellis, Manolis1 aKolcic, Ivana1 aKooner, Ishminder, K1 aKooner, Jaspal, S1 aKors, Jan, A1 aLakatta, Edward, G1 aLage, Kasper1 aLauner, Lenore, J1 aLevy, Daniel1 aLundby, Alicia1 aMacfarlane, Peter, W1 aMay, Dalit1 aMeitinger, Thomas1 aMetspalu, Andres1 aNappo, Stefania1 aNaitza, Silvia1 aNeph, Shane1 aNord, Alex, S1 aNutile, Teresa1 aOkin, Peter, M1 aOlsen, Jesper, V1 aOostra, Ben, A1 aPenninger, Josef, M1 aPennacchio, Len, A1 aPers, Tune, H1 aPerz, Siegfried1 aPeters, Annette1 aPinto, Yigal, M1 aPfeufer, Arne1 aPilia, Maria, Grazia1 aPramstaller, Peter, P1 aPrins, Bram, P1 aRaitakari, Olli, T1 aRaychaudhuri, Soumya1 aRice, Ken, M1 aRossin, Elizabeth, J1 aRotter, Jerome, I1 aSchafer, Sebastian1 aSchlessinger, David1 aSchmidt, Carsten, O1 aSehmi, Jobanpreet1 aSilljé, Herman, H W1 aSinagra, Gianfranco1 aSinner, Moritz, F1 aSlowikowski, Kamil1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aSpiering, Wilko1 aStamatoyannopoulos, John, A1 aStolk, Ronald, P1 aStrauch, Konstantin1 aTan, Sian-Tsung1 aTarasov, Kirill, V1 aTrinh, Bosco1 aUitterlinden, André, G1 avan den Boogaard, Malou1 aDuijn, Cornelia, M1 aGilst, Wiek, H1 aViikari, Jorma, S1 aVisscher, Peter, M1 aVitart, Veronique1 aVölker, Uwe1 aWaldenberger, Melanie1 aWeichenberger, Christian, X1 aWestra, Harm-Jan1 aWijmenga, Cisca1 aWolffenbuttel, Bruce, H1 aYang, Jian1 aBezzina, Connie, R1 aMunroe, Patricia, B1 aSnieder, Harold1 aWright, Alan, F1 aRudan, Igor1 aBoyer, Laurie, A1 aAsselbergs, Folkert, W1 avan Veldhuisen, Dirk, J1 aStricker, Bruno, H1 aPsaty, Bruce, M1 aCiullo, Marina1 aSanna, Serena1 aLehtimäki, Terho1 aWilson, James, F1 aBandinelli, Stefania1 aAlonso, Alvaro1 aGasparini, Paolo1 aJukema, Wouter1 aKääb, Stefan1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aHeckbert, Susan, R1 ade Boer, Rudolf, A1 aNewton-Cheh, Christopher1 aHicks, Andrew, A1 aChambers, John, C1 aJamshidi, Yalda1 aVisel, Axel1 aChristoffels, Vincent, M1 aIsaacs, Aaron1 aSamani, Nilesh, J1 ade Bakker, Paul, I W uhttps://chs-nhlbi.org/node/726203355nas a2200529 4500008004100000022001400041245009100055210006900146260001600215300001100231490000700242520178200249100002202031700002202053700001702075700001902092700002402111700001202135700002602147700002702173700002002200700002202220700002002242700002502262700002802287700002402315700001902339700002402358700002202382700002702404700002502431700001702456700003002473700001902503700002202522700002202544700002002566700002402586700002202610700002002632700001902652700002602671700002002697700002002717710005202737856003602789 2016 eng d a1875-890800aEvaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease.0 aEvaluation of a Genetic Risk Score to Improve Risk Prediction fo c2016 Jun 18 a921-320 v533 aEffective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI = [1.13-1.21] per standard deviation increase in GRS; p-value = 2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI = [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI = [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex = 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.
1 aChouraki, Vincent1 aReitz, Christiane1 aMaury, Fleur1 aBis, Joshua, C1 aBellenguez, Céline1 aYu, Lei1 aJakobsdottir, Johanna1 aMukherjee, Shubhabrata1 aAdams, Hieab, H1 aChoi, Seung, Hoan1 aLarson, Eric, B1 aFitzpatrick, Annette1 aUitterlinden, André, G1 aDe Jager, Philip, L1 aHofman, Albert1 aGudnason, Vilmundur1 aVardarajan, Badri1 aIbrahim-Verbaas, Carla1 avan der Lee, Sven, J1 aLopez, Oscar1 aDartigues, Jean-François1 aBerr, Claudine1 aAmouyel, Philippe1 aBennett, David, A1 aDuijn, Cornelia1 aDeStefano, Anita, L1 aLauner, Lenore, J1 aIkram, Arfan, M1 aCrane, Paul, K1 aLambert, Jean-Charles1 aMayeux, Richard1 aSeshadri, Sudha1 aInternational Genomics of Alzheimer’s Project uhttps://chs-nhlbi.org/node/718506025nas a2201489 4500008004100000022001400041245009200055210006900147260001500216300000900231490000700240520184700247100002002094700002002114700002202134700002002156700002502176700002402201700002602225700002002251700002202271700002002293700001602313700002002329700002302349700002302372700002102395700001902416700002102435700001702456700002102473700001602494700002302510700001602533700002002549700002102569700002102590700002102611700002302632700002402655700002802679700002302707700002002730700002402750700001802774700002202792700002202814700002002836700002002856700001202876700002402888700002402912700001902936700002202955700002202977700002302999700002503022700002403047700001903071700002503090700002003115700001703135700002203152700002203174700001203196700002403208700002103232700001703253700001803270700002803288700001803316700002303334700001903357700002103376700001803397700001903415700002603434700001703460700002403477700002503501700001903526700002303545700001803568700002003586700002303606700002103629700002103650700002103671700002603692700002203718700001903740700002603759700001903785700002003804700002203824700002303846700002403869700002203893700002103915700001903936700002703955700002303982700002604005700001804031700001804049700002804067700002604095700002004121700002404141700002104165700002104186700002304207700002204230700001804252700001604270700002004286700002104306700002004327700002104347700002104368700002204389700001804411700002304429700002504452700002204477856003604499 2016 eng d a1537-660500aExome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.0 aExome Genotyping Identifies Pleiotropic Variants Associated with c2016 Jul 7 a8-210 v993 aRed blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
1 aChami, Nathalie1 aChen, Ming-Huei1 aSlater, Andrew, J1 aEicher, John, D1 aEvangelou, Evangelos1 aTajuddin, Salman, M1 aLove-Gregory, Latisha1 aKacprowski, Tim1 aSchick, Ursula, M1 aNomura, Akihiro1 aGiri, Ayush1 aLessard, Samuel1 aBrody, Jennifer, A1 aSchurmann, Claudia1 aPankratz, Nathan1 aYanek, Lisa, R1 aManichaikul, Ani1 aPazoki, Raha1 aMihailov, Evelin1 aHill, David1 aRaffield, Laura, M1 aBurt, Amber1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aO'Donoghue, Michelle, L1 aCrosslin, David, R1 ade Denus, Simon1 aDubé, Marie-Pierre1 aElliott, Paul1 aEngström, Gunnar1 aEvans, Michele, K1 aFloyd, James, S1 aFornage, Myriam1 aGao, He1 aGreinacher, Andreas1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHernesniemi, Jussi1 aHighland, Heather, M1 aHirschhorn, Joel, N1 aHofman, Albert1 aIrvin, Marguerite, R1 aKähönen, Mika1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLi, Jin1 aLiewald, David, C M1 aLinneberg, Allan1 aLiu, Yongmei1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMathias, Rasika, A1 aMelander, Olle1 aMetspalu, Andres1 aMononen, Nina1 aNalls, Mike, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aO'Donnell, Chris, J1 aOrho-Melander, Marju1 aPedersen, Oluf1 aPetersmann, Astrid1 aPolfus, Linda1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRaitoharju, Emma1 aRichard, Melissa1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchmidt, Frank1 aSmith, Albert, Vernon1 aStarr, John, M1 aTaylor, Kent, D1 aTeumer, Alexander1 aThuesen, Betina, H1 aTorstenson, Eric, S1 aTracy, Russell, P1 aTzoulaki, Ioanna1 aZakai, Neil, A1 aVacchi-Suzzi, Caterina1 aDuijn, Cornelia, M1 avan Rooij, Frank, J A1 aCushman, Mary1 aDeary, Ian, J1 aEdwards, Digna, R Velez1 aVergnaud, Anne-Claire1 aWallentin, Lars1 aWaterworth, Dawn, M1 aWhite, Harvey, D1 aWilson, James, G1 aZonderman, Alan, B1 aKathiresan, Sekar1 aGrarup, Niels1 aEsko, Tõnu1 aLoos, Ruth, J F1 aLange, Leslie, A1 aFaraday, Nauder1 aAbumrad, Nada, A1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aAuer, Paul, L1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aLettre, Guillaume uhttps://chs-nhlbi.org/node/713805079nas 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/700405559nas a2201297 4500008004100000022001400041245013800055210006900193260001500262300001000277490000700287520188700294100002402181700002202205700002002227700002002247700001602267700002302283700001602306700002002322700001202342700002802354700002102382700002102403700002802424700002102452700001702473700002102490700002602511700002302537700002702560700002402587700002502611700001902636700001602655700002002671700002602691700002002717700002402737700002202761700002502783700002102808700001702829700001802846700001902864700002302883700002602906700001702932700001902949700002402968700002102992700002803013700002003041700002003061700002103081700002103102700002303123700001903146700002003165700002003185700001203205700002403217700002403241700002103265700002403286700002103310700002103331700002103352700002003373700002403393700002203417700001903439700001803458700001703476700002203493700002203515700001803537700002103555700002403576700002403600700002103624700002403645700002003669700002603689700002303715700002303738700001803761700001803779700001803797700002203815700002403837700002003861700002003881700002203901700002203923700001903945700002103964700002203985700002004007700001604027700002004043700002104063700001804084700002304102700002104125700001904146700002204165700002004187700001804207856003604225 2016 eng d a1537-660500aLarge-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.0 aLargeScale Exomewide Association Analysis Identifies Loci for Wh c2016 Jul 7 a22-390 v993 aWhite blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aEicher, John, D1 aChami, Nathalie1 aGiri, Ayush1 aBrody, Jennifer, A1 aHill, David1 aKacprowski, Tim1 aLi, Jin1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMihailov, Evelin1 aO'Donoghue, Michelle, L1 aPankratz, Nathan1 aPazoki, Raha1 aPolfus, Linda, M1 aSmith, Albert, Vernon1 aSchurmann, Claudia1 aVacchi-Suzzi, Caterina1 aWaterworth, Dawn, M1 aEvangelou, Evangelos1 aYanek, Lisa, R1 aBurt, Amber1 aChen, Ming-Huei1 avan Rooij, Frank, J A1 aFloyd, James, S1 aGreinacher, Andreas1 aHarris, Tamara, B1 aHighland, Heather, M1 aLange, Leslie, A1 aLiu, Yongmei1 aMägi, Reedik1 aNalls, Mike, A1 aMathias, Rasika, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aStarr, John, M1 aTardif, Jean-Claude1 aTzoulaki, Ioanna1 aEdwards, Digna, R Velez1 aWallentin, Lars1 aBartz, Traci, M1 aBecker, Lewis, C1 aDenny, Joshua, C1 aRaffield, Laura, M1 aRioux, John, D1 aFriedrich, Nele1 aFornage, Myriam1 aGao, He1 aHirschhorn, Joel, N1 aLiewald, David, C M1 aRich, Stephen, S1 aUitterlinden, Andre1 aBastarache, Lisa1 aBecker, Diane, M1 aBoerwinkle, Eric1 ade Denus, Simon1 aBottinger, Erwin, P1 aHayward, Caroline1 aHofman, Albert1 aHomuth, Georg1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLu, Yingchang1 aMetspalu, Andres1 aO'Donnell, Chris, J1 aQuarells, Rakale, C1 aRichard, Melissa1 aTorstenson, Eric, S1 aTaylor, Kent, D1 aVergnaud, Anne-Claire1 aZonderman, Alan, B1 aCrosslin, David, R1 aDeary, Ian, J1 aDörr, Marcus1 aElliott, Paul1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKähönen, Mika1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aSlater, Andrew, J1 aDehghan, Abbas1 aWhite, Harvey, D1 aGanesh, Santhi, K1 aLoos, Ruth, J F1 aEsko, Tõnu1 aFaraday, Nauder1 aWilson, James, G1 aCushman, Mary1 aJohnson, Andrew, D1 aEdwards, Todd, L1 aZakai, Neil, A1 aLettre, Guillaume1 aReiner, Alex, P1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/714604937nas a2201345 4500008004100000022001400041245012400055210006900179260001300248300001200261490000700273520113500280100001601415700001901431700002301450700002301473700002301496700001901519700001801538700002401556700001801580700001801598700001701616700001901633700002001652700002201672700002301694700001901717700001901736700001801755700001901773700001601792700001401808700002601822700001501848700002601863700001601889700001301905700001301918700001901931700002201950700002001972700002101992700002002013700001402033700001902047700001802066700002402084700002202108700001902130700002402149700002002173700001202193700002702205700002202232700002002254700002402274700002802298700002402326700002102350700002402371700002102395700002202416700002802438700002102466700002702487700003002514700002002544700001502564700002402579700002002603700001702623700002302640700001902663700001902682700002202701700002202723700001802745700002202763700001902785700001902804700001402823700001802837700001402855700002102869700002302890700002802913700001702941700001902958700001902977700001702996700002003013700002103033700002403054700002503078700002303103700002303126700002103149700002603170700002203196700002003218700002003238700002003258700002003278700002903298700001703327700002303344710002603367710002303393710002603416710002503442710006603467710002203533856003603555 2016 eng d a1546-171800aMeta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.0 aMetaanalysis identifies common and rare variants influencing blo c2016 Oct a1162-700 v483 aMeta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
1 aLiu, Chunyu1 aKraja, Aldi, T1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aFranceschini, Nora1 aBis, Joshua, C1 aRice, Kenneth1 aMorrison, Alanna, C1 aLu, Yingchang1 aWeiss, Stefan1 aGuo, Xiuqing1 aPalmas, Walter1 aMartin, Lisa, W1 aChen, Yii-Der Ida1 aSurendran, Praveen1 aDrenos, Fotios1 aCook, James, P1 aAuer, Paul, L1 aChu, Audrey, Y1 aGiri, Ayush1 aZhao, Wei1 aJakobsdottir, Johanna1 aLin, Li-An1 aStafford, Jeanette, M1 aAmin, Najaf1 aMei, Hao1 aYao, Jie1 aVoorman, Arend1 aLarson, Martin, G1 aGrove, Megan, L1 aSmith, Albert, V1 aHwang, Shih-Jen1 aChen, Han1 aHuan, Tianxiao1 aKosova, Gulum1 aStitziel, Nathan, O1 aKathiresan, Sekar1 aSamani, Nilesh1 aSchunkert, Heribert1 aDeloukas, Panos1 aLi, Man1 aFuchsberger, Christian1 aPattaro, Cristian1 aGorski, Mathias1 aKooperberg, Charles1 aPapanicolaou, George, J1 aRossouw, Jacques, E1 aFaul, Jessica, D1 aKardia, Sharon, L R1 aBouchard, Claude1 aRaffel, Leslie, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aVasan, Ramachandran, S1 aO'Donnell, Christopher, J1 aTaylor, Kent, D1 aLiu, Kiang1 aBottinger, Erwin, P1 aGottesman, Omri1 aDaw, Warwick1 aGiulianini, Franco1 aGanesh, Santhi1 aSalfati, Elias1 aHarris, Tamara, B1 aLauner, Lenore, J1 aDörr, Marcus1 aFelix, Stephan, B1 aRettig, Rainer1 aVölzke, Henry1 aKim, Eric1 aLee, Wen-Jane1 aLee, I-Te1 aSheu, Wayne, H-H1 aTsosie, Krystal, S1 aEdwards, Digna, R Velez1 aLiu, Yongmei1 aCorrea, Adolfo1 aWeir, David, R1 aVölker, Uwe1 aRidker, Paul, M1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aReiner, Alexander, P1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aEdwards, Todd, L1 aChakravarti, Aravinda1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aLoos, Ruth, J F1 aFornage, Myriam1 aEhret, Georg, B1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aChasman, Daniel, I1 aCHD Exome+ Consortium1 aExomeBP Consortium1 aGoT2DGenes Consortium1 aT2D-GENES Consortium1 aMyocardial Infarction Genetics and CARDIoGRAM Exome Consortia1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/726405480nas a2201321 4500008004100000022001400041245007700055210006900132260001600201520175400217100002301971700001901994700002402013700001902037700001802056700002102074700002302095700001702118700002002135700001802155700001702173700002002190700002002210700002802230700002502258700001802283700002402301700001702325700002402342700002102366700002002387700001902407700001302426700003102439700001602470700001702486700002302503700001802526700002202544700002502566700002002591700002102611700001902632700001902651700002102670700002102691700002202712700002202734700002302756700001902779700001802798700001902816700001802835700001902853700002002872700002402892700001902916700002202935700002002957700001902977700002502996700002203021700002303043700002003066700002303086700001903109700002603128700002203154700002103176700002003197700001603217700002503233700002303258700002303281700002203304700002603326700002103352700002203373700002003395700002203415700002003437700002303457700002803480700002203508700002203530700001703552700002303569700002503592700001803617700002403635700002103659700002103680700002103701700002203722700001803744700001903762700002203781700002403803700002203827700002003849700002903869700002003898700002103918700002203939700002103961700002303982700001904005700002204024700002404046700003004070710002204100856003604122 2016 eng d a1942-326800aMultiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.0 aMultiethnic ExomeWide Association Study of Subclinical Atheroscl c2016 Nov 213 aBACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.
METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).
CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.
1 aNatarajan, Pradeep1 aBis, Joshua, C1 aBielak, Lawrence, F1 aCox, Amanda, J1 aDörr, Marcus1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aIsaacs, Aaron1 aJhun, Min, A1 aKavousi, Maryam1 aLi-Gao, Ruifang1 aLyytikäinen, Leo-Pekka1 aMarioni, Riccardo, E1 aSchminke, Ulf1 aStitziel, Nathan, O1 aTada, Hayato1 avan Setten, Jessica1 aSmith, Albert, V1 aVojinovic, Dina1 aYanek, Lisa, R1 aYao, Jie1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aBaber, Usman1 aBorecki, Ingrid, B1 aCarr, Jeffrey1 aChen, Yii-Der Ida1 aCupples, Adrienne, L1 ade Jong, Pim, A1 ade Koning, Harry1 ade Vos, Bob, D1 aDemirkan, Ayse1 aFuster, Valentin1 aFranco, Oscar, H1 aGoodarzi, Mark, O1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHoffmann, Udo1 aHofman, Albert1 aIšgum, Ivana1 aJukema, Wouter1 aKähönen, Mika1 aKardia, Sharon, L R1 aKral, Brian, G1 aLauner, Lenore, J1 aMassaro, Joseph1 aMehran, Roxana1 aMitchell, Braxton, D1 aMosley, Thomas, H1 ade Mutsert, Renée1 aNewman, Anne, B1 aNguyen, Khanh-Dung1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOudkerk, Matthijs1 aPankow, James, S1 aPeloso, Gina, M1 aPost, Wendy1 aProvince, Michael, A1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRivadeneira, Fernando1 aRosendaal, Frits1 aSartori, Samantha1 aTaylor, Kent, D1 aTeumer, Alexander1 aTrompet, Stella1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Lugt, Aad1 aVölker, Uwe1 aWardlaw, Joanna, M1 aWassel, Christina, L1 aWeiss, Stefan1 aWojczynski, Mary, K1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBowden, Donald, W1 aDeary, Ian, J1 aDehghan, Abbas1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aLehtimäki, Terho1 aMathias, Rasika1 aMook-Kanamori, Dennis, O1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRotter, Jerome, I1 aWilson, James, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aKathiresan, Sekar1 aPeyser, Patricia, A1 aO'Donnell, Christopher, J1 aCHARGE Consortium uhttps://chs-nhlbi.org/node/725703468nas a2200541 4500008004100000022001400041245007100055210006900126260001300195300001000208490000600218520192500224100002302149700001702172700002602189700001602215700002602231700002002257700002302277700002502300700002202325700001802347700001902365700002002384700002202404700002202426700002002448700002402468700002202492700001402514700002002528700002402548700002502572700001602597700001902613700002802632700001602660700001902676700001902695700002402714700002202738700002102760700002302781700002002804700001802824710004802842856003602890 2016 eng d a1942-326800aNovel Genetic Loci Associated With Retinal Microvascular Diameter.0 aNovel Genetic Loci Associated With Retinal Microvascular Diamete c2016 Feb a45-540 v93 aBACKGROUND: There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.
METHODS AND RESULTS: This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).
CONCLUSIONS: Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
1 aJensen, Richard, A1 aSim, Xueling1 aSmith, Albert, Vernon1 aLi, Xiaohui1 aJakobsdottir, Johanna1 aCheng, Ching-Yu1 aBrody, Jennifer, A1 aCotch, Mary, Frances1 aMcKnight, Barbara1 aKlein, Ronald1 aWang, Jie, Jin1 aKifley, Annette1 aHarris, Tamara, B1 aLauner, Lenore, J1 aTaylor, Kent, D1 aKlein, Barbara, E K1 aRaffel, Leslie, J1 aLi, Xiang1 aIkram, Arfan, M1 aKlaver, Caroline, C1 avan der Lee, Sven, J1 aMutlu, Unal1 aHofman, Albert1 aUitterlinden, André, G1 aLiu, Chunyu1 aKraja, Aldi, T1 aMitchell, Paul1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aWong, Tien, Y1 aCHARGE Exome Chip Blood Pressure Consortium uhttps://chs-nhlbi.org/node/690006109nas a2201525 4500008004100000022001400041245009200055210006900147260001500216300001000231490000700241520179700248100002002045700002002065700002002085700002002105700002002125700001902145700002402164700002202188700002202210700002102232700001802253700002302271700001602294700002302310700002102333700002102354700001602375700001702391700001702408700002502425700002102450700001202471700002602483700002302509700002102532700002102553700001602574700002302590700002802613700001702641700002302658700002002681700002102701700001802722700002302740700002202763700001802785700001902803700002602822700002302848700002102871700002302892700002002915700002502935700002002960700002002980700002203000700002403022700002203046700002003068700002103088700002403109700001903133700002403152700002003176700001803196700002403214700002003238700002603258700002203284700002203306700002403328700002803352700002403380700001703404700002203421700002203443700002103465700002503486700002103511700001203532700001703544700002103561700002103582700001803603700002103621700002103642700001603663700002703679700001903706700002303725700002203748700002203770700002503792700001903817700002803836700002403864700002003888700002103908700002003929700002003949700002103969700002003990700001604010700002404026700002204050700001804072700002404090700001704114700001904131700001904150700002604169700002804195700002104223700001904244700002104263700002204284700002204306700002004328700001804348700002004366700002204386700002304408710003804431710003204469710004604501856003604547 2016 eng d a1537-660500aPlatelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.0 aPlateletRelated Variants Identified by Exomechip Metaanalysis in c2016 Jul 7 a40-550 v993 aPlatelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
1 aEicher, John, D1 aChami, Nathalie1 aKacprowski, Tim1 aNomura, Akihiro1 aChen, Ming-Huei1 aYanek, Lisa, R1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aSlater, Andrew, J1 aPankratz, Nathan1 aPolfus, Linda1 aSchurmann, Claudia1 aGiri, Ayush1 aBrody, Jennifer, A1 aLange, Leslie, A1 aManichaikul, Ani1 aHill, David1 aPazoki, Raha1 aElliot, Paul1 aEvangelou, Evangelos1 aTzoulaki, Ioanna1 aGao, He1 aVergnaud, Anne-Claire1 aMathias, Rasika, A1 aBecker, Diane, M1 aBecker, Lewis, C1 aBurt, Amber1 aCrosslin, David, R1 aLyytikäinen, Leo-Pekka1 aNikus, Kjell1 aHernesniemi, Jussi1 aKähönen, Mika1 aRaitoharju, Emma1 aMononen, Nina1 aRaitakari, Olli, T1 aLehtimäki, Terho1 aCushman, Mary1 aZakai, Neil, A1 aNickerson, Deborah, A1 aRaffield, Laura, M1 aQuarells, Rakale1 aWiller, Cristen, J1 aPeloso, Gina, M1 aAbecasis, Goncalo, R1 aLiu, Dajiang, J1 aDeloukas, Panos1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aFornage, Myriam1 aRichard, Melissa1 aTardif, Jean-Claude1 aRioux, John, D1 aDubé, Marie-Pierre1 ade Denus, Simon1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSmith, Albert, Vernon1 aHarris, Tamara, B1 aLauner, Lenore, J1 aGudnason, Vilmundur1 aEdwards, Digna, R Velez1 aTorstenson, Eric, S1 aLiu, Yongmei1 aTracy, Russell, P1 aRotter, Jerome, I1 aRich, Stephen, S1 aHighland, Heather, M1 aBoerwinkle, Eric1 aLi, Jin1 aLange, Ethan1 aWilson, James, G1 aMihailov, Evelin1 aMägi, Reedik1 aHirschhorn, Joel1 aMetspalu, Andres1 aEsko, Tõnu1 aVacchi-Suzzi, Caterina1 aNalls, Mike, A1 aZonderman, Alan, B1 aEvans, Michele, K1 aEngström, Gunnar1 aOrho-Melander, Marju1 aMelander, Olle1 aO'Donoghue, Michelle, L1 aWaterworth, Dawn, M1 aWallentin, Lars1 aWhite, Harvey, D1 aFloyd, James, S1 aBartz, Traci, M1 aRice, Kenneth, M1 aPsaty, Bruce, M1 aStarr, J, M1 aLiewald, David, C M1 aHayward, Caroline1 aDeary, Ian, J1 aGreinacher, Andreas1 aVölker, Uwe1 aThiele, Thomas1 aVölzke, Henry1 avan Rooij, Frank, J A1 aUitterlinden, André, G1 aFranco, Oscar, H1 aDehghan, Abbas1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aKathiresan, Sekar1 aFaraday, Nauder1 aAuer, Paul, L1 aReiner, Alex, P1 aLettre, Guillaume1 aJohnson, Andrew, D1 aGlobal Lipids Genetics Consortium1 aCARDIoGRAM Exome Consortium1 aMyocardial Infarction Genetics Consortium uhttps://chs-nhlbi.org/node/713903298nas a2200793 4500008004100000022001400041245008800055210006900143260001300212300001300225490000700238520090200245100002601147700002501173700001901198700002201217700002201239700002101261700002001282700001401302700002101316700002101337700002401358700002301382700002101405700001601426700001801442700003001460700002101490700002601511700002001537700001801557700002001575700002301595700002201618700002001640700002001660700002001680700002101700700002101721700002401742700002301766700002001789700002401809700002101833700002001854700001701874700002801891700002001919700002201939700001901961700003001980700002802010700002202038700001902060700001802079700002002097700002802117700002102145700002002166700002002186700002302206700002402229700002302253710007602276710004502352710007102397856003602468 2016 eng d a1553-740400aRare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.0 aRare Functional Variant in TM2D3 is Associated with LateOnset Al c2016 Oct ae10063270 v123 aWe performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
1 aJakobsdottir, Johanna1 avan der Lee, Sven, J1 aBis, Joshua, C1 aChouraki, Vincent1 aLi-Kroeger, David1 aYamamoto, Shinya1 aGrove, Megan, L1 aNaj, Adam1 aVronskaya, Maria1 aSalazar, Jose, L1 aDeStefano, Anita, L1 aBrody, Jennifer, A1 aSmith, Albert, V1 aAmin, Najaf1 aSims, Rebecca1 aIbrahim-Verbaas, Carla, A1 aChoi, Seung-Hoan1 aSatizabal, Claudia, L1 aLopez, Oscar, L1 aBeiser, Alexa1 aIkram, Arfan, M1 aGarcia, Melissa, E1 aHayward, Caroline1 aVarga, Tibor, V1 aRipatti, Samuli1 aFranks, Paul, W1 aHallmans, Göran1 aRolandsson, Olov1 aJansson, Jan-Håkon1 aPorteous, David, J1 aSalomaa, Veikko1 aEiriksdottir, Gudny1 aRice, Kenneth, M1 aBellen, Hugo, J1 aLevy, Daniel1 aUitterlinden, André, G1 aEmilsson, Valur1 aRotter, Jerome, I1 aAspelund, Thor1 aO'Donnell, Christopher, J1 aFitzpatrick, Annette, L1 aLauner, Lenore, J1 aHofman, Albert1 aSan Wang, Li-1 aWilliams, Julie1 aSchellenberg, Gerard, D1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aShulman, Joshua, M1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium1 aAlzheimer’s Disease Genetic Consortium1 aGenetic and Environmental Risk in Alzheimer’s Disease consortium uhttps://chs-nhlbi.org/node/726006988nas a2201993 4500008004100000022001400041245011600055210006900171260001600240520137500256100001201631700001301643700001801656700002201674700002201696700002501718700001801743700002701761700002001788700002801808700001901836700002001855700002101875700001801896700001601914700002801930700001901958700002501977700002302002700002302025700002302048700002502071700001902096700002102115700002102136700002202157700002102179700002302200700001502223700001802238700001902256700002102275700001702296700001702313700001602330700002002346700002802366700001802394700001902412700002002431700001702451700001802468700001802486700002202504700002102526700002102547700002902568700002302597700002202620700001702642700002202659700003202681700002102713700002302734700002102757700003102778700001402809700002202823700001902845700001602864700002102880700002102901700002302922700002302945700002402968700001902992700002103011700002303032700002103055700002003076700002403096700001803120700001703138700002003155700001803175700002003193700002403213700002103237700002103258700002503279700002203304700001603326700002103342700001703363700002203380700002303402700002003425700001803445700002403463700002203487700002203509700001903531700001903550700001703569700002803586700002403614700002303638700002503661700002003686700002403706700002103730700002403751700002203775700002203797700002303819700002203842700001703864700002103881700002103902700001703923700002003940700001803960700002503978700001904003700002104022700001904043700002004062700002104082700002504103700001804128700001904146700002004165700001904185700001904204700002004223700002904243700002004272700001104292700002304303700002004326700001904346700002004365700002604385700002404411700001904435700002104454700002004475700002404495700002104519700002304540700002804563700001804591700002304609700001704632700001904649700002604668700001904694700001904713700001804732700002304750700002104773700002304794700002304817700001904840700001904859710003904878710004104917856003604958 2016 eng d a1533-345000aSOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.0 aSOS2 and ACP1 Loci Identified through LargeScale Exome Chip Anal c2016 Dec 053 aGenome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
1 aLi, Man1 aLi, Yong1 aWeeks, Olivia1 aMijatovic, Vladan1 aTeumer, Alexander1 aHuffman, Jennifer, E1 aTromp, Gerard1 aFuchsberger, Christian1 aGorski, Mathias1 aLyytikäinen, Leo-Pekka1 aNutile, Teresa1 aSedaghat, Sanaz1 aSorice, Rossella1 aTin, Adrienne1 aYang, Qiong1 aAhluwalia, Tarunveer, S1 aArking, Dan, E1 aBihlmeyer, Nathan, A1 aBöger, Carsten, A1 aCarroll, Robert, J1 aChasman, Daniel, I1 aCornelis, Marilyn, C1 aDehghan, Abbas1 aFaul, Jessica, D1 aFeitosa, Mary, F1 aGambaro, Giovanni1 aGasparini, Paolo1 aGiulianini, Franco1 aHeid, Iris1 aHuang, Jinyan1 aImboden, Medea1 aJackson, Anne, U1 aJeff, Janina1 aJhun, Min, A1 aKatz, Ronit1 aKifley, Annette1 aKilpeläinen, Tuomas, O1 aKumar, Ashish1 aLaakso, Markku1 aLi-Gao, Ruifang1 aLohman, Kurt1 aLu, Yingchang1 aMägi, Reedik1 aMalerba, Giovanni1 aMihailov, Evelin1 aMohlke, Karen, L1 aMook-Kanamori, Dennis, O1 aRobino, Antonietta1 aRuderfer, Douglas1 aSalvi, Erika1 aSchick, Ursula, M1 aSchulz, Christina-Alexandra1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTraglia, Michela1 aYerges-Armstrong, Laura, M1 aZhao, Wei1 aGoodarzi, Mark, O1 aKraja, Aldi, T1 aLiu, Chunyu1 aWessel, Jennifer1 aBoerwinkle, Eric1 aBorecki, Ingrid, B1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBraga, Daniele1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarey, David, J1 aChristensen, Cramer1 aCoresh, Josef1 aCrook, Errol1 aCurhan, Gary, C1 aCusi, Daniele1 ade Boer, Ian, H1 ade Vries, Aiko, P J1 aDenny, Joshua, C1 aDevuyst, Olivier1 aDreisbach, Albert, W1 aEndlich, Karlhans1 aEsko, Tõnu1 aFranco, Oscar, H1 aFulop, Tibor1 aGerhard, Glenn, S1 aGlümer, Charlotte1 aGottesman, Omri1 aGrarup, Niels1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHayward, Caroline1 aHocking, Lynne1 aHofman, Albert1 aHu, Frank, B1 aHusemoen, Lise, Lotte N1 aJackson, Rebecca, D1 aJørgensen, Torben1 aJørgensen, Marit, E1 aKähönen, Mika1 aKardia, Sharon, L R1 aKönig, Wolfgang1 aKooperberg, Charles1 aKriebel, Jennifer1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLehtimäki, Terho1 aLevy, Daniel1 aLinksted, Pamela1 aLinneberg, Allan1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLupo, Antonio1 aMeisinger, Christine1 aMelander, Olle1 aMetspalu, Andres1 aMitchell, Paul1 aNauck, Matthias1 aNürnberg, Peter1 aOrho-Melander, Marju1 aParsa, Afshin1 aPedersen, Oluf1 aPeters, Annette1 aPeters, Ulrike1 aPolasek, Ozren1 aPorteous, David1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aQi, Lu1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRettig, Rainer1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRossouw, Jacques, E1 aSchmidt, Frank1 aSiscovick, David1 aSoranzo, Nicole1 aStrauch, Konstantin1 aToniolo, Daniela1 aTurner, Stephen, T1 aUitterlinden, André, G1 aUlivi, Sheila1 aVelayutham, Dinesh1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWang, Jie, Jin1 aWeir, David, R1 aWitte, Daniel1 aKuivaniemi, Helena1 aFox, Caroline, S1 aFranceschini, Nora1 aGoessling, Wolfram1 aKöttgen, Anna1 aChu, Audrey, Y1 aCHARGE Glycemic-T2D Working Group,1 aCHARGE Blood Pressure Working Group, uhttps://chs-nhlbi.org/node/725504071nas a2200973 4500008004100000022001400041245007600055210006800131260001600199300001200215490000600227520134400233100002101577700001901598700001801617700002401635700002301659700002001682700001701702700001801719700002101737700002101758700002001779700002101799700002101820700002001841700002001861700002101881700002601902700002101928700001201949700002401961700002001985700002402005700001902029700001902048700001802067700002202085700002202107700001802129700002302147700002502170700002002195700002102215700001902236700002402255700002202279700003602301700001902337700001902356700002602375700002002401700002602421700002102447700002002468700002302488700001702511700002102528700002302549700002802572700001902600700001402619700001902633700002302652700002002675700002202695700002402717700001802741700002202759700002402781700002202805700002602827700002402853700001902877700002302896700001702919700002102936700002302957700002002980700002103000700002403021700001603045856003603061 2017 eng d a1945-458900aThe complex genetics of gait speed: genome-wide meta-analysis approach.0 acomplex genetics of gait speed genomewide metaanalysis approach c2017 Jan 10 a209-2460 v93 aEmerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
1 aBen-Avraham, Dan1 aKarasik, David1 aVerghese, Joe1 aLunetta, Kathryn, L1 aSmith, Jennifer, A1 aEicher, John, D1 aVered, Rotem1 aDeelen, Joris1 aArnold, Alice, M1 aBuchman, Aron, S1 aTanaka, Toshiko1 aFaul, Jessica, D1 aNethander, Maria1 aFornage, Myriam1 aAdams, Hieab, H1 aMatteini, Amy, M1 aCallisaya, Michele, L1 aSmith, Albert, V1 aYu, Lei1 aDe Jager, Philip, L1 aEvans, Denis, A1 aGudnason, Vilmundur1 aHofman, Albert1 aPattie, Alison1 aCorley, Janie1 aLauner, Lenore, J1 aKnopman, Davis, S1 aParimi, Neeta1 aTurner, Stephen, T1 aBandinelli, Stefania1 aBeekman, Marian1 aGutman, Danielle1 aSharvit, Lital1 aMooijaart, Simon, P1 aLiewald, David, C1 aHouwing-Duistermaat, Jeanine, J1 aOhlsson, Claes1 aMoed, Matthijs1 aVerlinden, Vincent, J1 aMellström, Dan1 avan der Geest, Jos, N1 aKarlsson, Magnus1 aHernandez, Dena1 aMcWhirter, Rebekah1 aLiu, Yongmei1 aThomson, Russell1 aTranah, Gregory, J1 aUitterlinden, André, G1 aWeir, David, R1 aZhao, Wei1 aStarr, John, M1 aJohnson, Andrew, D1 aIkram, Arfan, M1 aBennett, David, A1 aCummings, Steven, R1 aDeary, Ian, J1 aHarris, Tamara, B1 aKardia, Sharon, L R1 aMosley, Thomas, H1 aSrikanth, Velandai, K1 aWindham, Beverly, G1 aNewman, Ann, B1 aWalston, Jeremy, D1 aDavies, Gail1 aEvans, Daniel, S1 aSlagboom, Eline, P1 aFerrucci, Luigi1 aKiel, Douglas, P1 aMurabito, Joanne, M1 aAtzmon, Gil uhttps://chs-nhlbi.org/node/734006088nas a2201561 4500008004100000022001400041245007200055210006900127260001600196520173100212100002801943700002101971700002401992700001802016700002002034700002202054700002502076700001602101700001802117700001802135700001802153700002002171700002002191700001502211700002302226700003002249700001902279700001302298700002102311700002802332700002002360700002402380700002002404700001902424700001802443700002102461700002102482700002102503700001702524700002202541700001902563700001902582700002002601700002502621700002302646700002202669700002402691700002102715700002402736700002202760700002202782700001702804700002302821700001902844700002202863700002302885700001902908700002002927700002002947700002402967700001802991700002203009700001203031700001303043700002103056700001503077700002503092700002103117700002203138700002103160700002203181700002703203700001703230700002503247700002003272700002303292700001803315700002003333700001503353700002303368700002603391700002203417700001603439700001903455700001703474700002203491700002403513700002403537700002203561700002603583700002003609700002103629700002403650700002103674700001803695700002403713700001703737700002603754700001603780700002803796700001903824700001903843700002103862700002003883700002303903700002403926700001903950700002703969700002203996700002204018700002404040700001804064700002204082700001904104700002204123700002304145700002304168700001804191700002904209700002004238700001904258700002204277700001804299700002404317700002204341700001904363700002404382700001504406700002204421700002304443700002404466856003604490 2017 eng d a1460-208300aDiscovery of novel heart rate-associated loci using the Exome Chip.0 aDiscovery of novel heart rateassociated loci using the Exome Chi c2017 Apr 033 aBackground Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
1 avan den Berg, Marten, E1 aWarren, Helen, R1 aCabrera, Claudia, P1 aVerweij, Niek1 aMifsud, Borbala1 aHaessler, Jeffrey1 aBihlmeyer, Nathan, A1 aFu, Yi-Ping1 aWeiss, Stefan1 aLin, Henry, J1 aGrarup, Niels1 aLi-Gao, Ruifang1 aPistis, Giorgio1 aShah, Nabi1 aBrody, Jennifer, A1 aMüller-Nurasyid, Martina1 aLin, Honghuang1 aMei, Hao1 aSmith, Albert, V1 aLyytikäinen, Leo-Pekka1 aHall, Leanne, M1 avan Setten, Jessica1 aTrompet, Stella1 aPrins, Bram, P1 aIsaacs, Aaron1 aRadmanesh, Farid1 aMarten, Jonathan1 aEntwistle, Aiman1 aKors, Jan, A1 aSilva, Claudia, T1 aAlonso, Alvaro1 aBis, Joshua, C1 ade Boer, Rudolf1 ade Haan, Hugoline, G1 ade Mutsert, Renée1 aDedoussis, George1 aDominiczak, Anna, F1 aDoney, Alex, S F1 aEllinor, Patrick, T1 aEppinga, Ruben, N1 aFelix, Stephan, B1 aGuo, Xiuqing1 aHagemeijer, Yanick1 aHansen, Torben1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHuang, Paul, L1 aHwang, Shih-Jen1 aKähönen, Mika1 aKanters, Jørgen, K1 aKolcic, Ivana1 aLauner, Lenore, J1 aLi, Man1 aYao, Jie1 aLinneberg, Allan1 aLiu, Simin1 aMacfarlane, Peter, W1 aMangino, Massimo1 aMorris, Andrew, D1 aMulas, Antonella1 aMurray, Alison, D1 aNelson, Christopher, P1 aOrrù, Marco1 aPadmanabhan, Sandosh1 aPeters, Annette1 aPorteous, David, J1 aPoulter, Neil1 aPsaty, Bruce, M1 aQi, Lihong1 aRaitakari, Olli, T1 aRivadeneira, Fernando1 aRoselli, Carolina1 aRudan, Igor1 aSattar, Naveed1 aSever, Peter1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStanton, Alice, V1 aStirrups, Kathleen, E1 aTaylor, Kent, D1 aTobin, Martin, D1 aUitterlinden, Andre1 aVaartjes, Ilonca1 aHoes, Arno, W1 avan der Meer, Peter1 aVölker, Uwe1 aWaldenberger, Melanie1 aXie, Zhijun1 aZoledziewska, Magdalena1 aTinker, Andrew1 aPolasek, Ozren1 aRosand, Jonathan1 aJamshidi, Yalda1 aDuijn, Cornelia, M1 aZeggini, Eleftheria1 aJukema, Wouter1 aAsselbergs, Folkert, W1 aSamani, Nilesh, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aWilson, James1 aLubitz, Steven, A1 aKääb, Stefan1 aSotoodehnia, Nona1 aCaulfield, Mark, J1 aPalmer, Colin, N A1 aSanna, Serena1 aMook-Kanamori, Dennis, O1 aDeloukas, Panos1 aPedersen, Oluf1 aRotter, Jerome, I1 aDörr, Marcus1 aO'Donnell, Chris, J1 aHayward, Caroline1 aArking, Dan, E1 aKooperberg, Charles1 aHarst, Pim1 aEijgelsheim, Mark1 aStricker, Bruno, H1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/736309668nas a2203061 4500008004100000022001400041245007500055210006900130260001300199300001400212490000700226520116500233653002801398653003001426653001001456653003201466653003801498653002201536653001301558653001101571653001101582653002501593653001401618653001701632100002001649700002001669700001501689700002501704700001501729700002001744700002101764700001801785700001601803700003101819700002201850700003001872700002401902700002901926700001801955700001701973700002801990700001702018700001902035700001902054700002102073700002102094700002302115700002402138700002102162700001802183700002002201700002302221700002202244700002302266700001702289700002202306700001902328700002402347700001902371700002102390700002102411700002502432700002302457700001702480700001802497700002202515700002102537700002102558700002402579700002002603700002402623700001602647700002502663700002102688700002002709700002002729700001402749700002002763700002002783700002502803700002502828700002202853700002302875700002102898700002202919700001302941700002302954700002202977700002302999700002203022700002103044700001803065700001603083700002003099700002403119700001903143700002203162700002203184700002403206700002303230700002203253700001403275700002003289700002003309700002103329700002603350700002703376700002003403700002503423700001903448700002503467700002103492700002203513700001903535700001503554700001903569700001803588700002503606700002203631700002403653700002003677700002203697700001903719700001603738700002403754700001903778700002203797700002303819700002403842700001603866700002103882700002003903700001803923700001803941700001803959700002303977700002104000700002204021700002404043700002004067700002504087700002004112700002004132700001904152700002104171700002204192700002404214700002104238700003004259700002404289700002104313700002204334700002104356700002804377700002104405700001904426700002904445700002504474700002204499700002204521700002504543700002304568700001804591700002304609700001904632700001904651700002004670700002404690700002004714700001904734700001804753700002004771700002104791700001804812700002104830700002204851700002004873700002004893700002104913700002004934700001904954700002304973700001804996700002205014700001605036700002005052700002205072700001805094700001905112700002205131700002105153700001705174700002305191700002605214700001705240700002805257700002105285700002105306700002005327700002605347700002205373700002405395700002805419700001905447700002605466700002105492700002405513700002605537700002305563700001705586700001805603700001405621700002405635700002005659700002005679700002005699700002305719700002605742700002705768700001805795700002005813700001905833700002605852700001405878700002105892700002105913700002005934700002205954700002105976700002105997700002306018700001306041700002306054700001706077700002406094700001406118700001906132700001806151700001506169700001406184700001706198700002806215700002406243700001706267700002206284700001906306700002206325700002006347700002006367700002306387700002206410710003406432710002906466710002406495710002006519710003106539856003606570 2017 eng d a1546-171800aExome-wide association study of plasma lipids in >300,000 individuals.0 aExomewide association study of plasma lipids in 300000 individua c2017 Dec a1758-17660 v493 aWe screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aExome10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aHumans10aLipids10aMacular Degeneration10aPhenotype10aRisk Factors1 aLiu, Dajiang, J1 aPeloso, Gina, M1 aYu, Haojie1 aButterworth, Adam, S1 aWang, Xiao1 aMahajan, Anubha1 aSaleheen, Danish1 aEmdin, Connor1 aAlam, Dewan1 aAlves, Alexessander, Couto1 aAmouyel, Philippe1 aDi Angelantonio, Emanuele1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aAuer, Paul, L1 aBaber, Usman1 aBallantyne, Christie, M1 aBang, Lia, E1 aBenn, Marianne1 aBis, Joshua, C1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrandslund, Ivan1 aBrown, Morris1 aBusonero, Fabio1 aCaulfield, Mark, J1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Eugene1 aChen, Yii-Der Ida1 aChowdhury, Raj1 aChristensen, Cramer1 aChu, Audrey, Y1 aConnell, John, M1 aCucca, Francesco1 aCupples, Adrienne, L1 aDamrauer, Scott, M1 aDavies, Gail1 aDeary, Ian, J1 aDedoussis, George1 aDenny, Joshua, C1 aDominiczak, Anna1 aDubé, Marie-Pierre1 aEbeling, Tapani1 aEiriksdottir, Gudny1 aEsko, Tõnu1 aFarmaki, Aliki-Eleni1 aFeitosa, Mary, F1 aFerrario, Marco1 aFerrieres, Jean1 aFord, Ian1 aFornage, Myriam1 aFranks, Paul, W1 aFrayling, Timothy, M1 aFrikke-Schmidt, Ruth1 aFritsche, Lars, G1 aFrossard, Philippe1 aFuster, Valentin1 aGanesh, Santhi, K1 aGao, Wei1 aGarcia, Melissa, E1 aGieger, Christian1 aGiulianini, Franco1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGrarup, Niels1 aGroop, Leif1 aGrove, Megan, L1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHirschhorn, Joel, N1 aHolmen, Oddgeir, L1 aHuffman, Jennifer1 aHuo, Yong1 aHveem, Kristian1 aJabeen, Sehrish1 aJackson, Anne, U1 aJakobsdottir, Johanna1 aJarvelin, Marjo-Riitta1 aJensen, Gorm, B1 aJørgensen, Marit, E1 aJukema, Wouter1 aJustesen, Johanne, M1 aKamstrup, Pia, R1 aKanoni, Stavroula1 aKarpe, Fredrik1 aKee, Frank1 aKhera, Amit, V1 aKlarin, Derek1 aKoistinen, Heikki, A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo1 aLangenberg, Claudia1 aLangsted, Anne1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLiewald, David, C M1 aLin, Li, An1 aLinneberg, Allan1 aLoos, Ruth, J F1 aLu, Yingchang1 aLu, Xiangfeng1 aMägi, Reedik1 aMälarstig, Anders1 aManichaikul, Ani1 aManning, Alisa, K1 aMäntyselkä, Pekka1 aMarouli, Eirini1 aMasca, Nicholas, G D1 aMaschio, Andrea1 aMeigs, James, B1 aMelander, Olle1 aMetspalu, Andres1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMulas, Antonella1 aMüller-Nurasyid, Martina1 aMunroe, Patricia, B1 aNeville, Matt, J1 aNielsen, Jonas, B1 aNielsen, Sune, F1 aNordestgaard, Børge, G1 aOrdovas, Jose, M1 aMehran, Roxana1 aO'Donnell, Christoper, J1 aOrho-Melander, Marju1 aMolony, Cliona, M1 aMuntendam, Pieter1 aPadmanabhan, Sandosh1 aPalmer, Colin, N A1 aPasko, Dorota1 aPatel, Aniruddh, P1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPisinger, Charlotta1 aPistis, Giorgio1 aPolasek, Ozren1 aPoulter, Neil1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRasheed, Asif1 aRauramaa, Rainer1 aReilly, Dermot, F1 aReiner, Alex, P1 aRenstrom, Frida1 aRich, Stephen, S1 aRidker, Paul, M1 aRioux, John, D1 aRobertson, Neil, R1 aRoden, Dan, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSanna, Serena1 aSattar, Naveed1 aSchmidt, Ellen, M1 aScott, Robert, A1 aSever, Peter1 aSevilla, Raquel, S1 aShaffer, Christian, M1 aSim, Xueling1 aSivapalaratnam, Suthesh1 aSmall, Kerrin, S1 aSmith, Albert, V1 aSmith, Blair, H1 aSomayajula, Sangeetha1 aSoutham, Lorraine1 aSpector, Timothy, D1 aSpeliotes, Elizabeth, K1 aStarr, John, M1 aStirrups, Kathleen, E1 aStitziel, Nathan1 aStrauch, Konstantin1 aStringham, Heather, M1 aSurendran, Praveen1 aTada, Hayato1 aTall, Alan, R1 aTang, Hua1 aTardif, Jean-Claude1 aTaylor, Kent, D1 aTrompet, Stella1 aTsao, Philip, S1 aTuomilehto, Jaakko1 aTybjaerg-Hansen, Anne1 avan Zuydam, Natalie, R1 aVarbo, Anette1 aVarga, Tibor, V1 aVirtamo, Jarmo1 aWaldenberger, Melanie1 aWang, Nan1 aWareham, Nick, J1 aWarren, Helen, R1 aWeeke, Peter, E1 aWeinstock, Joshua1 aWessel, Jennifer1 aWilson, James, G1 aWilson, Peter, W F1 aXu, Ming1 aYaghootkar, Hanieh1 aYoung, Robin1 aZeggini, Eleftheria1 aZhang, He1 aZheng, Neil, S1 aZhang, Weihua1 aZhang, Yan1 aZhou, Wei1 aZhou, Yanhua1 aZoledziewska, Magdalena1 aHowson, Joanna, M M1 aDanesh, John1 aMcCarthy, Mark, I1 aCowan, Chad, A1 aAbecasis, Goncalo1 aDeloukas, Panos1 aMusunuru, Kiran1 aWiller, Cristen, J1 aKathiresan, Sekar1 aCharge Diabetes Working Group1 aEPIC-InterAct Consortium1 aEPIC-CVD Consortium1 aGOLD Consortium1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/757304213nas a2200973 4500008004100000022001400041245013200055210006900187260001600256300001000272490000600282520142300288100001801711700002401729700003001753700002601783700002701809700002001836700001801856700001901874700002801893700002201921700002401943700001801967700002201985700002002007700002202027700001802049700001802067700002302085700002202108700002602130700002202156700002202178700002402200700001902224700002102243700002302264700002102287700002402308700002602332700002302358700002002381700002202401700002002423700002002443700001702463700002502480700001902505700002202524700001302546700001702559700003002576700002402606700002302630700001802653700002202671700001402693700001802707700002102725700002802746700001702774700002202791700001902813700001902832700002402851700001902875700001702894700001802911700001902929700002302948700002402971700002202995700002003017700001803037700002203055700001503077700001903092700002303111700002203134700002503156700002203181856003603203 2017 eng d a2045-232200aGenetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.0 aGenetic Interactions with Age Sex Body Mass Index and Hypertensi c2017 Sep 12 a113030 v73 aIt is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
1 aWeng, Lu-Chen1 aLunetta, Kathryn, L1 aMüller-Nurasyid, Martina1 aSmith, Albert, Vernon1 aThériault, Sébastien1 aWeeke, Peter, E1 aBarnard, John1 aBis, Joshua, C1 aLyytikäinen, Leo-Pekka1 aKleber, Marcus, E1 aMartinsson, Andreas1 aLin, Henry, J1 aRienstra, Michiel1 aTrompet, Stella1 aKrijthe, Bouwe, P1 aDörr, Marcus1 aKlarin, Derek1 aChasman, Daniel, I1 aSinner, Moritz, F1 aWaldenberger, Melanie1 aLauner, Lenore, J1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aParé, Guillaume1 aTeixeira, Pedro, L1 aDenny, Joshua, C1 aShoemaker, Benjamin1 aVan Wagoner, David, R1 aSmith, Jonathan, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aKähönen, Mika1 aNikus, Kjell1 aDelgado, Graciela, E1 aMelander, Olle1 aEngström, Gunnar1 aYao, Jie1 aGuo, Xiuqing1 aChristophersen, Ingrid, E1 aEllinor, Patrick, T1 aGeelhoed, Bastiaan1 aVerweij, Niek1 aMacfarlane, Peter1 aFord, Ian1 aHeeringa, Jan1 aFranco, Oscar, H1 aUitterlinden, André, G1 aVölker, Uwe1 aTeumer, Alexander1 aRose, Lynda, M1 aKääb, Stefan1 aGudnason, Vilmundur1 aArking, Dan, E1 aConen, David1 aRoden, Dan, M1 aChung, Mina, K1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aLehtimäki, Terho1 aMärz, Winfried1 aSmith, Gustav1 aRotter, Jerome, I1 aHarst, Pim1 aJukema, Wouter1 aStricker, Bruno, H1 aFelix, Stephan, B1 aAlbert, Christine, M1 aLubitz, Steven, A uhttps://chs-nhlbi.org/node/759504580nas a2200937 4500008004100000022001400041245022100055210006900276260001300345300001200358490000700370520179400377100002102171700002402192700002202216700002202238700002702260700002202287700002002309700002102329700001602350700002102366700001602387700001202403700002102415700001902436700002302455700001902478700002302497700002102520700002402541700002502565700001502590700002102605700002902626700002202655700002302677700002202700700001902722700002002741700001702761700002202778700001202800700002002812700002102832700001802853700002302871700002302894700002902917700001802946700002502964700002102989700001903010700002503029700002403054700001903078700001703097700002303114700002003137700002403157700002203181700002003203700001803223700002003241700002503261700002803286700002403314700002103338700002403359700001903383700002103402700001703423700002903440700002403469700002203493700002703515700002003542700002303562700002103585856003603606 2017 eng d a1468-624400aA genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.0 agenomewide interaction analysis of tricyclictetracyclic antidepr c2017 May a313-3230 v543 aBACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.
METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.
CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.
1 aNoordam, Raymond1 aSitlani, Colleen, M1 aAvery, Christy, L1 aStewart, James, D1 aGogarten, Stephanie, M1 aWiggins, Kerri, L1 aTrompet, Stella1 aWarren, Helen, R1 aSun, Fangui1 aEvans, Daniel, S1 aLi, Xiaohui1 aLi, Jin1 aSmith, Albert, V1 aBis, Joshua, C1 aBrody, Jennifer, A1 aBusch, Evan, L1 aCaulfield, Mark, J1 aChen, Yii-der, I1 aCummings, Steven, R1 aCupples, Adrienne, L1 aDuan, Qing1 aFranco, Oscar, H1 aMéndez-Giráldez, Rául1 aHarris, Tamara, B1 aHeckbert, Susan, R1 avan Heemst, Diana1 aHofman, Albert1 aFloyd, James, S1 aKors, Jan, A1 aLauner, Lenore, J1 aLi, Yun1 aLi-Gao, Ruifang1 aLange, Leslie, A1 aLin, Henry, J1 ade Mutsert, Renée1 aNapier, Melanie, D1 aNewton-Cheh, Christopher1 aPoulter, Neil1 aReiner, Alexander, P1 aRice, Kenneth, M1 aRoach, Jeffrey1 aRodriguez, Carlos, J1 aRosendaal, Frits, R1 aSattar, Naveed1 aSever, Peter1 aSeyerle, Amanda, A1 aSlagboom, Eline1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStott, David, J1 aStürmer, Til1 aTaylor, Kent, D1 aThornton, Timothy, A1 aUitterlinden, André, G1 aWilhelmsen, Kirk, C1 aWilson, James, G1 aGudnason, Vilmundur1 aJukema, Wouter1 aLaurie, Cathy, C1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aStricker, Bruno, H1 aWhitsel, Eric, A uhttps://chs-nhlbi.org/node/735304812nas a2201345 4500008004100000022001400041245014400055210006900199260001600268300001000284490000800294520106400302100002601366700001801392700002101410700001301431700002001444700002001464700002301484700002001507700002001527700001801547700002001565700001701585700002301602700001901625700002301644700001801667700002001685700002101705700002301726700001901749700001901768700002301787700001901810700001801829700001801847700002401865700001801889700002201907700002001929700002101949700002101970700002001991700002202011700002102033700002002054700001402074700002002088700001602108700001902124700002002143700002802163700002102191700001702212700002002229700001402249700002102263700002202284700002302306700001502329700001502344700001802359700002202377700002302399700002202422700001902444700002102463700001202484700002402496700002202520700001702542700002002559700002202579700002202601700002002623700001402643700002202657700002102679700002002700700002002720700002302740700002002763700002202783700002202805700001502827700002302842700002302865700002402888700002202912700001702934700001802951700001802969700001802987700002103005700002103026700001603047700002003063700002103083700002103104700002903125700002103154700002403175700003003199700001903229700002503248700002203273700002203295700002003317700002503337700002003362700002203382710002603404856003603430 2017 eng d a1537-660500aGenome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.0 aGenomewide Transethnic Metaanalysis Identifies Seven Genetic Loc c2017 Jan 05 a51-630 v1003 aGenome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.
1 avan Rooij, Frank, J A1 aQayyum, Rehan1 aSmith, Albert, V1 aZhou, Yi1 aTrompet, Stella1 aTanaka, Toshiko1 aKeller, Margaux, F1 aChang, Li-Ching1 aSchmidt, Helena1 aYang, Min-Lee1 aChen, Ming-Huei1 aHayes, James1 aJohnson, Andrew, D1 aYanek, Lisa, R1 aMueller, Christian1 aLange, Leslie1 aFloyd, James, S1 aGhanbari, Mohsen1 aZonderman, Alan, B1 aJukema, Wouter1 aHofman, Albert1 aDuijn, Cornelia, M1 aDesch, Karl, C1 aSaba, Yasaman1 aOzel, Ayse, B1 aSnively, Beverly, M1 aWu, Jer-Yuarn1 aSchmidt, Reinhold1 aFornage, Myriam1 aKlein, Robert, J1 aFox, Caroline, S1 aMatsuda, Koichi1 aKamatani, Naoyuki1 aWild, Philipp, S1 aStott, David, J1 aFord, Ian1 aSlagboom, Eline1 aYang, Jaden1 aChu, Audrey, Y1 aLambert, Amy, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aHofer, Edith1 aGinsburg, David1 aHu, Bella1 aKeating, Brendan1 aSchick, Ursula, M1 aBrody, Jennifer, A1 aLi, Jun, Z1 aChen, Zhao1 aZeller, Tanja1 aGuralnik, Jack, M1 aChasman, Daniel, I1 aPeters, Luanne, L1 aKubo, Michiaki1 aBecker, Diane, M1 aLi, Jin1 aEiriksdottir, Gudny1 aRotter, Jerome, I1 aLevy, Daniel1 aGrossmann, Vera1 aPatel, Kushang, V1 aChen, Chien-Hsiun1 aRidker, Paul, M1 aTang, Hua1 aLauner, Lenore, J1 aRice, Kenneth, M1 aLi-Gao, Ruifang1 aFerrucci, Luigi1 aEvans, Michelle, K1 aChoudhuri, Avik1 aTrompouki, Eirini1 aAbraham, Brian, J1 aYang, Song1 aTakahashi, Atsushi1 aKamatani, Yoichiro1 aKooperberg, Charles1 aHarris, Tamara, B1 aJee, Sun, Ha1 aCoresh, Josef1 aTsai, Fuu-Jen1 aLongo, Dan, L1 aChen, Yuan-Tsong1 aFelix, Janine, F1 aYang, Qiong1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aBecker, Lewis, C1 aMook-Kanamori, Dennis, O1 aWilson, James, G1 aGudnason, Vilmundur1 aO'Donnell, Christopher, J1 aDehghan, Abbas1 aCupples, Adrienne, L1 aNalls, Michael, A1 aMorris, Andrew, P1 aOkada, Yukinori1 aReiner, Alexander, P1 aZon, Leonard, I1 aGanesh, Santhi, K1 aBioBank Japan Project uhttps://chs-nhlbi.org/node/736408180nas a2202449 4500008004100000022001400041245010000055210006900155260001600224300000700240490000600247520139100253100002501644700002301669700001901692700003101711700001801742700001901760700002201779700001701801700001801818700002201836700002101858700001801879700001601897700002001913700002101933700002501954700002401979700002002003700001802023700001802041700002302059700001602082700002102098700001902119700002202138700001802160700001902178700002102197700002102218700002302239700002102262700001802283700002002301700002802321700002002349700002202369700002102391700001502412700001602427700002102443700002502464700002102489700002402510700002402534700001702558700003502575700002102610700002402631700002102655700001602676700002302692700001902715700001902734700002102753700002102774700001202795700002002807700002202827700001802849700002202867700002102889700001902910700001802929700002202947700002202969700001902991700002103010700001803031700001903049700002103068700001803089700002003107700002003127700001803147700002003165700002003185700002303205700002203228700001603250700002103266700001803287700002803305700001803333700002703351700002503378700002203403700002503425700002103450700002203471700001903493700001603512700001703528700002303545700002203568700002003590700002103610700002103631700001503652700002203667700001703689700001403706700001703720700002103737700002303758700002103781700002103802700002303823700002803846700002203874700001903896700002003915700001703935700002303952700002503975700002204000700002004022700001704042700002304059700002604082700001904108700002004127700001904147700002504166700001904191700001904210700002004229700001904249700002304268700002304291700002304314700002004337700002104357700002204378700001604400700002004416700002504436700002004461700001904481700001704500700001704517700001504534700002004549700002304569700001604592700002004608700002504628700003504653700002704688700002604715700002204741700002004763700002504783700002304808700002404831700002804855700001904883700002304902700002304925700002704948700001704975700002404992700001905016700002605035700001705061700002305078700001605101700002205117700002105139700002705160700002105187700002205208700001605230700001205246700001705258700002205275700002005297700002305317700002205340700002405362700002205386700002005408700002405428700002105452700002605473700002805499700002505527700002005552700002105572700002005593700001905613700002205632700001905654700002105673856003605694 2017 eng d a2041-172300aLarge meta-analysis of genome-wide association studies identifies five loci for lean body mass.0 aLarge metaanalysis of genomewide association studies identifies c2017 Jul 19 a800 v83 aLean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
1 aZillikens, Carola, M1 aDemissie, Serkalem1 aHsu, Yi-Hsiang1 aYerges-Armstrong, Laura, M1 aChou, Wen-Chi1 aStolk, Lisette1 aLivshits, Gregory1 aBroer, Linda1 aJohnson, Toby1 aKoller, Daniel, L1 aKutalik, Zoltán1 aLuan, Jian'an1 aMalkin, Ida1 aRied, Janina, S1 aSmith, Albert, V1 aThorleifsson, Gudmar1 aVandenput, Liesbeth1 aZhao, Jing, Hua1 aZhang, Weihua1 aAghdassi, Ali1 aÅkesson, Kristina1 aAmin, Najaf1 aBaier, Leslie, J1 aBarroso, Inês1 aBennett, David, A1 aBertram, Lars1 aBiffar, Rainer1 aBochud, Murielle1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aBuchman, Aron, S1 aByberg, Liisa1 aCampbell, Harry1 aObanda, Natalia, Campos1 aCauley, Jane, A1 aCawthon, Peggy, M1 aCederberg, Henna1 aChen, Zhao1 aCho, Nam, H1 aChoi, Hyung, Jin1 aClaussnitzer, Melina1 aCollins, Francis1 aCummings, Steven, R1 aDe Jager, Philip, L1 aDemuth, Ilja1 aDhonukshe-Rutten, Rosalie, A M1 aDiatchenko, Luda1 aEiriksdottir, Gudny1 aEnneman, Anke, W1 aErdos, Mike1 aEriksson, Johan, G1 aEriksson, Joel1 aEstrada, Karol1 aEvans, Daniel, S1 aFeitosa, Mary, F1 aFu, Mao1 aGarcia, Melissa1 aGieger, Christian1 aGirke, Thomas1 aGlazer, Nicole, L1 aGrallert, Harald1 aGrewal, Jagvir1 aHan, Bok-Ghee1 aHanson, Robert, L1 aHayward, Caroline1 aHofman, Albert1 aHoffman, Eric, P1 aHomuth, Georg1 aHsueh, Wen-Chi1 aHubal, Monica, J1 aHubbard, Alan1 aHuffman, Kim, M1 aHusted, Lise, B1 aIllig, Thomas1 aIngelsson, Erik1 aIttermann, Till1 aJansson, John-Olov1 aJordan, Joanne, M1 aJula, Antti1 aKarlsson, Magnus1 aKhaw, Kay-Tee1 aKilpeläinen, Tuomas, O1 aKlopp, Norman1 aKloth, Jacqueline, S L1 aKoistinen, Heikki, A1 aKraus, William, E1 aKritchevsky, Stephen1 aKuulasmaa, Teemu1 aKuusisto, Johanna1 aLaakso, Markku1 aLahti, Jari1 aLang, Thomas1 aLangdahl, Bente, L1 aLauner, Lenore, J1 aLee, Jong-Young1 aLerch, Markus, M1 aLewis, Joshua, R1 aLind, Lars1 aLindgren, Cecilia1 aLiu, Yongmei1 aLiu, Tian1 aLiu, Youfang1 aLjunggren, Osten1 aLorentzon, Mattias1 aLuben, Robert, N1 aMaixner, William1 aMcGuigan, Fiona, E1 aMedina-Gómez, Carolina1 aMeitinger, Thomas1 aMelhus, Håkan1 aMellström, Dan1 aMelov, Simon1 aMichaëlsson, Karl1 aMitchell, Braxton, D1 aMorris, Andrew, P1 aMosekilde, Leif1 aNewman, Anne1 aNielson, Carrie, M1 aO'Connell, Jeffrey, R1 aOostra, Ben, A1 aOrwoll, Eric, S1 aPalotie, Aarno1 aParker, Stephen, C J1 aPeacock, Munro1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPrince, Richard, L1 aRäikkönen, Katri1 aRalston, Stuart, H1 aRipatti, Samuli1 aRobbins, John, A1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSatterfield, Suzanne1 aSchadt, Eric, E1 aSchipf, Sabine1 aScott, Laura1 aSehmi, Joban1 aShen, Jian1 aShin, Chan, Soo1 aSigurdsson, Gunnar1 aSmith, Shad1 aSoranzo, Nicole1 aStančáková, Alena1 aSteinhagen-Thiessen, Elisabeth1 aStreeten, Elizabeth, A1 aStyrkarsdottir, Unnur1 aSwart, Karin, M A1 aTan, Sian-Tsung1 aTarnopolsky, Mark, A1 aThompson, Patricia1 aThomson, Cynthia, A1 aThorsteinsdottir, Unnur1 aTikkanen, Emmi1 aTranah, Gregory, J1 aTuomilehto, Jaakko1 avan Schoor, Natasja, M1 aVerma, Arjun1 aVollenweider, Peter1 aVölzke, Henry1 aWactawski-Wende, Jean1 aWalker, Mark1 aWeedon, Michael, N1 aWelch, Ryan1 aWichmann, H-Erich1 aWiden, Elisabeth1 aWilliams, Frances, M K1 aWilson, James, F1 aWright, Nicole, C1 aXie, Weijia1 aYu, Lei1 aZhou, Yanhua1 aChambers, John, C1 aDöring, Angela1 aDuijn, Cornelia, M1 aEcons, Michael, J1 aGudnason, Vilmundur1 aKooner, Jaspal, S1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aStefansson, Kari1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aOssowski, Vicky1 aWaterworth, Dawn1 aLoos, Ruth, J F1 aKarasik, David1 aHarris, Tamara, B1 aOhlsson, Claes1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/760006999nas a2202113 4500008004100000022001400041245011100055210006900166260001300235300001200248490000700260520104100267100003001308700002201338700002201360700001701382700002301399700001801422700001901440700001901459700002101478700002501499700001801524700002201542700001501564700001801579700002501597700001801622700002001640700003001660700001801690700002301708700002601731700001801757700002001775700002201795700002301817700002301840700002201863700002801885700002101913700001801934700002801952700001701980700001901997700002602016700002702042700001302069700002102082700001802103700002202121700002202143700001802165700002202183700001502205700002102220700001902241700001602260700002302276700002302299700002002322700001602342700002502358700002102383700002302404700002602427700001802453700002302471700001902494700002302513700002602536700001902562700002002581700002002601700002002621700002202641700002202663700002202685700002402707700002502731700002202756700002002778700002602798700002002824700001902844700002102863700002002884700001802904700002302922700002002945700002002965700001502985700002103000700001803021700002403039700002303063700002503086700001903111700001503130700001903145700002203164700001403186700002003200700002203220700001703242700002203259700002503281700001203306700002103318700001803339700001903357700001803376700002903394700002003423700002103443700002503464700002003489700002203509700002703531700002303558700001703581700002503598700002003623700001803643700002103661700002203682700001903704700002903723700002303752700002503775700003203800700001903832700001903851700002203870700002403892700002803916700001903944700002103963700001703984700002404001700002204025700001804047700001704065700002104082700002004103700002404123700001904147700002004166700001904186700001704205700002104222700001504243700002304258700002204281700002304303700001904326700002204345700002204367700002004389700002204409700002304431700001904454700002204473700002404495700001904519700001804538700001904556700002304575700002304598700002404621700002204645700002404667700002204691700002404713710003804737710005304775710002104828856003604849 2017 eng d a1546-171800aLarge-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.0 aLargescale analyses of common and rare variants identify 12 new c2017 Jun a946-9520 v493 aAtrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.
1 aChristophersen, Ingrid, E1 aRienstra, Michiel1 aRoselli, Carolina1 aYin, Xiaoyan1 aGeelhoed, Bastiaan1 aBarnard, John1 aLin, Honghuang1 aArking, Dan, E1 aSmith, Albert, V1 aAlbert, Christine, M1 aChaffin, Mark1 aTucker, Nathan, R1 aLi, Molong1 aKlarin, Derek1 aBihlmeyer, Nathan, A1 aLow, Siew-Kee1 aWeeke, Peter, E1 aMüller-Nurasyid, Martina1 aSmith, Gustav1 aBrody, Jennifer, A1 aNiemeijer, Maartje, N1 aDörr, Marcus1 aTrompet, Stella1 aHuffman, Jennifer1 aGustafsson, Stefan1 aSchurmann, Claudia1 aKleber, Marcus, E1 aLyytikäinen, Leo-Pekka1 aSeppälä, Ilkka1 aMalik, Rainer1 aHorimoto, Andrea, R V R1 aPerez, Marco1 aSinisalo, Juha1 aAeschbacher, Stefanie1 aThériault, Sébastien1 aYao, Jie1 aRadmanesh, Farid1 aWeiss, Stefan1 aTeumer, Alexander1 aChoi, Seung, Hoan1 aWeng, Lu-Chen1 aClauss, Sebastian1 aDeo, Rajat1 aRader, Daniel, J1 aShah, Svati, H1 aSun, Albert1 aHopewell, Jemma, C1 aDebette, Stephanie1 aChauhan, Ganesh1 aYang, Qiong1 aWorrall, Bradford, B1 aParé, Guillaume1 aKamatani, Yoichiro1 aHagemeijer, Yanick, P1 aVerweij, Niek1 aSiland, Joylene, E1 aKubo, Michiaki1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aBis, Joshua, C1 aPerz, Siegfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aMagnani, Jared, W1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShoemaker, Benjamin1 aPadmanabhan, Sandosh1 aHaessler, Jeffrey1 aBartz, Traci, M1 aWaldenberger, Melanie1 aLichtner, Peter1 aArendt, Marina1 aKrieger, Jose, E1 aKähönen, Mika1 aRisch, Lorenz1 aMansur, Alfredo, J1 aPeters, Annette1 aSmith, Blair, H1 aLind, Lars1 aScott, Stuart, A1 aLu, Yingchang1 aBottinger, Erwin, B1 aHernesniemi, Jussi1 aLindgren, Cecilia, M1 aWong, Jorge, A1 aHuang, Jie1 aEskola, Markku1 aMorris, Andrew, P1 aFord, Ian1 aReiner, Alex, P1 aDelgado, Graciela1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aSandhu, Roopinder, K1 aLi, Man1 aBoerwinkle, Eric1 aEisele, Lewin1 aLannfelt, Lars1 aRost, Natalia1 aAnderson, Christopher, D1 aTaylor, Kent, D1 aCampbell, Archie1 aMagnusson, Patrik, K1 aPorteous, David1 aHocking, Lynne, J1 aVlachopoulou, Efthymia1 aPedersen, Nancy, L1 aNikus, Kjell1 aOrho-Melander, Marju1 aHamsten, Anders1 aHeeringa, Jan1 aDenny, Joshua, C1 aKriebel, Jennifer1 aDarbar, Dawood1 aNewton-Cheh, Christopher1 aShaffer, Christian1 aMacfarlane, Peter, W1 aHeilmann-Heimbach, Stefanie1 aAlmgren, Peter1 aHuang, Paul, L1 aSotoodehnia, Nona1 aSoliman, Elsayed, Z1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aVölker, Uwe1 aJöckel, Karl-Heinz1 aSinner, Moritz, F1 aLin, Henry, J1 aGuo, Xiuqing1 aDichgans, Martin1 aIngelsson, Erik1 aKooperberg, Charles1 aMelander, Olle1 aLoos, Ruth, J F1 aLaurikka, Jari1 aConen, David1 aRosand, Jonathan1 aHarst, Pim1 aLokki, Marja-Liisa1 aKathiresan, Sekar1 aPereira, Alexandre1 aJukema, Wouter1 aHayward, Caroline1 aRotter, Jerome, I1 aMärz, Winfried1 aLehtimäki, Terho1 aStricker, Bruno, H1 aChung, Mina, K1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aRoden, Dan, M1 aKääb, Stefan1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aTanaka, Toshihiro1 aLunetta, Kathryn, L1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aMETASTROKE Consortium of the ISGC1 aNeurology Working Group of the CHARGE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/739606419nas a2201621 4500008004100000022001400041245011300055210006900168260001600237300001400253490000800267520184900275100002102124700002102145700002002166700002202186700002002208700002602228700001702254700002002271700002302291700002502314700002002339700001902359700001902378700002202397700002202419700002102441700002602462700002202488700002102510700002202531700002802553700001902581700001802600700002202618700002402640700002302664700002402687700001802711700002002729700002202749700002102771700002402792700001902816700002002835700002102855700001702876700002102893700002602914700002002940700002002960700001702980700002002997700002203017700001703039700001903056700001503075700002003090700002003110700002403130700001903154700002103173700001903194700002203213700002203235700002503257700001903282700002503301700002103326700002103347700002403368700001703392700002203409700002203431700002303453700003003476700002003506700002203526700002203548700001903570700002003589700001803609700002003627700002603647700002303673700002103696700002603717700002203743700002203765700002003787700002503807700002003832700002303852700002203875700002103897700002203918700002303940700002303963700001603986700002404002700002804026700001804054700001904072700002104091700002004112700002004132700002304152700002404175700002204199700002304221700001804244700002204262700002504284700001904309700001704328700002204345700001904367700002104386700001504407700002404422700002004446700002304466700002004489700002404509700002004533700001504553700002104568700002004589700002404609700002204633700002204655700002104677700001804698700002704716700001804743856003604761 2017 eng d a1558-823800aLarge-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.0 aLargescale genomewide analysis identifies genetic variants assoc c2017 May 01 a1798-18120 v1273 aBACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.
METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.
RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.
CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
FUNDING: For detailed information per study, see Acknowledgments.
1 aWild, Philipp, S1 aFelix, Janine, F1 aSchillert, Arne1 aTeumer, Alexander1 aChen, Ming-Huei1 aLeening, Maarten, J G1 aVölker, Uwe1 aGroßmann, Vera1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aShah, Sanjiv, J1 aPramana, Setia1 aLieb, Wolfgang1 aSchmidt, Reinhold1 aStanton, Alice, V1 aMalzahn, Dörthe1 aSmith, Albert, Vernon1 aSundström, Johan1 aMinelli, Cosetta1 aRuggiero, Daniela1 aLyytikäinen, Leo-Pekka1 aTiller, Daniel1 aSmith, Gustav1 aMonnereau, Claire1 aDi Tullio, Marco, R1 aMusani, Solomon, K1 aMorrison, Alanna, C1 aPers, Tune, H1 aMorley, Michael1 aKleber, Marcus, E1 aAragam, Jayashri1 aBenjamin, Emelia, J1 aBis, Joshua, C1 aBisping, Egbert1 aBroeckel, Ulrich1 aCheng, Susan1 aDeckers, Jaap, W1 aM, Fabiola, del Greco1 aEdelmann, Frank1 aFornage, Myriam1 aFranke, Lude1 aFriedrich, Nele1 aHarris, Tamara, B1 aHofer, Edith1 aHofman, Albert1 aHuang, Jie1 aHughes, Alun, D1 aKähönen, Mika1 aInvestigators, Knhi1 aKruppa, Jochen1 aLackner, Karl, J1 aLannfelt, Lars1 aLaskowski, Rafael1 aLauner, Lenore, J1 aLeosdottir, Margrét1 aLin, Honghuang1 aLindgren, Cecilia, M1 aLoley, Christina1 aMacRae, Calum, A1 aMascalzoni, Deborah1 aMayet, Jamil1 aMedenwald, Daniel1 aMorris, Andrew, P1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNappo, Stefania1 aNilsson, Peter, M1 aNuding, Sebastian1 aNutile, Teresa1 aPeters, Annette1 aPfeufer, Arne1 aPietzner, Diana1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aRuohonen, Saku, T1 aSacco, Ralph, L1 aSamdarshi, Tandaw, E1 aSchmidt, Helena1 aSharp, Andrew, S P1 aShields, Denis, C1 aSorice, Rossella1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSurendran, Praveen1 aThom, Simon1 aTöglhofer, Anna, M1 aUitterlinden, André, G1 aWachter, Rolf1 aVölzke, Henry1 aZiegler, Andreas1 aMünzel, Thomas1 aMärz, Winfried1 aCappola, Thomas, P1 aHirschhorn, Joel, N1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aFox, Ervin, R1 aDueker, Nicole, D1 aJaddoe, Vincent, W V1 aMelander, Olle1 aRuss, Martin1 aLehtimäki, Terho1 aCiullo, Marina1 aHicks, Andrew, A1 aLind, Lars1 aGudnason, Vilmundur1 aPieske, Burkert1 aBarron, Anthony, J1 aZweiker, Robert1 aSchunkert, Heribert1 aIngelsson, Erik1 aLiu, Kiang1 aArnett, Donna, K1 aPsaty, Bruce, M1 aBlankenberg, Stefan1 aLarson, Martin, G1 aFelix, Stephan, B1 aFranco, Oscar, H1 aZeller, Tanja1 aVasan, Ramachandran, S1 aDörr, Marcus uhttps://chs-nhlbi.org/node/737309467nas a2203025 4500008004100000022001400041245013800055210006900193260001600262520108200278100002001360700001601380700001701396700001901413700002701432700002501459700002201484700002401506700002101530700001901551700002601570700002401596700002501620700001601645700001901661700002001680700001701700700002101717700002001738700001701758700002201775700002001797700001901817700002101836700001601857700001901873700002801892700002001920700002501940700001701965700002001982700002302002700002102025700002202046700001502068700001902083700001702102700002202119700001802141700002602159700002202185700002002207700002202227700002002249700002002269700001902289700002102308700002702329700002502356700001802381700002102399700001902420700002102439700002202460700001802482700002502500700001502525700002402540700002102564700001902585700002102604700002002625700002002645700002702665700002202692700001802714700002602732700002302758700001902781700001702800700001802817700002102835700002402856700002102880700001802901700001802919700002002937700002202957700002402979700002103003700001803024700002403042700002303066700001703089700002003106700002303126700001803149700002103167700002103188700001803209700002003227700002103247700002303268700001203291700002603303700002203329700002303351700001703374700002003391700002203411700001903433700002703452700001603479700002703495700001903522700002303541700002203564700001603586700002003602700002203622700001803644700001803662700002003680700002403700700001803724700002203742700002003764700002403784700001203808700001503820700002003835700002903855700002003884700002003904700002103924700001703945700002203962700002403984700002104008700002504029700002304054700001904077700002904096700001904125700001404144700002504158700001904183700002104202700001904223700002704242700001804269700002604287700002304313700001604336700001804352700002004370700002204390700002004412700002304432700002204455700001604477700001804493700002404511700002004535700002304555700002204578700001804600700002004618700002204638700002104660700002104681700001904702700002004721700002204741700001904763700002004782700001604802700002104818700002404839700002804863700001704891700002404908700001604932700002304948700002004971700001304991700002705004700001705031700001605048700001705064700002305081700002905104700002405133700002005157700001505177700002305192700002605215700002005241700001905261700001905280700002105299700002205320700002205342700002405364700002205388700002205410700002305432700002005455700001605475700001805491700001905509700002005528700002405548700002105572700002105593700002105614700001605635700001705651700001805668700002605686700002005712700002105732700001905753700002105772700002005793700001905813700002205832700002305854700002405877700002005901700002005921700001905941700001605960700001905976700002305995700001906018700002106037700002006058700002306078700002106101700002106122700002906143700002406172700001806196700002306214700002606237700001906263700002206282700001706304700002106321700002006342700002306362700002006385856003606405 2017 eng d a1524-456300aNovel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.0 aNovel Blood Pressure Locus and Gene Discovery Using GenomeWide A c2017 Jul 243 aElevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
1 aWain, Louise, V1 aVaez, Ahmad1 aJansen, Rick1 aJoehanes, Roby1 avan der Most, Peter, J1 aErzurumluoglu, Mesut1 aO'Reilly, Paul, F1 aCabrera, Claudia, P1 aWarren, Helen, R1 aRose, Lynda, M1 aVerwoert, Germaine, C1 aHottenga, Jouke-Jan1 aStrawbridge, Rona, J1 aEsko, Tõnu1 aArking, Dan, E1 aHwang, Shih-Jen1 aGuo, Xiuqing1 aKutalik, Zoltán1 aTrompet, Stella1 aShrine, Nick1 aTeumer, Alexander1 aRied, Janina, S1 aBis, Joshua, C1 aSmith, Albert, V1 aAmin, Najaf1 aNolte, Ilja, M1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aWareham, Nicholas, J1 aHofer, Edith1 aJoshi, Peter, K1 aKristiansson, Kati1 aTraglia, Michela1 aHavulinna, Aki, S1 aGoel, Anuj1 aNalls, Mike, A1 aSõber, Siim1 aVuckovic, Dragana1 aLuan, Jian'an1 aM, Fabiola, del Greco1 aAyers, Kristin, L1 aMarrugat, Jaume1 aRuggiero, Daniela1 aLopez, Lorna, M1 aNiiranen, Teemu1 aEnroth, Stefan1 aJackson, Anne, U1 aNelson, Christopher, P1 aHuffman, Jennifer, E1 aZhang, Weihua1 aMarten, Jonathan1 aGandin, Ilaria1 aHarris, Sarah, E1 aZemunik, Tatijana1 aLu, Yingchang1 aEvangelou, Evangelos1 aShah, Nabi1 ade Borst, Martin, H1 aMangino, Massimo1 aPrins, Bram, P1 aCampbell, Archie1 aLi-Gao, Ruifang1 aChauhan, Ganesh1 aOldmeadow, Christopher1 aAbecasis, Goncalo1 aAbedi, Maryam1 aBarbieri, Caterina, M1 aBarnes, Michael, R1 aBatini, Chiara1 aBeilby, John1 aBlake, Tineka1 aBoehnke, Michael1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrown, Morris1 aBrumat, Marco1 aCampbell, Harry1 aChambers, John, C1 aCocca, Massimiliano1 aCollins, Francis1 aConnell, John1 aCordell, Heather, J1 aDamman, Jeffrey, J1 aDavies, Gail1 ade Geus, Eco, J1 ade Mutsert, Renée1 aDeelen, Joris1 aDemirkale, Yusuf1 aDoney, Alex, S F1 aDörr, Marcus1 aFarrall, Martin1 aFerreira, Teresa1 aFrånberg, Mattias1 aGao, He1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGiulianini, Franco1 aGow, Alan, J1 aHamsten, Anders1 aHarris, Tamara, B1 aHofman, Albert1 aHolliday, Elizabeth, G1 aHui, Jennie1 aJarvelin, Marjo-Riitta1 aJohansson, Asa1 aJohnson, Andrew, D1 aJousilahti, Pekka1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKhaw, Kay-Tee1 aKolcic, Ivana1 aKoskinen, Seppo1 aLangenberg, Claudia1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aMach, François1 aMamasoula, Chrysovalanto1 aMenni, Cristina1 aMifsud, Borbala1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNandakumar, Priyanka1 aNguyen, Quang, Tri1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalotie, Aarno1 aParé, Guillaume1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPoulter, Neil1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRen, Meixia1 aRice, Kenneth1 aRidker, Paul, M1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRotter, Jerome, I1 aRudan, Igor1 aSaba, Yasaman1 aPierre, Aude, Saint1 aSala, Cinzia, F1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aScott, Rodney1 aSeelen, Marc, A1 aShields, Denis, C1 aSiscovick, David1 aSorice, Rossella1 aStanton, Alice1 aStott, David, J1 aSundström, Johan1 aSwertz, Morris1 aTaylor, Kent, D1 aThom, Simon1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, André, G1 aVölker, Uwe1 aVollenweider, Peter1 aWild, Sarah1 aWillemsen, Gonneke1 aWright, Alan, F1 aYao, Jie1 aThériault, Sébastien1 aConen, David1 aAttia, John1 aSever, Peter1 aDebette, Stephanie1 aMook-Kanamori, Dennis, O1 aZeggini, Eleftheria1 aSpector, Tim, D1 aHarst, Pim1 aPalmer, Colin, N A1 aVergnaud, Anne-Claire1 aLoos, Ruth, J F1 aPolasek, Ozren1 aStarr, John, M1 aGirotto, Giorgia1 aHayward, Caroline1 aKooner, Jaspal, S1 aLindgren, Cecila, M1 aVitart, Veronique1 aSamani, Nilesh, J1 aTuomilehto, Jaakko1 aGyllensten, Ulf1 aKnekt, Paul1 aDeary, Ian, J1 aCiullo, Marina1 aElosua, Roberto1 aKeavney, Bernard, D1 aHicks, Andrew, A1 aScott, Robert, A1 aGasparini, Paolo1 aLaan, Maris1 aLiu, Yongmei1 aWatkins, Hugh1 aHartman, Catharina, A1 aSalomaa, Veikko1 aToniolo, Daniela1 aPerola, Markus1 aWilson, James, F1 aSchmidt, Helena1 aZhao, Jing Hua1 aLehtimäki, Terho1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aPeters, Annette1 aRettig, Rainer1 aJames, Alan1 aJukema, Wouter1 aStrachan, David, P1 aPalmas, Walter1 aMetspalu, Andres1 aIngelsson, Erik1 aBoomsma, Dorret, I1 aFranco, Oscar, H1 aBochud, Murielle1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aElliott, Paul1 aChasman, Daniel, I1 aChakravarti, Aravinda1 aKnight, Joanne1 aMorris, Andrew, P1 aLevy, Daniel1 aTobin, Martin, D1 aSnieder, Harold1 aCaulfield, Mark, J1 aEhret, Georg, B uhttps://chs-nhlbi.org/node/749217687nas a2205785 4500008004100000022001400041245012100055210006900176260001300245300001400258490000700272520145500279653004101734653002201775653002401797653002501821653001001846653003001856653001901886653003801905653001301943653001101956653002101967653002701988653002702015653001402042653001502056653002602071653003602097653002902133653002702162653003402189100001802223700002502241700001702266700002402283700002702307700002602334700002102360700001702381700002102398700001902419700002002438700002802458700003202486700002202518700002102540700002202561700002102583700001802604700002202622700001802644700001802662700002002680700002502700700002002725700002302745700002202768700002902790700002202819700002002841700002102861700002102882700002002903700001802923700002102941700001802962700002102980700002503001700001903026700001703045700001903062700001903081700002603100700002103126700002303147700001903170700002303189700001503212700002703227700002103254700002203275700001303297700003203310700002003342700002003362700001803382700003103400700002003431700002203451700002003473700001803493700002403511700001903535700002303554700002303577700002403600700001703624700002703641700001703668700002103685700001903706700002303725700002103748700002703769700002303796700002303819700002403842700001903866700002003885700001803905700001903923700001603942700002503958700002103983700002204004700002304026700001704049700002604066700002004092700001804112700002104130700002604151700001904177700002304196700001404219700001904233700002204252700002404274700001904298700002304317700002304340700002204363700002204385700002004407700001904427700002104446700001804467700001704485700002304502700002604525700002004551700001804571700001604589700002204605700002104627700001904648700002004667700002304687700002604710700002204736700002504758700001804783700002004801700002304821700002604844700002304870700001604893700002304909700001804932700001304950700001804963700001704981700002604998700001905024700002005043700002105063700001705084700002105101700001605122700002105138700001705159700001805176700002005194700001805214700001505232700002805247700001905275700001805294700002105312700002205333700002405355700001805379700001705397700002205414700001605436700001805452700002505470700002305495700002105518700002005539700001905559700002305578700002505601700002405626700002105650700002005671700001205691700001805703700001705721700001805738700002205756700002005778700001905798700003205817700001905849700001805868700002005886700001805906700002105924700002405945700001705969700001805986700001706004700002006021700001806041700001806059700002006077700001706097700001606114700002006130700002506150700002206175700002006197700002106217700002406238700002006262700001906282700002106301700002106322700002106343700002006364700002206384700002006406700001606426700002006442700002206462700002306484700002106507700001806528700002206546700002506568700002206593700002906615700002306644700002906667700002006696700002006716700002106736700002506757700002106782700001806803700001806821700002006839700002106859700002306880700002006903700002206923700001906945700002306964700002406987700001907011700002507030700002107055700002807076700002107104700002107125700002407146700002207170700002307192700002707215700002607242700002207268700002007290700001607310700001707326700001707343700001807360700002107378700001607399700002007415700002007435700002207455700001807477700002307495700002007518700001107538700002507549700002407574700002907598700002207627700002107649700002107670700002107691700002407712700002207736700002307758700001807781700002007799700002107819700002107840700002207861700002007883700002107903700002107924700001807945700002207963700002407985700002208009700002208031700001908053700002008072700001808092700001908110700002308129700002108152700001508173700002008188700002008208700002208228700002108250700002208271700002308293700002108316700002408337700001908361700002208380700002408402700002208426700002308448700002108471700002208492700002108514700002108535700002508556700002208581700003008603700002508633700002208658700002908680700002408709700002208733700002608755700002208781700003008803700002408833700002508857700002108882700002408903700002308927700001708950700001208967700002108979700002309000700002109023700002709044700002209071700002209093700002909115700002709144700002109171700002309192700001709215700002809232700001909260700002309279700002109302700002109323700002609344700002509370700002409395700002209419700001909441700002009460700001809480700001909498700001809517700002509535700001609560700001909576700002809595700002209623700001809645700001909663700002009682700001609702700002209718700002309740700002309763700001909786700002309805700001809828700002109846700002409867700002209891700002609913700002009939700001709959700003009976700002010006700002710026700002210053700002110075700001510096700002410111700002810135700001910163700002110182700002610203700002310229700002310252700002110275700001910296700001910315700002310334700003010357700001910387700001810406700002610424700001510450700002010465700002210485700002510507700001910532700001610551700001910567700002010586700002110606700002110627700002610648700002110674700002410695700001610719700002110735700002810756700001810784700002110802700002210823700002210845700001710867700001910884700002010903700002410923700001810947700002710965700002210992700002011014700002011034700002311054700001911077700002411096700001711120700002311137700003011160700002411190700002411214700002211238700002311260700001711283700002311300700002311323700003111346700002011377700001811397700002411415700002411439700002211463700002811485700002011513700002711533700001611560700002211576700003111598700002211629700002311651700002111674700001811695700002611713700002011739700002011759700002811779710002011807710003811827856003611865 2017 eng d a1546-171800aRare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.0 aRare coding variants in PLCG2 ABI3 and TREM2 implicate microglia c2017 Sep a1373-13840 v493 aWe identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
10aAdaptor Proteins, Signal Transducing10aAlzheimer Disease10aAmino Acid Sequence10aCase-Control Studies10aExome10aGene Expression Profiling10aGene Frequency10aGenetic Predisposition to Disease10aGenotype10aHumans10aImmunity, Innate10aLinkage Disequilibrium10aMembrane Glycoproteins10aMicroglia10aOdds Ratio10aPhospholipase C gamma10aPolymorphism, Single Nucleotide10aProtein Interaction Maps10aReceptors, Immunologic10aSequence Homology, Amino Acid1 aSims, Rebecca1 avan der Lee, Sven, J1 aNaj, Adam, C1 aBellenguez, Céline1 aBadarinarayan, Nandini1 aJakobsdottir, Johanna1 aKunkle, Brian, W1 aBoland, Anne1 aRaybould, Rachel1 aBis, Joshua, C1 aMartin, Eden, R1 aGrenier-Boley, Benjamin1 aHeilmann-Heimbach, Stefanie1 aChouraki, Vincent1 aKuzma, Amanda, B1 aSleegers, Kristel1 aVronskaya, Maria1 aRuiz, Agustin1 aGraham, Robert, R1 aOlaso, Robert1 aHoffmann, Per1 aGrove, Megan, L1 aVardarajan, Badri, N1 aHiltunen, Mikko1 aNöthen, Markus, M1 aWhite, Charles, C1 aHamilton-Nelson, Kara, L1 aEpelbaum, Jacques1 aMaier, Wolfgang1 aChoi, Seung-Hoan1 aBeecham, Gary, W1 aDulary, Cécile1 aHerms, Stefan1 aSmith, Albert, V1 aFunk, Cory, C1 aDerbois, Céline1 aForstner, Andreas, J1 aAhmad, Shahzad1 aLi, Hongdong1 aBacq, Delphine1 aHarold, Denise1 aSatizabal, Claudia, L1 aValladares, Otto1 aSquassina, Alessio1 aThomas, Rhodri1 aBrody, Jennifer, A1 aQu, Liming1 aSánchez-Juan, Pascual1 aMorgan, Taniesha1 aWolters, Frank, J1 aZhao, Yi1 aGarcia, Florentino, Sanchez1 aDenning, Nicola1 aFornage, Myriam1 aMalamon, John1 aNaranjo, Maria, Candida De1 aMajounie, Elisa1 aMosley, Thomas, H1 aDombroski, Beth1 aWallon, David1 aLupton, Michelle, K1 aDupuis, Josée1 aWhitehead, Patrice1 aFratiglioni, Laura1 aMedway, Christopher1 aJian, Xueqiu1 aMukherjee, Shubhabrata1 aKeller, Lina1 aBrown, Kristelle1 aLin, Honghuang1 aCantwell, Laura, B1 aPanza, Francesco1 aMcGuinness, Bernadette1 aMoreno-Grau, Sonia1 aBurgess, Jeremy, D1 aSolfrizzi, Vincenzo1 aProitsi, Petra1 aAdams, Hieab, H1 aAllen, Mariet1 aSeripa, Davide1 aPastor, Pau1 aCupples, Adrienne, L1 aPrice, Nathan, D1 aHannequin, Didier1 aFrank-García, Ana1 aLevy, Daniel1 aChakrabarty, Paramita1 aCaffarra, Paolo1 aGiegling, Ina1 aBeiser, Alexa, S1 aGiedraitis, Vilmantas1 aHampel, Harald1 aGarcia, Melissa, E1 aWang, Xue1 aLannfelt, Lars1 aMecocci, Patrizia1 aEiriksdottir, Gudny1 aCrane, Paul, K1 aPasquier, Florence1 aBoccardi, Virginia1 aHenández, Isabel1 aBarber, Robert, C1 aScherer, Martin1 aTarraga, Lluis1 aAdams, Perrie, M1 aLeber, Markus1 aChen, Yuning1 aAlbert, Marilyn, S1 aRiedel-Heller, Steffi1 aEmilsson, Valur1 aBeekly, Duane1 aBraae, Anne1 aSchmidt, Reinhold1 aBlacker, Deborah1 aMasullo, Carlo1 aSchmidt, Helena1 aDoody, Rachelle, S1 aSpalletta, Gianfranco1 aJr, W, T Longstre1 aFairchild, Thomas, J1 aBossù, Paola1 aLopez, Oscar, L1 aFrosch, Matthew, P1 aSacchinelli, Eleonora1 aGhetti, Bernardino1 aYang, Qiong1 aHuebinger, Ryan, M1 aJessen, Frank1 aLi, Shuo1 aKamboh, Ilyas1 aMorris, John1 aSotolongo-Grau, Oscar1 aKatz, Mindy, J1 aCorcoran, Chris1 aDunstan, Melanie1 aBraddel, Amy1 aThomas, Charlene1 aMeggy, Alun1 aMarshall, Rachel1 aGerrish, Amy1 aChapman, Jade1 aAguilar, Miquel1 aTaylor, Sarah1 aHill, Matt1 aFairén, Mònica, Díez1 aHodges, Angela1 aVellas, Bruno1 aSoininen, Hilkka1 aKloszewska, Iwona1 aDaniilidou, Makrina1 aUphill, James1 aPatel, Yogen1 aHughes, Joseph, T1 aLord, Jenny1 aTurton, James1 aHartmann, Annette, M1 aCecchetti, Roberta1 aFenoglio, Chiara1 aSerpente, Maria1 aArcaro, Marina1 aCaltagirone, Carlo1 aOrfei, Maria, Donata1 aCiaramella, Antonio1 aPichler, Sabrina1 aMayhaus, Manuel1 aGu, Wei1 aLleo, Alberto1 aFortea, Juan1 aBlesa, Rafael1 aBarber, Imelda, S1 aBrookes, Keeley1 aCupidi, Chiara1 aMaletta, Raffaele, Giovanni1 aCarrell, David1 aSorbi, Sandro1 aMoebus, Susanne1 aUrbano, Maria1 aPilotto, Alberto1 aKornhuber, Johannes1 aBosco, Paolo1 aTodd, Stephen1 aCraig, David1 aJohnston, Janet1 aGill, Michael1 aLawlor, Brian1 aLynch, Aoibhinn1 aFox, Nick, C1 aHardy, John1 aAlbin, Roger, L1 aApostolova, Liana, G1 aArnold, Steven, E1 aAsthana, Sanjay1 aAtwood, Craig, S1 aBaldwin, Clinton, T1 aBarnes, Lisa, L1 aBarral, Sandra1 aBeach, Thomas, G1 aBecker, James, T1 aBigio, Eileen, H1 aBird, Thomas, D1 aBoeve, Bradley, F1 aBowen, James, D1 aBoxer, Adam1 aBurke, James, R1 aBurns, Jeffrey, M1 aBuxbaum, Joseph, D1 aCairns, Nigel, J1 aCao, Chuanhai1 aCarlson, Chris, S1 aCarlsson, Cynthia, M1 aCarney, Regina, M1 aCarrasquillo, Minerva, M1 aCarroll, Steven, L1 aDiaz, Carolina, Ceballos1 aChui, Helena, C1 aClark, David, G1 aCribbs, David, H1 aCrocco, Elizabeth, A1 aDeCarli, Charles1 aDick, Malcolm1 aDuara, Ranjan1 aEvans, Denis, A1 aFaber, Kelley, M1 aFallon, Kenneth, B1 aFardo, David, W1 aFarlow, Martin, R1 aFerris, Steven1 aForoud, Tatiana, M1 aGalasko, Douglas, R1 aGearing, Marla1 aGeschwind, Daniel, H1 aGilbert, John, R1 aGraff-Radford, Neill, R1 aGreen, Robert, C1 aGrowdon, John, H1 aHamilton, Ronald, L1 aHarrell, Lindy, E1 aHonig, Lawrence, S1 aHuentelman, Matthew, J1 aHulette, Christine, M1 aHyman, Bradley, T1 aJarvik, Gail, P1 aAbner, Erin1 aJin, Lee-Way1 aJun, Gyungah1 aKarydas, Anna1 aKaye, Jeffrey, A1 aKim, Ronald1 aKowall, Neil, W1 aKramer, Joel, H1 aLaFerla, Frank, M1 aLah, James, J1 aLeverenz, James, B1 aLevey, Allan, I1 aLi, Ge1 aLieberman, Andrew, P1 aLunetta, Kathryn, L1 aLyketsos, Constantine, G1 aMarson, Daniel, C1 aMartiniuk, Frank1 aMash, Deborah, C1 aMasliah, Eliezer1 aMcCormick, Wayne, C1 aMcCurry, Susan, M1 aMcDavid, Andrew, N1 aMcKee, Ann, C1 aMesulam, Marsel1 aMiller, Bruce, L1 aMiller, Carol, A1 aMiller, Joshua, W1 aMorris, John, C1 aMurrell, Jill, R1 aMyers, Amanda, J1 aO'Bryant, Sid1 aOlichney, John, M1 aPankratz, Vernon, S1 aParisi, Joseph, E1 aPaulson, Henry, L1 aPerry, William1 aPeskind, Elaine1 aPierce, Aimee1 aPoon, Wayne, W1 aPotter, Huntington1 aQuinn, Joseph, F1 aRaj, Ashok1 aRaskind, Murray1 aReisberg, Barry1 aReitz, Christiane1 aRingman, John, M1 aRoberson, Erik, D1 aRogaeva, Ekaterina1 aRosen, Howard, J1 aRosenberg, Roger, N1 aSager, Mark, A1 aSaykin, Andrew, J1 aSchneider, Julie, A1 aSchneider, Lon, S1 aSeeley, William, W1 aSmith, Amanda, G1 aSonnen, Joshua, A1 aSpina, Salvatore1 aStern, Robert, A1 aSwerdlow, Russell, H1 aTanzi, Rudolph, E1 aThornton-Wells, Tricia, A1 aTrojanowski, John, Q1 aTroncoso, Juan, C1 aVan Deerlin, Vivianna, M1 aVan Eldik, Linda, J1 aVinters, Harry, V1 aVonsattel, Jean, Paul1 aWeintraub, Sandra1 aWelsh-Bohmer, Kathleen, A1 aWilhelmsen, Kirk, C1 aWilliamson, Jennifer1 aWingo, Thomas, S1 aWoltjer, Randall, L1 aWright, Clinton, B1 aYu, Chang-En1 aYu, Lei1 aGarzia, Fabienne1 aGolamaully, Feroze1 aSeptier, Gislain1 aEngelborghs, Sebastien1 aVandenberghe, Rik1 aDe Deyn, Peter, P1 aFernadez, Carmen, Muñoz1 aBenito, Yoland, Aladro1 aThonberg, Håkan1 aForsell, Charlotte1 aLilius, Lena1 aKinhult-Ståhlbom, Anne1 aKilander, Lena1 aBrundin, RoseMarie1 aConcari, Letizia1 aHelisalmi, Seppo1 aKoivisto, Anne, Maria1 aHaapasalo, Annakaisa1 aDermecourt, Vincent1 aFiévet, Nathalie1 aHanon, Olivier1 aDufouil, Carole1 aBrice, Alexis1 aRitchie, Karen1 aDubois, Bruno1 aHimali, Jayanadra, J1 aKeene, Dirk1 aTschanz, JoAnn1 aFitzpatrick, Annette, L1 aKukull, Walter, A1 aNorton, Maria1 aAspelund, Thor1 aLarson, Eric, B1 aMunger, Ron1 aRotter, Jerome, I1 aLipton, Richard, B1 aBullido, María, J1 aHofman, Albert1 aMontine, Thomas, J1 aCoto, Eliecer1 aBoerwinkle, Eric1 aPetersen, Ronald, C1 aAlvarez, Victoria1 aRivadeneira, Fernando1 aReiman, Eric, M1 aGallo, Maura1 aO'Donnell, Christopher, J1 aReisch, Joan, S1 aBruni, Amalia, Cecilia1 aRoyall, Donald, R1 aDichgans, Martin1 aSano, Mary1 aGalimberti, Daniela1 aSt George-Hyslop, Peter1 aScarpini, Elio1 aTsuang, Debby, W1 aMancuso, Michelangelo1 aBonuccelli, Ubaldo1 aWinslow, Ashley, R1 aDaniele, Antonio1 aWu, Chuang-Kuo1 aPeters, Oliver1 aNacmias, Benedetta1 aRiemenschneider, Matthias1 aHeun, Reinhard1 aBrayne, Carol1 aRubinsztein, David, C1 aBras, Jose1 aGuerreiro, Rita1 aAl-Chalabi, Ammar1 aShaw, Christopher, E1 aCollinge, John1 aMann, David1 aTsolaki, Magda1 aClarimon, Jordi1 aSussams, Rebecca1 aLovestone, Simon1 aO'Donovan, Michael, C1 aOwen, Michael, J1 aBehrens, Timothy, W1 aMead, Simon1 aGoate, Alison, M1 aUitterlinden, André, G1 aHolmes, Clive1 aCruchaga, Carlos1 aIngelsson, Martin1 aBennett, David, A1 aPowell, John1 aGolde, Todd, E1 aGraff, Caroline1 aDe Jager, Philip, L1 aMorgan, Kevin1 aErtekin-Taner, Nilufer1 aCombarros, Onofre1 aPsaty, Bruce, M1 aPassmore, Peter1 aYounkin, Steven, G1 aBerr, Claudine1 aGudnason, Vilmundur1 aRujescu, Dan1 aDickson, Dennis, W1 aDartigues, Jean-François1 aDeStefano, Anita, L1 aOrtega-Cubero, Sara1 aHakonarson, Hakon1 aCampion, Dominique1 aBoada, Merce1 aKauwe, John, Keoni1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aIkram, Arfan, M1 aJones, Lesley1 aHaines, Jonathan, L1 aTzourio, Christophe1 aLauner, Lenore, J1 aEscott-Price, Valentina1 aMayeux, Richard1 aDeleuze, Jean-Francois1 aAmin, Najaf1 aHolmans, Peter, A1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aDuijn, Cornelia, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aLambert, Jean-Charles1 aSeshadri, Sudha1 aWilliams, Julie1 aSchellenberg, Gerard, D1 aARUK Consortium1 aGERAD/PERADES, CHARGE, ADGC, EADI uhttps://chs-nhlbi.org/node/758705196nas a2201345 4500008004100000022001400041245009400055210006900149260001300218300001200231490000700243520143500250100001901685700002401704700002101728700002501749700002101774700002301795700002101818700001701839700001801856700003001874700002001904700001801924700001801942700002001960700002801980700002102008700001802029700001902047700002202066700002802088700001302116700002202129700002202151700001202173700001902185700002402204700002102228700001902249700001802268700002402286700002002310700001702330700002202347700002202369700001902391700002102410700002402431700001702455700001602472700001902488700002202507700002702529700002402556700002202580700002402602700002002626700002602646700002202672700002302694700001902717700002102736700001602757700002302773700002402796700001302820700001702833700002002850700002202870700002202892700002902914700002002943700002602963700002402989700002203013700002503035700002003060700001903080700002203099700001803121700001703139700002103156700002403177700002103201700001703222700002003239700002303259700002403282700001903306700002403325700002003349700002303369700002403392700002103416700002203437700001903459700001903478700001903497700001503516700002303531700001903554700002303573700002203596700001803618700002003636700002703656700002403683700002203707700002103729700002403750700002203774700001803796856003603814 2018 eng d a2574-830000aCommon and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.0 aCommon and Rare Coding Genetic Variation Underlying the Electroc c2018 May ae0020370 v113 aBACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.
METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.
RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.
CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
1 aLin, Honghuang1 avan Setten, Jessica1 aSmith, Albert, V1 aBihlmeyer, Nathan, A1 aWarren, Helen, R1 aBrody, Jennifer, A1 aRadmanesh, Farid1 aHall, Leanne1 aGrarup, Niels1 aMüller-Nurasyid, Martina1 aBoutin, Thibaud1 aVerweij, Niek1 aLin, Henry, J1 aLi-Gao, Ruifang1 avan den Berg, Marten, E1 aMarten, Jonathan1 aWeiss, Stefan1 aPrins, Bram, P1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aMei, Hao1 aHarris, Tamara, B1 aLauner, Lenore, J1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aConnell, John, M1 aHuang, Paul, L1 aWeng, Lu-Chen1 aJameson, Heather, S1 aHucker, William1 aHanley, Alan1 aTucker, Nathan, R1 aChen, Yii-Der Ida1 aBis, Joshua, C1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aKors, Jan, A1 aXie, Zhijun1 aWen, Chengping1 aMagnani, Jared, W1 aNelson, Christopher, P1 aKanters, Jørgen, K1 aSinner, Moritz, F1 aStrauch, Konstantin1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aBork-Jensen, Jette1 aPedersen, Oluf1 aLinneberg, Allan1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aYao, Jie1 aGuo, Xiuqing1 aTaylor, Kent, D1 aSotoodehnia, Nona1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aEijgelsheim, Mark1 aPadmanabhan, Sandosh1 aSmith, Blair, H1 aVölzke, Henry1 aFelix, Stephan, B1 aHomuth, Georg1 aVölker, Uwe1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aKähönen, Mika1 aRaitakari, Olli, T1 aGudnason, Vilmundur1 aArking, Dan, E1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aBenjamin, Emelia, J1 aRosand, Jonathan1 aSamani, Nilesh, J1 aHansen, Torben1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aJukema, Wouter1 aStricker, Bruno, H1 aHayward, Caroline1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aWilson, James, G1 aEllinor, Patrick, T1 aLubitz, Steven, A1 aIsaacs, Aaron uhttps://chs-nhlbi.org/node/780105244nas a2201057 4500008004100000022001400041245014200055210006900197260001600266520216400282100001702446700002602463700002102489700002402510700001902534700002302553700001802576700001802594700001702612700002502629700002102654700001902675700002202694700001302716700002202729700001402751700002302765700001802788700001902806700002002825700002402845700001802869700002202887700001602909700002102925700002402946700002402970700001902994700002303013700002603036700001903062700002403081700002203105700002303127700001803150700003703168700001903205700002103224700002003245700002103265700002003286700001603306700002403322700001903346700002003365700002503385700002803410700002703438700002003465700002203485700002503507700002103532700002303553700002103576700002703597700002603624700001703650700002503667700002303692700002303715700002203738700002303760700002003783700002203803700002403825700002203849700002203871700002103893700001803914700002003932700002403952700002003976700002303996700001904019700002004038700002004058700002204078700002004100710003004120856003604150 2018 eng d a1524-462800aExome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.0 aExome Chip Analysis Identifies LowFrequency and Rare Variants in c2018 Jul 123 aBACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.
METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.
RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).
CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
1 aJian, Xueqiu1 aSatizabal, Claudia, L1 aSmith, Albert, V1 aWittfeld, Katharina1 aBis, Joshua, C1 aSmith, Jennifer, A1 aHsu, Fang-Chi1 aNho, Kwangsik1 aHofer, Edith1 aHagenaars, Saskia, P1 aNyquist, Paul, A1 aMishra, Aniket1 aAdams, Hieab, H H1 aLi, Shuo1 aTeumer, Alexander1 aZhao, Wei1 aFreedman, Barry, I1 aSaba, Yasaman1 aYanek, Lisa, R1 aChauhan, Ganesh1 avan Buchem, Mark, A1 aCushman, Mary1 aRoyle, Natalie, A1 aBryan, Nick1 aNiessen, Wiro, J1 aWindham, Beverly, G1 aDeStefano, Anita, L1 aHabes, Mohamad1 aHeckbert, Susan, R1 aPalmer, Nicholette, D1 aLewis, Cora, E1 aEiriksdottir, Gudny1 aMaillard, Pauline1 aMathias, Rasika, A1 aHomuth, Georg1 aValdés-Hernández, Maria, Del C1 aDivers, Jasmin1 aBeiser, Alexa, S1 aLangner, Sönke1 aRice, Kenneth, M1 aBastin, Mark, E1 aYang, Qiong1 aMaldjian, Joseph, A1 aStarr, John, M1 aSidney, Stephen1 aRisacher, Shannon, L1 aUitterlinden, André, G1 aGudnason, Vilmundur, G1 aNauck, Matthias1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aBoerwinkle, Eric1 aDuijn, Cornelia, M1 aMazoyer, Bernard1 avon Sarnowski, Bettina1 aGottesman, Rebecca, F1 aLevy, Daniel1 aSigurdsson, Sigurdur1 aVernooij, Meike, W1 aTurner, Stephen, T1 aSchmidt, Reinhold1 aWardlaw, Joanna, M1 aPsaty, Bruce, M1 aMosley, Thomas, H1 aDeCarli, Charles, S1 aSaykin, Andrew, J1 aBowden, Donald, W1 aBecker, Diane, M1 aDeary, Ian, J1 aSchmidt, Helena1 aKardia, Sharon, L R1 aIkram, Arfan, M1 aDebette, Stephanie1 aGrabe, Hans, J1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aFornage, Myriam1 aneuroCHARGE Working Group uhttps://chs-nhlbi.org/node/779605658nas a2201489 4500008004100000022001400041245010600055210006900161260001500230300000700245490000700252520146500259100001901724700002101743700002301764700002701787700001901814700002501833700002501858700002301883700002501906700002901931700002201960700002301982700001702005700001702022700001802039700002202057700002002079700002102099700001802120700002002138700001902158700001802177700002802195700002102223700001302244700003002257700001902287700002502306700002102331700001902352700002302371700002002394700002402414700002102438700001802459700002102477700001802498700001902516700002002535700002102555700002302576700002402599700002202623700002402645700001702669700002202686700002202708700002202730700002302752700001902775700001702794700002002811700001702831700002202848700002202870700001202892700002102904700002702925700001902952700001702971700002002988700001903008700002003027700002303047700002103070700002203091700002203113700002403135700002003159700002403179700002803203700001903231700002003250700002403270700002103294700002403315700001703339700001903356700002603375700002103401700001603422700002703438700001803465700002303483700002103506700002803527700002403555700001903579700001903598700002403617700002403641700002203665700001803687700002203705700002903727700002403756700003203780700002103812700001603833700002203849700002403871700002003895700001603915700002303931700001803954700002203972700002003994700001504014700002104029700002404050700001904074700001904093700002004112856003604132 2018 eng d a1474-760X00aExome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.0 aExomechip metaanalysis identifies novel loci associated with car c2018 07 17 a870 v193 aBACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.
RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.
CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
1 aPrins, Bram, P1 aMead, Timothy, J1 aBrody, Jennifer, A1 aSveinbjornsson, Gardar1 aNtalla, Ioanna1 aBihlmeyer, Nathan, A1 avan den Berg, Marten1 aBork-Jensen, Jette1 aCappellani, Stefania1 aVan Duijvenboden, Stefan1 aKlena, Nikolai, T1 aGabriel, George, C1 aLiu, Xiaoqin1 aGulec, Cagri1 aGrarup, Niels1 aHaessler, Jeffrey1 aHall, Leanne, M1 aIorio, Annamaria1 aIsaacs, Aaron1 aLi-Gao, Ruifang1 aLin, Honghuang1 aLiu, Ching-Ti1 aLyytikäinen, Leo-Pekka1 aMarten, Jonathan1 aMei, Hao1 aMüller-Nurasyid, Martina1 aOrini, Michele1 aPadmanabhan, Sandosh1 aRadmanesh, Farid1 aRamirez, Julia1 aRobino, Antonietta1 aSchwartz, Molly1 avan Setten, Jessica1 aSmith, Albert, V1 aVerweij, Niek1 aWarren, Helen, R1 aWeiss, Stefan1 aAlonso, Alvaro1 aArnar, David, O1 aBots, Michiel, L1 ade Boer, Rudolf, A1 aDominiczak, Anna, F1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aGuo, Xiuqing1 aFelix, Stephan, B1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHuang, Paul, L1 aJukema, J, W1 aKähönen, Mika1 aKors, Jan, A1 aLambiase, Pier, D1 aLauner, Lenore, J1 aLi, Man1 aLinneberg, Allan1 aNelson, Christopher, P1 aPedersen, Oluf1 aPerez, Marco1 aPeters, Annette1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRotter, Jerome, I1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Tim, D1 aStrauch, Konstantin1 aThorsteinsdottir, Unnur1 aTinker, Andrew1 aTrompet, Stella1 aUitterlinden, Andre1 aVaartjes, Ilonca1 avan der Meer, Peter1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWilson, James, G1 aXie, Zhijun1 aAsselbergs, Folkert, W1 aDörr, Marcus1 aDuijn, Cornelia, M1 aGasparini, Paolo1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHansen, Torben1 aKääb, Stefan1 aKanters, Jørgen, K1 aKooperberg, Charles1 aLehtimäki, Terho1 aLin, Henry, J1 aLubitz, Steven, A1 aMook-Kanamori, Dennis, O1 aConti, Francesco, J1 aNewton-Cheh, Christopher, H1 aRosand, Jonathan1 aRudan, Igor1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aSmith, Blair, H1 aHolm, Hilma1 aStricker, Bruno, H1 aUlivi, Sheila1 aSotoodehnia, Nona1 aApte, Suneel, S1 aHarst, Pim1 aStefansson, Kari1 aMunroe, Patricia, B1 aArking, Dan, E1 aLo, Cecilia, W1 aJamshidi, Yalda uhttps://chs-nhlbi.org/node/780905298nas a2201333 4500008004100000022001400041245011200055210006900167260001300236300001200249490000700261520154600268100002501814700002301839700002601862700002101888700001901909700001801928700001801946700002101964700002101985700002002006700001802026700001302044700003002057700002502087700001802112700001702130700001302147700002002160700002502180700001802205700001902223700002402242700002202266700002802288700001202316700001902328700002402347700001902371700001602390700002202406700002002428700002302448700002202471700002502493700002102518700001902539700001602558700002402574700001702598700002102615700002202636700002702658700002102685700002302706700001902729700001902748700002102767700002202788700002002810700002602830700002202856700002002878700001802898700001602916700002302932700002402955700001802979700002002997700002303017700002003040700001903060700001803079700002503097700002603122700002403148700001703172700001803189700001903207700002203226700002103248700002403269700002103293700001703314700002303331700002003354700001803374700002403392700002403416700002203440700002303462700003203485700002203517700002103539700002203560700002403582700002103606700001903627700001903646700001503665700002303680700002203703700002903725700002203754700001803776700002003794700002703814700002403841700002203865700001903887700002203906856003603928 2018 eng d a2574-830000aExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.0 aExomeChipWide Analysis of 95 626 Individuals Identifies 10 Novel c2018 Jan ae0017580 v113 aBACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.
METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.
CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
1 aBihlmeyer, Nathan, A1 aBrody, Jennifer, A1 aSmith, Albert, Vernon1 aWarren, Helen, R1 aLin, Honghuang1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aMarten, Jonathan1 aRadmanesh, Farid1 aHall, Leanne, M1 aGrarup, Niels1 aMei, Hao1 aMüller-Nurasyid, Martina1 aHuffman, Jennifer, E1 aVerweij, Niek1 aGuo, Xiuqing1 aYao, Jie1 aLi-Gao, Ruifang1 avan den Berg, Marten1 aWeiss, Stefan1 aPrins, Bram, P1 avan Setten, Jessica1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aBis, Joshua, C1 aAustin, Tom1 aChen, Yii-Der Ida1 aPsaty, Bruce, M1 aHarrris, Tamara, B1 aLauner, Lenore, J1 aPadmanabhan, Sandosh1 aDominiczak, Anna1 aHuang, Paul, L1 aXie, Zhijun1 aEllinor, Patrick, T1 aKors, Jan, A1 aCampbell, Archie1 aMurray, Alison, D1 aNelson, Christopher, P1 aTobin, Martin, D1 aBork-Jensen, Jette1 aHansen, Torben1 aPedersen, Oluf1 aLinneberg, Allan1 aSinner, Moritz, F1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aPerz, Siegfried1 aKolcic, Ivana1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aLin, Henry, J1 aTaylor, Kent, D1 ade Mutsert, Renée1 aTrompet, Stella1 aJukema, Wouter1 aMaan, Arie, C1 aStricker, Bruno, H C1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aVölker, Uwe1 aHomuth, Georg1 aVölzke, Henry1 aFelix, Stephan, B1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aRaitakari, Olli, T1 aKähönen, Mika1 aMononen, Nina1 aGudnason, Vilmundur1 aMunroe, Patricia, B1 aLubitz, Steven, A1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher, H1 aHayward, Caroline1 aRosand, Jonathan1 aSamani, Nilesh, J1 aKanters, Jørgen, K1 aWilson, James, G1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aEijgelsheim, Mark1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/778410328nas a2203505 4500008004100000022001400041245010900055210006900164260001300233300001400246490000700260520064200267100002500909700002100934700002600955700002000981700001701001700001201018700002301030700001601053700002401069700002101093700001801114700002201132700002501154700001701179700002501196700001601221700002801237700001601265700001501281700002101296700002301317700002001340700002201360700001601382700001801398700001701416700001901433700002001452700002301472700001401495700002301509700002701532700002101559700002001580700001601600700001801616700002101634700002701655700002301682700001501705700003301720700001501753700002301768700002701791700001801818700002101836700001901857700002201876700001801898700002301916700002101939700002001960700002001980700002202000700002102022700002102043700002102064700002202085700001902107700001602126700002202142700001602164700001902180700002202199700002602221700001902247700001902266700001802285700002102303700002102324700002102345700002302366700002402389700002102413700001802434700002102452700002002473700002602493700002202519700002002541700001902561700002402580700002102604700002402625700001702649700002402666700002002690700001802710700001802728700002602746700002902772700001802801700002002819700002002839700001902859700002502878700002102903700002302924700002102947700001902968700002102987700002603008700002203034700002103056700001503077700001703092700002403109700001703133700002003150700002003170700002203190700002103212700002603233700002203259700002103281700001703302700001903319700002403338700002503362700002003387700002003407700001603427700001703443700002703460700001903487700001903506700002303525700002003548700002203568700001903590700001603609700002003625700002203645700002403667700001803691700001603709700001903725700001803744700002203762700002003784700002303804700002103827700001603848700001803864700002203882700002003904700002203924700002403946700001203970700001503982700002503997700001704022700002004039700002004059700001804079700002804097700002004125700002904145700002004174700002104194700002104215700001704236700002204253700002404275700002104299700001904320700002504339700002704364700002004391700001904411700001904430700002904449700001904478700002204497700001404519700002504533700001904558700001904577700001904596700002704615700001904642700002004661700001904681700002604700700002304726700002304749700001604772700001904788700001804807700002004825700002004845700002204865700002004887700002304907700001904930700002204949700001604971700002204987700001805009700002005027700002005047700002205067700002305089700002205112700002005134700001705154700002105171700002105192700002005213700001705233700002105250700001905271700002005290700002305310700002505333700002205358700002205380700002005402700002205422700002105444700002405465700002105489700002105510700002005531700002305551700002405574700002805598700001605626700002705642700002305669700002605692700002605718700002205744700001705766700002405783700002205807700001805829700001905847700002305866700002105889700002005910700001305930700002205943700001805965700001905983700002506002700002306027700001706050700002106067700001706088700002206105700002406127700001906151700002306170700002406193700001906217700002906236700002306265700001806288700002106306700002106327700001706348700002006365700001506385700002506400700002406425700001706449700002406466700002906490700002106519700002106540700002106561700003006582700002106612700002006633700002106653700002306674700002006697700001806717700002306735710002806758856003606786 2018 eng d a1546-171800aGenetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.0 aGenetic analysis of over 1 million people identifies 535 new loc c2018 Oct a1412-14250 v503 aHigh blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
1 aEvangelou, Evangelos1 aWarren, Helen, R1 aMosen-Ansorena, David1 aMifsud, Borbala1 aPazoki, Raha1 aGao, He1 aNtritsos, Georgios1 aDimou, Niki1 aCabrera, Claudia, P1 aKaraman, Ibrahim1 aNg, Fu, Liang1 aEvangelou, Marina1 aWitkowska, Katarzyna1 aTzanis, Evan1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aEdwards, Digna, R Velez1 aSun, Yan, V1 aCho, Kelly1 aGaziano, Michael1 aWilson, Peter, W F1 aTsao, Philip, S1 aKovesdy, Csaba, P1 aEsko, Tõnu1 aMägi, Reedik1 aMilani, Lili1 aAlmgren, Peter1 aBoutin, Thibaud1 aDebette, Stephanie1 aDing, Jun1 aGiulianini, Franco1 aHolliday, Elizabeth, G1 aJackson, Anne, U1 aLi-Gao, Ruifang1 aLin, Wei-Yu1 aLuan, Jian'an1 aMangino, Massimo1 aOldmeadow, Christopher1 aPrins, Bram, Peter1 aQian, Yong1 aSargurupremraj, Muralidharan1 aShah, Nabi1 aSurendran, Praveen1 aThériault, Sébastien1 aVerweij, Niek1 aWillems, Sara, M1 aZhao, Jing-Hua1 aAmouyel, Philippe1 aConnell, John1 ade Mutsert, Renée1 aDoney, Alex, S F1 aFarrall, Martin1 aMenni, Cristina1 aMorris, Andrew, D1 aNoordam, Raymond1 aParé, Guillaume1 aPoulter, Neil, R1 aShields, Denis, C1 aStanton, Alice1 aThom, Simon1 aAbecasis, Goncalo1 aAmin, Najaf1 aArking, Dan, E1 aAyers, Kristin, L1 aBarbieri, Caterina, M1 aBatini, Chiara1 aBis, Joshua, C1 aBlake, Tineka1 aBochud, Murielle1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrumat, Marco1 aCampbell, Archie1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChauhan, Ganesh1 aCiullo, Marina1 aCocca, Massimiliano1 aCollins, Francis1 aCordell, Heather, J1 aDavies, Gail1 ade Borst, Martin, H1 ade Geus, Eco, J1 aDeary, Ian, J1 aDeelen, Joris1 aM, Fabiola, del Greco1 aDemirkale, Cumhur, Yusuf1 aDörr, Marcus1 aEhret, Georg, B1 aElosua, Roberto1 aEnroth, Stefan1 aErzurumluoglu, Mesut1 aFerreira, Teresa1 aFrånberg, Mattias1 aFranco, Oscar, H1 aGandin, Ilaria1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGoel, Anuj1 aGow, Alan, J1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHarris, Sarah, E1 aHartman, Catharina, A1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHofer, Edith1 aHofman, Albert1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aIngelsson, Erik1 aJames, Alan1 aJansen, Rick1 aJarvelin, Marjo-Riitta1 aJoehanes, Roby1 aJohansson, Asa1 aJohnson, Andrew, D1 aJoshi, Peter, K1 aJousilahti, Pekka1 aJukema, Wouter1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKeavney, Bernard, D1 aKhaw, Kay-Tee1 aKnekt, Paul1 aKnight, Joanne1 aKolcic, Ivana1 aKooner, Jaspal, S1 aKoskinen, Seppo1 aKristiansson, Kati1 aKutalik, Zoltán1 aLaan, Maris1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLopez, Lorna, M1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aMamasoula, Chrysovalanto1 aMarrugat, Jaume1 aMarten, Jonathan1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNalls, Mike, A1 aNandakumar, Priyanka1 aNelson, Christopher, P1 aNiiranen, Teemu1 aNolte, Ilja, M1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aO'Reilly, Paul, F1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPalotie, Aarno1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPramstaller, Peter, P1 aNguyen, Quang, Tri1 aRaitakari, Olli, T1 aRen, Meixia1 aRettig, Rainer1 aRice, Kenneth1 aRidker, Paul, M1 aRied, Janina, S1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRose, Lynda, M1 aRotter, Jerome, I1 aRudan, Igor1 aRuggiero, Daniela1 aSaba, Yasaman1 aSala, Cinzia, F1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aSchmidt, Helena1 aShrine, Nick1 aSiscovick, David1 aSmith, Albert, V1 aSnieder, Harold1 aSõber, Siim1 aSorice, Rossella1 aStarr, John, M1 aStott, David, J1 aStrachan, David, P1 aStrawbridge, Rona, J1 aSundström, Johan1 aSwertz, Morris, A1 aTaylor, Kent, D1 aTeumer, Alexander1 aTobin, Martin, D1 aTomaszewski, Maciej1 aToniolo, Daniela1 aTraglia, Michela1 aTrompet, Stella1 aTuomilehto, Jaakko1 aTzourio, Christophe1 aUitterlinden, André, G1 aVaez, Ahmad1 avan der Most, Peter, J1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aVerwoert, Germaine, C1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVuckovic, Dragana1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWright, Alan, F1 aYao, Jie1 aZemunik, Tatijana1 aZhang, Weihua1 aAttia, John, R1 aButterworth, Adam, S1 aChasman, Daniel, I1 aConen, David1 aCucca, Francesco1 aDanesh, John1 aHayward, Caroline1 aHowson, Joanna, M M1 aLaakso, Markku1 aLakatta, Edward, G1 aLangenberg, Claudia1 aMelander, Olle1 aMook-Kanamori, Dennis, O1 aPalmer, Colin, N A1 aRisch, Lorenz1 aScott, Robert, A1 aScott, Rodney, J1 aSever, Peter1 aSpector, Tim, D1 aHarst, Pim1 aWareham, Nicholas, J1 aZeggini, Eleftheria1 aLevy, Daniel1 aMunroe, Patricia, B1 aNewton-Cheh, Christopher1 aBrown, Morris, J1 aMetspalu, Andres1 aHung, Adriana, M1 aO'Donnell, Christopher, J1 aEdwards, Todd, L1 aPsaty, Bruce, M1 aTzoulaki, Ioanna1 aBarnes, Michael, R1 aWain, Louise, V1 aElliott, Paul1 aCaulfield, Mark, J1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/784504406nas a2201225 4500008004100000022001400041245011600055210006900171260001600240300000900256490000600265520095200271100002001223700002001243700001701263700001601280700002601296700001901322700002201341700001901363700002501382700001701407700001801424700002201442700001901464700002001483700001801503700002501521700002501546700002301571700001901594700002301613700001601636700001601652700002801668700002001696700002101716700002101737700001801758700001901776700001601795700001801811700002001829700002401849700001801873700002101891700002501912700002601937700002601963700002401989700002202013700001802035700002202053700001802075700001902093700001302112700002102125700002002146700002202166700002302188700002102211700002202232700002102254700002002275700002102295700002502316700002002341700002002361700001402381700002202395700001902417700002602436700002202462700002402484700002502508700002002533700002002553700002602573700002802599700003302627700002302660700001302683700001702696700002002713700002402733700002402757700001902781700002202800700002302822700002202845700001902867700001802886700002302904700002002927700002602947700002102973700002502994700002003019700002303039700002203062700002003084700002003104700002003124856003603144 2018 eng d a2041-172300aGenome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.0 aGenomewide association study of 23500 individuals identifies 7 l c2018 Sep 26 a39450 v93 aThe volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.
1 aVojinovic, Dina1 aAdams, Hieab, H1 aJian, Xueqiu1 aYang, Qiong1 aSmith, Albert, Vernon1 aBis, Joshua, C1 aTeumer, Alexander1 aScholz, Markus1 aArmstrong, Nicola, J1 aHofer, Edith1 aSaba, Yasaman1 aLuciano, Michelle1 aBernard, Manon1 aTrompet, Stella1 aYang, Jingyun1 aGillespie, Nathan, A1 avan der Lee, Sven, J1 aNeumann, Alexander1 aAhmad, Shahzad1 aAndreassen, Ole, A1 aAmes, David1 aAmin, Najaf1 aArfanakis, Konstantinos1 aBastin, Mark, E1 aBecker, Diane, M1 aBeiser, Alexa, S1 aBeyer, Frauke1 aBrodaty, Henry1 aBryan, Nick1 aBülow, Robin1 aDale, Anders, M1 aDe Jager, Philip, L1 aDeary, Ian, J1 aDeCarli, Charles1 aFleischman, Debra, A1 aGottesman, Rebecca, F1 avan der Grond, Jeroen1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHomuth, Georg1 aKnopman, David, S1 aKwok, John, B1 aLewis, Cora, E1 aLi, Shuo1 aLoeffler, Markus1 aLopez, Oscar, L1 aMaillard, Pauline1 aMarroun, Hanan, El1 aMather, Karen, A1 aMosley, Thomas, H1 aMuetzel, Ryan, L1 aNauck, Matthias1 aNyquist, Paul, A1 aPanizzon, Matthew, S1 aPausova, Zdenka1 aPsaty, Bruce, M1 aRice, Ken1 aRotter, Jerome, I1 aRoyle, Natalie1 aSatizabal, Claudia, L1 aSchmidt, Reinhold1 aSchofield, Peter, R1 aSchreiner, Pamela, J1 aSidney, Stephen1 aStott, David, J1 aThalamuthu, Anbupalam1 aUitterlinden, André, G1 aHernández, Maria, C Valdés1 aVernooij, Meike, W1 aWen, Wei1 aWhite, Tonya1 aWitte, Veronica1 aWittfeld, Katharina1 aWright, Margaret, J1 aYanek, Lisa, R1 aTiemeier, Henning1 aKremen, William, S1 aBennett, David, A1 aJukema, Wouter1 aPaus, Tomáš1 aWardlaw, Joanna, M1 aSchmidt, Helena1 aSachdev, Perminder, S1 aVillringer, Arno1 aGrabe, Hans, Jörgen1 aLongstreth, W T1 aDuijn, Cornelia, M1 aLauner, Lenore, J1 aSeshadri, Sudha1 aIkram, Arfan, M1 aFornage, Myriam uhttps://chs-nhlbi.org/node/784905032nas a2201033 4500008004100000022001400041245016100055210006900216260001600285520189700301100002502198700002502223700002202248700002102270700002802291700001302319700002102332700002802353700001902381700002002400700002502420700001702445700002002462700002602482700002002508700002502528700001802553700001902571700002102590700002002611700002002631700001802651700002002669700002002689700002202709700002402731700002102755700002502776700002202801700001602823700002302839700002002862700002202882700002502904700001902929700003002948700001902978700001802997700002003015700002203035700002203057700002003079700001603099700002103115700001503136700002603151700002803177700001903205700002103224700001803245700002003263700002903283700002203312700002203334700003003356700002103386700001903407700002403426700002103450700002203471700002003493700002003513700002403533700002403557700002103581700002003602700002003622700001903642700001903661700003203680700002403712700002303736700003003759700002303789700002703812700002303839710010003862856003603962 2018 eng d a1524-453900aGenome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.0 aGenomeWide Association TransEthnic MetaAnalyses Identifies Novel c2018 Nov 203 aBACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.
METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.
RESULTS: We identified 13 novel genome-wide significant (p≤2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.
CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMarten, Jonathan1 aMastrangelo, Michael, A1 aSong, Ci1 aPankratz, Nathan1 aWard-Caviness, Cavin, K1 aYanek, Lisa, R1 aTrompet, Stella1 aDelgado, Graciela, E1 aGuo, Xiuqing1 aBartz, Traci, M1 aMartinez-Perez, Angel1 aGermain, Marine1 ade Haan, Hugoline, G1 aOzel, Ayse, B1 aPolasek, Ozren1 aSmith, Albert, V1 aEicher, John, D1 aReiner, Alex, P1 aTang, Weihong1 aDavies, Neil, M1 aStott, David, J1 aRotter, Jerome, I1 aTofler, Geoffrey, H1 aBoerwinkle, Eric1 ade Maat, Moniek, P M1 aKleber, Marcus, E1 aWelsh, Paul1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aVaidya, Dhananjay1 aSoria, José, Manuel1 aSuchon, Pierre1 aVlieg, Astrid, van Hylcka1 aDesch, Karl, C1 aKolcic, Ivana1 aJoshi, Peter, K1 aLauner, Lenore, J1 aHarris, Tamara, B1 aCampbell, Harry1 aRudan, Igor1 aBecker, Diane, M1 aLi, Jun, Z1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aCushman, Mary1 aPsaty, Bruce, M1 aMorange, Pierre-Emmanuel1 aMcKnight, Barbara1 aChong, Michael, R1 aFernandez-Cadenas, Israel1 aRosand, Jonathan1 aLindgren, Arne1 aGudnason, Vilmundur1 aWilson, James, F1 aHayward, Caroline1 aGinsburg, David1 aFornage, Myriam1 aRosendaal, Frits, R1 aSouto, Juan, Carlos1 aBecker, Lewis, C1 aJenny, Nancy, S1 aMärz, Winfried1 aJukema, Wouter1 aDehghan, Abbas1 aTrégouët, David-Alexandre1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aLowenstein, Charles, J1 aSmith, Nicholas, L1 aINVENT Consortium; MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC) uhttps://chs-nhlbi.org/node/792407247nas 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/791312060nas a2203745 4500008004100000022001400041245014000055210006900195260001600264300001200280490000800292520175500300100001702055700002302072700002602095700002002121700002202141700001902163700002102182700001902203700001702222700002302239700001802262700002002280700001702300700002002317700002102337700002302358700001702381700002102398700002802419700002402447700002102471700002302492700002002515700002002535700002202555700001702577700002202594700002002616700002602636700002402662700002202686700002102708700001402729700001702743700001702760700001702777700001702794700001902811700002202830700002002852700001302872700001902885700001902904700001502923700002302938700001502961700002102976700002902997700002803026700001803054700002103072700002003093700002903113700002103142700001903163700001803182700001903200700002003219700002303239700001403262700002703276700002103303700001903324700002103343700002103364700002503385700002303410700002703433700002003460700001703480700001703497700001803514700001803532700001703550700001903567700001803586700001903604700001603623700001903639700001603658700001603674700001403690700001703704700002403721700002103745700002403766700002103790700002303811700002103834700002403855700001603879700001703895700002103912700002203933700002603955700002003981700002304001700002404024700002404048700002104072700002304093700002104116700002304137700001804160700001504178700002204193700001704215700002504232700002104257700002404278700002104302700002104323700002504344700001204369700001904381700001604400700001604416700001704432700001804449700002504467700002204492700001404514700002004528700002004548700001904568700001904587700002304606700001704629700002504646700001704671700001904688700002104707700002204728700001804750700002404768700002304792700001904815700002504834700002204859700002404881700002104905700001904926700002204945700002304967700002404990700002205014700002005036700001905056700001305075700001905088700001505107700001805122700001705140700001705157700001505174700001605189700001505205700002005220700001705240700001505257700001805272700002005290700002205310700002105332700001705353700002305370700002205393700002205415700001805437700002205455700001905477700001905496700002005515700001605535700002205551700002505573700002205598700002605620700002105646700002305667700002005690700002405710700001905734700002305753700002005776700001905796700002005815700002305835700002605858700001905884700001605903700002805919700002505947700001805972700002405990700002506014700002206039700002006061700001706081700002406098700002306122700002006145700001906165700002406184700001406208700002006222700001906242700002106261700002806282700002606310700001606336700001606352700001706368700002406385700002006409700002406429700001306453700001906466700002306485700002106508700002106529700002206550700002206572700002206594700001806616700001806634700001606652700002006668700002406688700002006712700002306732700002206755700002106777700002206798700002706820700001706847700001906864700001906883700002206902700001906924700002206943700002006965700002706985700002007012700002907032700002607061700001907087700001907106700002207125700001707147700001707164700001507181700002607196700002507222700001807247700001907265700003007284700001707314700001507331700002307346700002107369700002107390700002307411700002207434700002407456700002407480700002807504700001707532700002307549700002007572700002007592700001607612700002107628700002907649700002107678700001807699700002207717700002007739700002307759700002507782700002307807700001907830700002007849700002007869700002007889700002207909700001807931700002107949700002107970700002307991700001808014700001808032700002408050700002408074700002508098700002008123700002308143710003508166710002908201710002108230710002708251856003608278 2018 eng d a1537-660500aA Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.0 aLargeScale Multiancestry Genomewide Study Accounting for Smoking c2018 Mar 01 a375-4000 v1023 aGenome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
1 aSung, Yun, J1 aWinkler, Thomas, W1 aFuentes, Lisa, de Las1 aBentley, Amy, R1 aBrown, Michael, R1 aKraja, Aldi, T1 aSchwander, Karen1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aKilpeläinen, Tuomas, O1 aRichard, Melissa, A1 aNoordam, Raymond1 aAslibekyan, Stella1 aAschard, Hugues1 aBartz, Traci, M1 aDorajoo, Rajkumar1 aLiu, Yongmei1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, Vernon1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aWarren, Helen, R1 aZhao, Wei1 aZhou, Yanhua1 aMatoba, Nana1 aSofer, Tamar1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGiulianini, Franco1 aGoel, Anuj1 aHarris, Sarah, E1 aHartwig, Fernando, Pires1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKuhnel, Brigitte1 aLeander, Karin1 aLee, Wen-Jane1 aLin, Keng-Hung1 aLuan, Jian, 'an1 aMcKenzie, Colin, A1 aMeian, He1 aNelson, Christopher, P1 aRauramaa, Rainer1 aSchupf, Nicole1 aScott, Robert, A1 aSheu, Wayne, H H1 aStančáková, Alena1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Heming1 aWang, Yajuan1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAlfred, Tamuno1 aAmin, Najaf1 aArking, Dan1 aAung, Tin1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCabrera, Claudia, P1 aCade, Brian1 aCaizheng, Yu1 aCampbell, Archie1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aChauhan, Ganesh1 aChristensen, Kaare1 aCocca, Massimiliano1 aCollins, Francis, S1 aConnell, John, M1 ade Mutsert, Renée1 ade Silva, Janaka1 aDebette, Stephanie1 aDörr, Marcus1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFisher, Virginia, A1 aForouhi, Nita, G1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGraff, Misa1 aGu, Charles1 aGu, Dongfeng1 aGupta, Preeti1 aHagenaars, Saskia, P1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHofman, Albert1 aHoward, Barbara, V1 aHunt, Steven1 aIrvin, Marguerite, R1 aJia, Yucheng1 aJoehanes, Roby1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKaufman, Joel1 aKerrison, Nicola, D1 aKhor, Chiea, Chuen1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKomulainen, Pirjo1 aKooperberg, Charles1 aKrieger, Jose, E1 aKubo, Michiaki1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLim, Sing, Hui1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Jingmin1 aLiu, Kiang1 aLiu, Yeheng1 aLoh, Marie1 aLohman, Kurt, K1 aLong, Jirong1 aLouie, Tin1 aMägi, Reedik1 aMahajan, Anubha1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilani, Lili1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMosley, Thomas, H1 aMunson, Peter1 aMurray, Alison, D1 aNalls, Mike, A1 aNasri, Ubaydah1 aNorris, Jill, M1 aNorth, Kari1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmas, Walter, R1 aPalmer, Nicholette, D1 aPankow, James, S1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRenstrom, Frida1 aRice, Treva, K1 aRidker, Paul, M1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSandow, Kevin1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSeshadri, Sudha1 aSever, Peter1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, X1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYuan, Jian-Min1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aChen, Yii-Der Ida1 ade Faire, Ulf1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aForrester, Terrence1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, Lessa1 aHung, Yi-Jen1 aJonas, Jost, B1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLehtimäki, Terho1 aLiang, Kae-Woei1 aMagnusson, Patrik, K E1 aNewman, Anne, B1 aOldehinkel, Albertine, J1 aPereira, Alexandre, C1 aRedline, Susan1 aRettig, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aKamatani, Yoichiro1 aLaurie, Cathy, C1 aBouchard, Claude1 aCooper, Richard, S1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aO'Connell, Jeff, R1 aPsaty, Bruce, M1 avan Dam, Rob, M1 aSims, Mario1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aFornage, Myriam1 aRotimi, Charles, N1 aProvince, Michael, A1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aReiner, Alex, P1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aCaulfield, Mark, J1 aElliott, Paul1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aChasman, Daniel, I1 aCHARGE Neurology Working Group1 aCOGENT-Kidney Consortium1 aGIANT Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/768616401nas a2205425 4500008004100000022001400041245013100055210006900186260001300255300001200268490000700280520096800287100001801255700002001273700002101293700003301314700002001347700001901367700002401386700002301410700002801433700002701461700002901488700001901517700002201536700001701558700001901575700002201594700001401616700002001630700002401650700001701674700002801691700002101719700002501740700001801765700001901783700002301802700001801825700001801843700001901861700002201880700002101902700001701923700002501940700002401965700002201989700001502011700002402026700002202050700002602072700002002098700002402118700002302142700002202165700002202187700001902209700002202228700002302250700002702273700001902300700001802319700002602337700002002363700002002383700002502403700001702428700002502445700002202470700001902492700002002511700002002531700002202551700002502573700002402598700001902622700002102641700002302662700002402685700002202709700001702731700001902748700001702767700002202784700001602806700002202822700002002844700002502864700001802889700002102907700002402928700002202952700002502974700002202999700002203021700002403043700002503067700002003092700001903112700002503131700002503156700002403181700001803205700002103223700002003244700002103264700002303285700002203308700002003330700002003350700001803370700002203388700002003410700002303430700002203453700002403475700001803499700001903517700002203536700002403558700002403582700002303606700002003629700002403649700002503673700002803698700001903726700002003745700002403765700002303789700002103812700002503833700003203858700002103890700002203911700001603933700001703949700001903966700001903985700002004004700002004024700001804044700002804062700002104090700001804111700002304129700002504152700003004177700002204207700002204229700002404251700001904275700002204294700001904316700001404335700001504349700001804364700002204382700002304404700002304427700002704450700001904477700002004496700002004516700003004536700002004566700001704586700001404603700001604617700002104633700002104654700002304675700002104698700002104719700002504740700002304765700002004788700002004808700002004828700002404848700002304872700002304895700002104918700001804939700002004957700002104977700003304998700002005031700001905051700002405070700002305094700002805117700002705145700002905172700001905201700002205220700001705242700001905259700002205278700001405300700002005314700002405334700001705358700002805375700002105403700002505424700001805449700001905467700002305486700001805509700001805527700001905545700002205564700002105586700001705607700002505624700002405649700002205673700001505695700002405710700002205734700002605756700002005782700002405802700002305826700002205849700002205871700001905893700002205912700002305934700002705957700001905984700001806003700002606021700002006047700002006067700002506087700001706112700002506129700002206154700001906176700002006195700002006215700002206235700002506257700002406282700001906306700002106325700002306346700002406369700002206393700001706415700001906432700001706451700002206468700001606490700002206506700002006528700002506548700001806573700002106591700002406612700002206636700002506658700002206683700002206705700002406727700002506751700002006776700001906796700002506815700002506840700002406865700001806889700002106907700002006928700002106948700002306969700002206992700002007014700002007034700001807054700002207072700002007094700002307114700002207137700002407159700001807183700001907201700002207220700002407242700002407266700002307290700002007313700002407333700002507357700002807382700001907410700002007429700002407449700002307473700002107496700002507517700003207542700002107574700002207595700001607617700001707633700001607650700002207666700002107688700001607709700002107725700001907746700002107765700002407786700001807810700002007828700002207848700002007870700002107890700003007911700002307941700001907964700001807983700002208001700001408023700002408037700002008061700001908081700002008100700001808120700002008138700002208158700002008180700002408200700001908224700002208243700002108265700001708286700002308303700002308326700002408349700001708373700002408390700002108414700002408435700002108459700002508480700001508505700001508520700002508535700002308560700001908583700002008602700001908622700003108641700002008672700002108692700001908713700002208732700001808754700003008772700001708802700002108819700002308840700003308863700002308896700001708919700001908936700002408955700002108979700002109000700002409021700002009045700002009065700001809085700002109103700002309124700001809147700002109165700001909186700002609205700001809231700001909249700001809268700001809286700002409304700001809328700001709346700003109363700001709394700001709411700002009428700002409448700001809472700001809490700001609508700002209524700001809546700002809564700002009592700002309612700002809635700002709663700002509690700001909715700001709734700001609751700002509767700002409792700001709816700001609833700001809849700002709867700001909894700002009913700002009933700003009953700002009983700001710003700001410020700001610034700002110050700002110071700002310092700002110115700002110136700002510157700002310182700002010205700002010225700002010245700002410265700002310289700002310312700002110335710002110356710008510377710006610462710002210528710001210550710004510562710002310607710002410630710002910654710005210683710002610735710005310761710004110814710003110855710002610886710002710912856003610939 2018 eng d a1546-171800aMultiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.0 aMultiancestry genomewide association study of 520000 subjects id c2018 Apr a524-5370 v503 aStroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aBis, Joshua, C1 aPastinen, Tomi1 aRuusalepp, Arno1 aSchadt, Eric, E1 aKoplev, Simon1 aBjörkegren, Johan, L M1 aCodoni, Veronica1 aCivelek, Mete1 aSmith, Nicholas, L1 aTrégouët, David, A1 aChristophersen, Ingrid, E1 aRoselli, Carolina1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aTai, Shyong, E1 aKooner, Jaspal, S1 aKato, Norihiro1 aHe, Jiang1 aHarst, Pim1 aElliott, Paul1 aChambers, John, C1 aTakeuchi, Fumihiko1 aJohnson, Andrew, D1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aAmin, Najaf1 aAparicio, Hugo, S1 aArnett, Donna, K1 aAttia, John1 aBeiser, Alexa, S1 aBerr, Claudine1 aBuring, Julie, E1 aBustamante, Mariana1 aCaso, Valeria1 aCheng, Yu-Ching1 aChoi, Seung, Hoan1 aChowhan, Ayesha1 aCullell, Natalia1 aDartigues, Jean-François1 aDelavaran, Hossein1 aDelgado, Pilar1 aDörr, Marcus1 aEngström, Gunnar1 aFord, Ian1 aGurpreet, Wander, S1 aHamsten, Anders1 aHeitsch, Laura1 aHozawa, Atsushi1 aIbanez, Laura1 aIlinca, Andreea1 aIngelsson, Martin1 aIwasaki, Motoki1 aJackson, Rebecca, D1 aJood, Katarina1 aJousilahti, Pekka1 aKaffashian, Sara1 aKalra, Lalit1 aKamouchi, Masahiro1 aKitazono, Takanari1 aKjartansson, Olafur1 aKloss, Manja1 aKoudstaal, Peter, J1 aKrupinski, Jerzy1 aLabovitz, Daniel, L1 aLaurie, Cathy, C1 aLevi, Christopher, R1 aLi, Linxin1 aLind, Lars1 aLindgren, Cecilia, M1 aLioutas, Vasileios1 aLiu, Yong, Mei1 aLopez, Oscar, L1 aMakoto, Hirata1 aMartinez-Majander, Nicolas1 aMatsuda, Koichi1 aMinegishi, Naoko1 aMontaner, Joan1 aMorris, Andrew, P1 aMuiño, Elena1 aMüller-Nurasyid, Martina1 aNorrving, Bo1 aOgishima, Soichi1 aParati, Eugenio, A1 aPeddareddygari, Leema, Reddy1 aPedersen, Nancy, L1 aPera, Joanna1 aPerola, Markus1 aPezzini, Alessandro1 aPileggi, Silvana1 aRabionet, Raquel1 aRiba-Llena, Iolanda1 aRibasés, Marta1 aRomero, Jose, R1 aRoquer, Jaume1 aRudd, Anthony, G1 aSarin, Antti-Pekka1 aSarju, Ralhan1 aSarnowski, Chloe1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSatoh, Mamoru1 aSattar, Naveed1 aSawada, Norie1 aSibolt, Gerli1 aSigurdsson, Ásgeir1 aSmith, Albert1 aSobue, Kenji1 aSoriano-Tárraga, Carolina1 aStanne, Tara1 aStine, Colin1 aStott, David, J1 aStrauch, Konstantin1 aTakai, Takako1 aTanaka, Hideo1 aTanno, Kozo1 aTeumer, Alexander1 aTomppo, Liisa1 aTorres-Aguila, Nuria, P1 aTouze, Emmanuel1 aTsugane, Shoichiro1 aUitterlinden, André, G1 aValdimarsson, Einar, M1 avan der Lee, Sven, J1 aVölzke, Henry1 aWakai, Kenji1 aWeir, David1 aWilliams, Stephen, R1 aWolfe, Charles, D A1 aWong, Quenna1 aXu, Huichun1 aYamaji, Taiki1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aAFGen Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium1 aInternational Genomics of Blood Pressure (iGEN-BP) Consortium1 aINVENT Consortium1 aSTARNET1 aBioBank Japan Cooperative Hospital Group1 aCOMPASS Consortium1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aInternational Stroke Genetics Consortium (ISGC)1 aMETASTROKE Consortium1 aNeurology Working Group of the CHARGE Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aUK Young Lacunar DNA Study1 aMEGASTROKE Consortium1 aMEGASTROKE Consortium: uhttps://chs-nhlbi.org/node/768308664nas a2202749 4500008004100000022001400041245007200055210006900127260001300196300001400209490000700223520107000230100002201300700002101322700001801343700002601361700002001387700002501407700001901432700001901451700002901470700002301499700001901522700001801541700002001559700002401579700002501603700001901628700002201647700002101669700002401690700002301714700001801737700002101755700002301776700002001799700002301819700001701842700002201859700001901881700002201900700003001922700001901952700001801971700001701989700001602006700002102022700002302043700002302066700002202089700001902111700002202130700002102152700002102173700001802194700002102212700002202233700001402255700001602269700001902285700001802304700002202322700001402344700002102358700002302379700002002402700002402422700001702446700001902463700002302482700002102505700002002526700002202546700002202568700002302590700002302613700002202636700001902658700002802677700001502705700001902720700002202739700002002761700002202781700001502803700002502818700001902843700001902862700001902881700002002900700002302920700001802943700002002961700002202981700002803003700002003031700002203051700002303073700002103096700002203117700001903139700002103158700001903179700002203198700001903220700002203239700002403261700002403285700001203309700001903321700001803340700001903358700001503377700002503392700002303417700001803440700002003458700001803478700001803496700002803514700002503542700002503567700002003592700001803612700002303630700002303653700002103676700002603697700002003723700002203743700001903765700002503784700002303809700002303832700002203855700003003877700001903907700002003926700002203946700002903968700002603997700001704023700001904040700002104059700001904080700002204099700002504121700002504146700001704171700002104188700002304209700001704232700002304249700002004272700002004292700001904312700002404331700002104355700002004376700002004396700002004416700002204436700001804458700001804476700002104494700002604515700001804541700002204559700001604581700002504597700002404622700002304646700002404669700002204693700002104715700002104736700002304757700001604780700002104796700001704817700002404834700002304858700001904881700002204900700002204922700002104944700002004965700001804985700002305003700002305026700002405049700002205073700002305095700001605118700001305134700002405147700002205171700002505193700002005218700002405238700002205262700002705284700002005311700002205331700001905353700002805372700001505400700002805415700002605443700001805469700002705487700001705514700001505531700002005546700001505566700001605581700001805597700002005615700002205635700001905657700001605676700002505692700001905717700001305736700002305749700001805772700001805790700002205808700002405830700002405854856003605878 2018 eng d a1546-171800aMulti-ethnic genome-wide association study for atrial fibrillation.0 aMultiethnic genomewide association study for atrial fibrillation c2018 Sep a1225-12330 v503 aAtrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
1 aRoselli, Carolina1 aChaffin, Mark, D1 aWeng, Lu-Chen1 aAeschbacher, Stefanie1 aAhlberg, Gustav1 aAlbert, Christine, M1 aAlmgren, Peter1 aAlonso, Alvaro1 aAnderson, Christopher, D1 aAragam, Krishna, G1 aArking, Dan, E1 aBarnard, John1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aBihlmeyer, Nathan, A1 aBis, Joshua, C1 aBloom, Heather, L1 aBoerwinkle, Eric1 aBottinger, Erwin, B1 aBrody, Jennifer, A1 aCalkins, Hugh1 aCampbell, Archie1 aCappola, Thomas, P1 aCarlquist, John1 aChasman, Daniel, I1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aChoi, Eue-Keun1 aChoi, Seung, Hoan1 aChristophersen, Ingrid, E1 aChung, Mina, K1 aCole, John, W1 aConen, David1 aCook, James1 aCrijns, Harry, J1 aCutler, Michael, J1 aDamrauer, Scott, M1 aDaniels, Brian, R1 aDarbar, Dawood1 aDelgado, Graciela1 aDenny, Joshua, C1 aDichgans, Martin1 aDörr, Marcus1 aDudink, Elton, A1 aDudley, Samuel, C1 aEsa, Nada1 aEsko, Tõnu1 aEskola, Markku1 aFatkin, Diane1 aFelix, Stephan, B1 aFord, Ian1 aFranco, Oscar, H1 aGeelhoed, Bastiaan1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGupta, Namrata1 aGustafsson, Stefan1 aGutmann, Rebecca1 aHamsten, Anders1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHernesniemi, Jussi1 aHocking, Lynne, J1 aHofman, Albert1 aHorimoto, Andrea, R V R1 aHuang, Jie1 aHuang, Paul, L1 aHuffman, Jennifer1 aIngelsson, Erik1 aIpek, Esra, Gucuk1 aIto, Kaoru1 aJimenez-Conde, Jordi1 aJohnson, Renee1 aJukema, Wouter1 aKääb, Stefan1 aKähönen, Mika1 aKamatani, Yoichiro1 aKane, John, P1 aKastrati, Adnan1 aKathiresan, Sekar1 aKatschnig-Winter, Petra1 aKavousi, Maryam1 aKessler, Thorsten1 aKietselaer, Bas, L1 aKirchhof, Paulus1 aKleber, Marcus, E1 aKnight, Stacey1 aKrieger, Jose, E1 aKubo, Michiaki1 aLauner, Lenore, J1 aLaurikka, Jari1 aLehtimäki, Terho1 aLeineweber, Kirsten1 aLemaitre, Rozenn, N1 aLi, Man1 aLim, Hong, Euy1 aLin, Henry, J1 aLin, Honghuang1 aLind, Lars1 aLindgren, Cecilia, M1 aLokki, Marja-Liisa1 aLondon, Barry1 aLoos, Ruth, J F1 aLow, Siew-Kee1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMacfarlane, Peter, W1 aMagnusson, Patrik, K1 aMahajan, Anubha1 aMalik, Rainer1 aMansur, Alfredo, J1 aMarcus, Gregory, M1 aMargolin, Lauren1 aMargulies, Kenneth, B1 aMärz, Winfried1 aMcManus, David, D1 aMelander, Olle1 aMohanty, Sanghamitra1 aMontgomery, Jay, A1 aMorley, Michael, P1 aMorris, Andrew, P1 aMüller-Nurasyid, Martina1 aNatale, Andrea1 aNazarian, Saman1 aNeumann, Benjamin1 aNewton-Cheh, Christopher1 aNiemeijer, Maartje, N1 aNikus, Kjell1 aNilsson, Peter1 aNoordam, Raymond1 aOellers, Heidi1 aOlesen, Morten, S1 aOrho-Melander, Marju1 aPadmanabhan, Sandosh1 aPak, Hui-Nam1 aParé, Guillaume1 aPedersen, Nancy, L1 aPera, Joanna1 aPereira, Alexandre1 aPorteous, David1 aPsaty, Bruce, M1 aPulit, Sara, L1 aPullinger, Clive, R1 aRader, Daniel, J1 aRefsgaard, Lena1 aRibasés, Marta1 aRidker, Paul, M1 aRienstra, Michiel1 aRisch, Lorenz1 aRoden, Dan, M1 aRosand, Jonathan1 aRosenberg, Michael, A1 aRost, Natalia1 aRotter, Jerome, I1 aSaba, Samir1 aSandhu, Roopinder, K1 aSchnabel, Renate, B1 aSchramm, Katharina1 aSchunkert, Heribert1 aSchurman, Claudia1 aScott, Stuart, A1 aSeppälä, Ilkka1 aShaffer, Christian1 aShah, Svati1 aShalaby, Alaa, A1 aShim, Jaemin1 aShoemaker, Benjamin1 aSiland, Joylene, E1 aSinisalo, Juha1 aSinner, Moritz, F1 aSlowik, Agnieszka1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Gustav1 aSmith, Jonathan, D1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSun, Albert1 aSun, Han1 aSvendsen, Jesper, H1 aTanaka, Toshihiro1 aTanriverdi, Kahraman1 aTaylor, Kent, D1 aTeder-Laving, Maris1 aTeumer, Alexander1 aThériault, Sébastien1 aTrompet, Stella1 aTucker, Nathan, R1 aTveit, Arnljot1 aUitterlinden, André, G1 aHarst, Pim1 aVan Gelder, Isabelle, C1 aVan Wagoner, David, R1 aVerweij, Niek1 aVlachopoulou, Efthymia1 aVölker, Uwe1 aWang, Biqi1 aWeeke, Peter, E1 aWeijs, Bob1 aWeiss, Raul1 aWeiss, Stefan1 aWells, Quinn, S1 aWiggins, Kerri, L1 aWong, Jorge, A1 aWoo, Daniel1 aWorrall, Bradford, B1 aYang, Pil-Sung1 aYao, Jie1 aYoneda, Zachary, T1 aZeller, Tanja1 aZeng, Lingyao1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/781104963nas a2201357 4500008004100000022001400041245010700055210006900162260001600231300000900247490000600256520112300262100001901385700001701404700002001421700002301441700002401464700001901488700002601507700002601533700002001559700002101579700001301600700002801613700001601641700002701657700001501684700001701699700002401716700001801740700002101758700002901779700002501808700001901833700001901852700002001871700001901891700001901910700002401929700001601953700002101969700001801990700001802008700002202026700002202048700001702070700002302087700002502110700002402135700001702159700002702176700002102203700002002224700002202244700001702266700002302283700002902306700002202335700002702357700001902384700002102403700002202424700002202446700002402468700002402492700002202516700002802538700002102566700002302587700002202610700002202632700003402654700001802688700001702706700001202723700002302735700002302758700002202781700001702803700001702820700002502837700002402862700002002886700002102906700002002927700002502947700002402972700001602996700002403012700001903036700002003055700002003075700002203095700002103117700001903138700002103157700002503178700001703203700001803220700001903238700001803257700001903275700002403294700002103318700002903339700002703368700002803395700001903423700002003442700002203462700002003484700001903504700002103523700002503544856003603569 2018 eng d a2041-172300aMultiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.0 aMultiethnic metaanalysis identifies ancestryspecific and crossan c2018 Jul 30 a29760 v93 aNearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
1 aWyss, Annah, B1 aSofer, Tamar1 aLee, Mi, Kyeong1 aTerzikhan, Natalie1 aNguyen, Jennifer, N1 aLahousse, Lies1 aLatourelle, Jeanne, C1 aSmith, Albert, Vernon1 aBartz, Traci, M1 aFeitosa, Mary, F1 aGao, Wei1 aAhluwalia, Tarunveer, S1 aTang, Wenbo1 aOldmeadow, Christopher1 aDuan, Qing1 ade Jong, Kim1 aWojczynski, Mary, K1 aWang, Xin-Qun1 aNoordam, Raymond1 aHartwig, Fernando, Pires1 aJackson, Victoria, E1 aWang, Tianyuan1 aObeidat, Ma'en1 aHobbs, Brian, D1 aHuan, Tianxiao1 aGui, Hongsheng1 aParker, Margaret, M1 aHu, Donglei1 aMogil, Lauren, S1 aKichaev, Gleb1 aJin, Jianping1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aKalhan, Ravi1 aHeckbert, Susan, R1 aPaternoster, Lavinia1 aBurkart, Kristin, M1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aWilson, James, G1 aVonk, Judith, M1 aSanders, Jason, L1 aBarr, Graham1 ade Mutsert, Renée1 aMenezes, Ana, Maria Bapt1 aAdams, Hieab, H H1 avan den Berge, Maarten1 aJoehanes, Roby1 aLevin, Albert, M1 aLiberto, Jennifer1 aLauner, Lenore, J1 aMorrison, Alanna, C1 aSitlani, Colleen, M1 aCeledón, Juan, C1 aKritchevsky, Stephen, B1 aScott, Rodney, J1 aChristensen, Kaare1 aRotter, Jerome, I1 aBonten, Tobias, N1 aWehrmeister, Fernando, César1 aBossé, Yohan1 aXiao, Shujie1 aOh, Sam1 aFranceschini, Nora1 aBrody, Jennifer, A1 aKaplan, Robert, C1 aLohman, Kurt1 aMcEvoy, Mark1 aProvince, Michael, A1 aRosendaal, Frits, R1 aTaylor, Kent, D1 aNickle, David, C1 aWilliams, Keoki1 aBurchard, Esteban, G1 aWheeler, Heather, E1 aSin, Don, D1 aGudnason, Vilmundur1 aNorth, Kari, E1 aFornage, Myriam1 aPsaty, Bruce, M1 aMyers, Richard, H1 aO'Connor, George1 aHansen, Torben1 aLaurie, Cathy, C1 aCassano, Patricia, A1 aSung, Joohon1 aKim, Woo, Jin1 aAttia, John, R1 aLange, Leslie1 aBoezen, Marike1 aThyagarajan, Bharat1 aRich, Stephen, S1 aMook-Kanamori, Dennis, O1 aHorta, Bernardo, Lessa1 aUitterlinden, André, G1 aIm, Hae, Kyung1 aCho, Michael, H1 aBrusselle, Guy, G1 aGharib, Sina, A1 aDupuis, Josée1 aManichaikul, Ani1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/781911027nas a2203421 4500008004100000022001400041245014400055210006900199260000900268300001300277490000700290520159600297100002101893700001901914700002301933700001701956700002301973700001901996700001702015700002302032700002002055700001702075700002002092700002102112700002302133700001702156700002002173700002202193700002102215700002402236700002102260700002002281700002002301700002402321700002202345700002102367700002502388700002802413700002002441700002202461700002002483700002102503700002402524700002402548700001702572700002202589700001602611700002102627700002002648700001302668700001902681700001502700700001502715700002302730700002102753700001402774700001802788700002102806700002002827700002902847700002202876700002102898700002202919700001802941700001702959700001902976700002502995700001903020700001703039700002303056700001903079700002103098700001703119700002503136700002303161700002203184700002703206700002003233700002203253700001703275700001803292700002103310700001803331700001703349700001903366700001803385700001903403700001603422700001603438700001903454700001903473700001403492700002103506700002003527700002103547700001803568700001803586700002203604700002203626700002603648700002803674700002303702700002103725700001903746700002603765700002303791700002103814700001503835700002003850700001503870700002203885700001703907700002203924700002503946700002103971700002203992700002104014700002404035700002104059700002504080700001904105700001204124700002104136700001904157700001604176700001704192700002504209700002104234700002204255700001404277700002004291700002004311700001904331700002304350700002004373700001704393700002204410700002304432700002804455700001904483700002104502700002804523700001904551700002204570700001904592700002304611700002404634700002204658700002004680700001904700700001304719700001504732700001704747700001704764700001504781700001504796700001804811700002304829700002204852700002104874700002104895700001704916700002104933700002304954700001904977700002704996700002205023700002005045700002305065700002605088700001805114700002305132700002005155700002405175700001805199700002205217700002305239700001805262700001905280700002405299700002205323700002405345700002505369700001905394700002205413700002005435700001405455700002005469700001605489700002405505700002305529700002005552700001905572700002405591700002605615700002305641700001405664700002005678700001905698700002105717700002305738700002805761700002405789700002605813700001605839700001905855700001705874700002405891700001305915700001705928700001905945700001405964700002305978700002106001700002106022700002206043700002206065700001806087700001606105700002006121700002006141700002306161700002206184700002106206700002206227700002306249700002306272700001906295700002206314700002106336700001906357700002106376700001906397700002206416700002906438700002706467700002906494700002706523700001906550700002306569700002106592700002206613700001706635700001706652700001506669700002606684700002506710700001806735700001906753700003006772700001706802700001506819700002106834700002306855700002206878700002406900700002306924700002406947700001706971700002606988700002007014700002007034700002007054700002107074700001807095700002907113700002007142700002307162700002507185700002107210700001807231700002207249700002307271700001907294700002007313700002407333700001907357700001807376700002407394700001807418700002307436700002407459700002007483700002507503700001707528710002407545856003607569 2018 eng d a1932-620300aNovel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.0 aNovel genetic associations for blood pressure identified via gen c2018 ae01981660 v133 aHeavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1 aFeitosa, Mary, F1 aKraja, Aldi, T1 aChasman, Daniel, I1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aBentley, Amy, R1 aBrown, Michael, R1 aSchwander, Karen1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aWojczynski, Mary, K1 aAlver, Maris1 aBoissel, Mathilde1 aCai, Qiuyin1 aCampbell, Archie1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLuan, Jian'an1 aMatoba, Nana1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRiaz, Muhammad1 aRueedi, Rico1 aRobino, Antonietta1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVitart, Veronique1 aWang, Yajuan1 aWare, Erin, B1 aWarren, Helen, R1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBoerwinkle, Eric1 aBorecki, Ingrid1 aBroeckel, Ulrich1 aBrown, Morris1 aBrumat, Marco1 aBurke, Gregory, L1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aCharumathi, Sabanayagam1 aChen, Yii-Der, Ida1 aConnell, John, M1 aCorrea, Adolfo1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDeng, Xuan1 aDing, Jingzhong1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEppinga, Ruben, N1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFelix, Stephan, B1 aForouhi, Nita, G1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGigante, Bruna1 aGu, Charles1 aGu, Dongfeng1 aHagenaars, Saskia, P1 aHallmans, Göran1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJohn, Ulrich1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLin, Shiow1 aLiu, Jianjun1 aLiu, Jingmin1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aNalls, Mike, A1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aNorris, Jill, M1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPerls, Thomas1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRoll, Kathryn1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRotter, Jerome, I1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aSchupf, Nicole1 aScott, William, R1 aSever, Peter, S1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVollenweider, Peter1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, Xing1 aBin Wei, Wen1 aWilliams, Christine1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLaakso, Markku1 aLaurie, Cathy, C1 aLeander, Karin1 aLehtimäki, Terho1 aStudy, Lifelines, Cohort1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPolasek, Ozren1 aPorteous, David, J1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aBouchard, Claude1 aChristensen, Kaare1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPereira, Alexandre, C1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aGauderman, James1 aZhu, Xiaofeng1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aKooperberg, Charles1 aPalmas, Walter1 aRice, Kenneth1 aMorrison, Alanna, C1 aElliott, Paul1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aRao, Dabeeru, C1 aProvince, Michael, A1 aLevy, Daniel1 aInterAct Consortium uhttps://chs-nhlbi.org/node/779204010nas a2200709 4500008004100000022001400041245010600055210006900161260001600230520196000246100001402206700002202220700002002242700001602262700002402278700002102302700002102323700001602344700002302360700002702383700002302410700001802433700002002451700002202471700002402493700001402517700002002531700002202551700002202573700002002595700002102615700002202636700002402658700002102682700002602703700002002729700002702749700002202776700002102798700002202819700002002841700002002861700002202881700002102903700002802924700002202952700001502974700002102989700002003010700002503030700002503055700001703080700001903097700002003116700002403136700001903160700001903179700002003198700002503218700002103243856003603264 2018 eng d a1535-497000aOmega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.0 aOmega3 Fatty Acids and Genomewide Interaction Analyses Reveal DP c2018 Sep 103 aRATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.
OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.
METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.
RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4×10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (P=2.1×10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1×10; β=36.2mL).
CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.
1 aXu, Jiayi1 aGaddis, Nathan, C1 aBartz, Traci, M1 aHou, Ruixue1 aManichaikul, Ani, W1 aPankratz, Nathan1 aSmith, Albert, V1 aSun, Fangui1 aTerzikhan, Natalie1 aMarkunas, Christina, A1 aPatchen, Bonnie, K1 aSchu, Matthew1 aBeydoun, May, A1 aBrusselle, Guy, G1 aEiriksdottir, Gudny1 aZhou, Xia1 aWood, Alexis, C1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aIkram, Arfan, M1 aJacobs, David, R1 aLauner, Lenore, J1 aLemaitre, Rozenn, N1 aO'Connor, George1 aOelsner, Elizabeth, C1 aPsaty, Bruce, M1 aRamachandran, Vasan, S1 aRohde, Rebecca, R1 aRich, Stephen, S1 aRotter, Jerome, I1 aSeshadri, Sudha1 aSmith, Lewis, J1 aTiemeier, Henning1 aTsai, Michael, Y1 aUitterlinden, André, G1 aVoruganti, Saroja1 aXu, Hanfei1 aZilhão, Nuno, R1 aFornage, Myriam1 aZillikens, Carola, M1 aLondon, Stephanie, J1 aBarr, Graham1 aDupuis, Josée1 aGharib, Sina, A1 aGudnason, Vilmundur1 aLahousse, Lies1 aNorth, Kari, E1 aSteffen, Lyn, M1 aCassano, Patricia, A1 aHancock, Dana, B uhttps://chs-nhlbi.org/node/777605872nas a2201645 4500008004100000022001400041245013800055210006900193260001600262300000900278490000600287520118400293100002401477700002301501700002001524700002401544700002001568700002001588700002601608700002101634700001901655700002801674700002201702700002201724700002801746700002301774700003001797700001901827700002501846700002401871700002301895700002101918700002201939700002001961700002201981700002002003700001802023700001802041700001702059700002002076700002702096700001902123700001802142700001402160700002402174700002102198700001902219700002402238700001902262700001902281700002202300700001902322700002402341700002002365700002202385700002402407700002202431700002102453700001702474700002202491700001602513700001902529700002102548700002002569700001802589700001702607700002302624700002202647700001902669700001802688700002002706700002202726700002502748700002202773700002402795700002202819700002502841700002002866700002802886700002002914700001802934700002602952700002302978700002203001700001603023700002203039700002403061700002903085700002203114700002303136700002003159700002403179700002403203700002003227700002403247700002303271700002803294700002803322700002603350700001703376700001903393700002603412700002203438700002103460700001803481700001903499700002203518700002503540700002403565700002103589700001803610700002003628700002103648700002403669700002203693700002303715700002103738700001903759700001903778700002203797700001703819700002403836700001803860700001903878700002003897700001803917700002403935700002403959700002103983700002304004700001504027700002304042700002104065700002004086700002504106700001804131700001904149700002204168856003604190 2018 eng d a2041-172300aPR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.0 aPR interval genomewide association metaanalysis identifies 50 lo c2018 Jul 25 a29040 v93 aElectrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
1 avan Setten, Jessica1 aBrody, Jennifer, A1 aJamshidi, Yalda1 aSwenson, Brenton, R1 aButler, Anne, M1 aCampbell, Harry1 aDel Greco, Fabiola, M1 aEvans, Daniel, S1 aGibson, Quince1 aGudbjartsson, Daniel, F1 aKerr, Kathleen, F1 aKrijthe, Bouwe, P1 aLyytikäinen, Leo-Pekka1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRitchie, Marylyn, D1 aRobino, Antonietta1 aSmith, Albert, V1 aSteri, Maristella1 aTanaka, Toshiko1 aTeumer, Alexander1 aTrompet, Stella1 aUlivi, Sheila1 aVerweij, Niek1 aYin, Xiaoyan1 aArnar, David, O1 aAsselbergs, Folkert, W1 aBader, Joel, S1 aBarnard, John1 aBis, Josh1 aBlankenberg, Stefan1 aBoerwinkle, Eric1 aBradford, Yuki1 aBuckley, Brendan, M1 aChung, Mina, K1 aCrawford, Dana1 aHoed, Marcel, den1 aDenny, Josh, C1 aDominiczak, Anna, F1 aEhret, Georg, B1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aFelix, Stephan, B1 aFranco, Oscar, H1 aFranke, Lude1 aHarris, Tamara, B1 aHolm, Hilma1 aIlaria, Gandin1 aIorio, Annamaria1 aKähönen, Mika1 aKolcic, Ivana1 aKors, Jan, A1 aLakatta, Edward, G1 aLauner, Lenore, J1 aLin, Honghuang1 aLin, Henry, J1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aLeach, Irene, Mateo1 aMeitinger, Thomas1 aMitchell, Braxton, D1 aMünzel, Thomas1 aPapanicolaou, George, J1 aPeters, Annette1 aPfeufer, Arne1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRotter, Jerome, I1 aRudan, Igor1 aSamani, Nilesh, J1 aSchlessinger, David1 aAldana, Claudia, T Silva1 aSinner, Moritz, F1 aSmith, Jonathan, D1 aSnieder, Harold1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStott, David, J1 aStrauch, Konstantin1 aTarasov, Kirill, V1 aThorsteinsdottir, Unnur1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWestra, Harm, Jan1 aWild, Philipp, S1 aZeller, Tanja1 aAlonso, Alvaro1 aAvery, Christy, L1 aBandinelli, Stefania1 aBenjamin, Emelia, J1 aCucca, Francesco1 aDörr, Marcus1 aFerrucci, Luigi1 aGasparini, Paolo1 aGudnason, Vilmundur1 aHayward, Caroline1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aJukema, Wouter1 aKääb, Stefan1 aLehtimäki, Terho1 aLiu, Yongmei1 aMunroe, Patricia, B1 aParsa, Afshin1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRoden, Dan, M1 aSchnabel, Renate, B1 aSinagra, Gianfranco1 aStefansson, Kari1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aWilson, James, F1 aGharib, Sina, A1 ade Bakker, Paul, I W1 aIsaacs, Aaron1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/781509584nas a2203049 4500008004100000022001400041245011700055210006900172260001300241300001200254490000700266520112500273100002001398700002101418700002101439700001401460700002301474700001901497700001301516700002401529700001901553700002001572700001701592700001801609700001201627700002301639700001201662700001801674700002001692700001801712700001901730700002301749700002001772700001801792700003601810700002001846700002001866700002001886700002301906700003001929700002101959700002001980700002002000700002102020700001202041700002602053700001302079700002002092700002302112700002202135700001902157700002702176700003202203700002102235700002102256700002002277700002402297700002102321700002502342700002102367700002002388700002002408700002402428700002102452700001602473700001802489700001902507700001902526700001602545700001702561700002202578700002302600700002302623700002102646700002302667700001902690700002202709700002202731700001902753700002402772700002402796700002102820700002002841700002202861700002602883700002002909700002502929700002202954700001402976700001502990700002603005700002503031700001503056700002003071700002503091700002303116700002903139700001703168700001903185700002503204700001803229700002203247700002403269700001803293700002103311700001803332700002003350700001703370700001903387700002103406700001803427700001303445700001503458700001803473700002203491700002703513700002103540700001803561700002103579700001903600700002403619700002303643700001803666700002103684700001503705700002103720700002603741700002203767700002103789700002503810700002303835700002003858700002403878700002103902700002503923700001803948700001803966700001803984700002104002700002004023700001904043700001304062700001604075700001704091700002204108700001904130700002104149700002404170700001904194700002404213700002204237700001904259700002004278700002304298700002004321700002004341700002304361700002404384700002204408700002304430700002404453700002204477700002204499700001504521700002204536700002404558700002204582700002504604700002104629700002204650700001904672700002104691700001804712700002204730700002204752700002304774700002504797700002304822700001904845700002004864700002504884700001804909700002004927700002604947700002404973700002504997700002005022700002105042700001605063700002005079700002405099700002805123700001705151700002305168700002205191700002505213700002905238700002305267700001705290700002005307700001905327700002105346700002005367700002205387700002105409700001605430700001805446700001905464700002605483700002205509700002005531700002405551700001905575700002605594700001905620700002005639700001905659700001205678700001505690700001705705700002005722700002305742700002105765700002605786700002805812700002305840700002105863700001905884700002005903700002105923700001905944700002505963700002005988700002406008700002106032700002206053700002806075700002206103700002306125700002506148700002106173700002406194700002106218700001906239700002506258700002206283700002006305700002106325700002106346700002206367700002206389700002206411710002306433710002106456710002106477856003606498 2018 eng d a1546-171800aRefining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.0 aRefining the accuracy of validated target identification through c2018 Apr a559-5710 v503 aWe aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
1 aMahajan, Anubha1 aWessel, Jennifer1 aWillems, Sara, M1 aZhao, Wei1 aRobertson, Neil, R1 aChu, Audrey, Y1 aGan, Wei1 aKitajima, Hidetoshi1 aTaliun, Daniel1 aRayner, William1 aGuo, Xiuqing1 aLu, Yingchang1 aLi, Man1 aJensen, Richard, A1 aHu, Yao1 aHuo, Shaofeng1 aLohman, Kurt, K1 aZhang, Weihua1 aCook, James, P1 aPrins, Bram, Peter1 aFlannick, Jason1 aGrarup, Niels1 aTrubetskoy, Vassily, Vladimirov1 aKravic, Jasmina1 aKim, Young, Jin1 aRybin, Denis, V1 aYaghootkar, Hanieh1 aMüller-Nurasyid, Martina1 aMeidtner, Karina1 aLi-Gao, Ruifang1 aVarga, Tibor, V1 aMarten, Jonathan1 aLi, Jin1 aSmith, Albert, Vernon1 aAn, Ping1 aLigthart, Symen1 aGustafsson, Stefan1 aMalerba, Giovanni1 aDemirkan, Ayse1 aTajes, Juan, Fernandez1 aSteinthorsdottir, Valgerdur1 aWuttke, Matthias1 aLecoeur, Cécile1 aPreuss, Michael1 aBielak, Lawrence, F1 aGraff, Marielisa1 aHighland, Heather, M1 aJustice, Anne, E1 aLiu, Dajiang, J1 aMarouli, Eirini1 aPeloso, Gina, Marie1 aWarren, Helen, R1 aAfaq, Saima1 aAfzal, Shoaib1 aAhlqvist, Emma1 aAlmgren, Peter1 aAmin, Najaf1 aBang, Lia, B1 aBertoni, Alain, G1 aBombieri, Cristina1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBurtt, Noel, P1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aCho, Yoon Shin1 aChristensen, Cramer1 aEastwood, Sophie, V1 aEckardt, Kai-Uwe1 aFischer, Krista1 aGambaro, Giovanni1 aGiedraitis, Vilmantas1 aGrove, Megan, L1 ade Haan, Hugoline, G1 aHackinger, Sophie1 aHai, Yang1 aHan, Sohee1 aTybjærg-Hansen, Anne1 aHivert, Marie-France1 aIsomaa, Bo1 aJäger, Susanne1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKäräjämäki, AnneMari1 aKim, Bong-Jo1 aKim, Sung, Soo1 aKoistinen, Heikki, A1 aKovacs, Peter1 aKriebel, Jennifer1 aKronenberg, Florian1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Jung-Jin1 aLehne, Benjamin1 aLi, Huaixing1 aLin, Keng-Hung1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jun1 aLoh, Marie1 aMägi, Reedik1 aMamakou, Vasiliki1 aMcKean-Cowdin, Roberta1 aNadkarni, Girish1 aNeville, Matt1 aNielsen, Sune, F1 aNtalla, Ioanna1 aPeyser, Patricia, A1 aRathmann, Wolfgang1 aRice, Kenneth1 aRich, Stephen, S1 aRode, Line1 aRolandsson, Olov1 aSchönherr, Sebastian1 aSelvin, Elizabeth1 aSmall, Kerrin, S1 aStančáková, Alena1 aSurendran, Praveen1 aTaylor, Kent, D1 aTeslovich, Tanya, M1 aThorand, Barbara1 aThorleifsson, Gudmar1 aTin, Adrienne1 aTönjes, Anke1 aVarbo, Anette1 aWitte, Daniel, R1 aWood, Andrew, R1 aYajnik, Pranav1 aYao, Jie1 aYengo, Loic1 aYoung, Robin1 aAmouyel, Philippe1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aChowdhury, Raj1 aCollins, Francis, S1 aDedoussis, George1 aDehghan, Abbas1 aDeloukas, Panos1 aFerrario, Marco, M1 aFerrieres, Jean1 aFlorez, Jose, C1 aFrossard, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHowson, Joanna, M M1 aIngelsson, Martin1 aKathiresan, Sekar1 aKee, Frank1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLindgren, Cecilia, M1 aMännistö, Satu1 aMeitinger, Thomas1 aMelander, Olle1 aMohlke, Karen, L1 aMoitry, Marie1 aMorris, Andrew, D1 aMurray, Alison, D1 ade Mutsert, Renée1 aOrho-Melander, Marju1 aOwen, Katharine, R1 aPerola, Markus1 aPeters, Annette1 aProvince, Michael, A1 aRasheed, Asif1 aRidker, Paul, M1 aRivadineira, Fernando1 aRosendaal, Frits, R1 aRosengren, Anders, H1 aSalomaa, Veikko1 aSheu, Wayne, H-H1 aSladek, Rob1 aSmith, Blair, H1 aStrauch, Konstantin1 aUitterlinden, André, G1 aVarma, Rohit1 aWiller, Cristen, J1 aBlüher, Matthias1 aButterworth, Adam, S1 aChambers, John, Campbell1 aChasman, Daniel, I1 aDanesh, John1 aDuijn, Cornelia1 aDupuis, Josée1 aFranco, Oscar, H1 aFranks, Paul, W1 aFroguel, Philippe1 aGrallert, Harald1 aGroop, Leif1 aHan, Bok-Ghee1 aHansen, Torben1 aHattersley, Andrew, T1 aHayward, Caroline1 aIngelsson, Erik1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKooner, Jaspal, Singh1 aKöttgen, Anna1 aKuulasmaa, Kari1 aLaakso, Markku1 aLin, Xu1 aLind, Lars1 aLiu, Yongmei1 aLoos, Ruth, J F1 aMarchini, Jonathan1 aMetspalu, Andres1 aMook-Kanamori, Dennis1 aNordestgaard, Børge, G1 aPalmer, Colin, N A1 aPankow, James, S1 aPedersen, Oluf1 aPsaty, Bruce, M1 aRauramaa, Rainer1 aSattar, Naveed1 aSchulze, Matthias, B1 aSoranzo, Nicole1 aSpector, Timothy, D1 aStefansson, Kari1 aStumvoll, Michael1 aThorsteinsdottir, Unnur1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aWareham, Nicholas, J1 aWilson, James, G1 aZeggini, Eleftheria1 aScott, Robert, A1 aBarroso, Inês1 aFrayling, Timothy, M1 aGoodarzi, Mark, O1 aMeigs, James, B1 aBoehnke, Michael1 aSaleheen, Danish1 aMorris, Andrew, P1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aExomeBP Consortium1 aMAGIC Consortium1 aGIANT Consortium uhttps://chs-nhlbi.org/node/766803490nas a2200517 4500008004100000022001400041245012600055210006900181260001600250520197900266100001902245700002002264700002702284700002002311700001702331700001902348700001302367700001802380700002802398700001602426700002002442700001702462700002102479700001402500700003002514700001802544700002202562700002202584700002002606700002202626700002102648700001702669700002102686700001802707700002402725700002302749700002002772700002002792700002002812700002002832700002002852700001702872700002402889700002302913856003602936 2019 eng d a1460-215600aAssociation of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.0 aAssociation of variants in HTRA1 and NOTCH3 with MRIdefined extr c2019 Mar 113 aWe report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.
1 aMishra, Aniket1 aChauhan, Ganesh1 aViolleau, Marie-Helene1 aVojinovic, Dina1 aJian, Xueqiu1 aBis, Joshua, C1 aLi, Shuo1 aSaba, Yasaman1 aGrenier-Boley, Benjamin1 aYang, Qiong1 aBartz, Traci, M1 aHofer, Edith1 aSoumaré, Aïcha1 aPeng, Fen1 aDuperron, Marie-Gabrielle1 aFoglio, Mario1 aMosley, Thomas, H1 aSchmidt, Reinhold1 aPsaty, Bruce, M1 aLauner, Lenore, J1 aBoerwinkle, Eric1 aZhu, Yicheng1 aMazoyer, Bernard1 aLathrop, Mark1 aBellenguez, Céline1 aDuijn, Cornelia, M1 aIkram, Arfan, M1 aSchmidt, Helena1 aLongstreth, W T1 aFornage, Myriam1 aSeshadri, Sudha1 aJoutel, Anne1 aTzourio, Christophe1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/798915950nas a2205365 4500008004100000022001400041245007300055210006900128260001600197300000900213490000700222520104400229100002001273700002001293700002501313700001501338700002001353700001901373700002201392700002601414700001501440700001901455700002001474700001901494700002301513700001701536700002301553700001801576700002801594700002101622700001701643700002001660700002201680700001901702700002301721700001801744700001901762700001801781700002401799700002301823700002101846700002501867700002701892700001201919700002001931700002101951700002501972700002101997700001702018700002702035700002302062700002002085700001702105700002002122700002102142700002202163700002602185700002002211700002002231700002002251700002102271700001702292700002202309700002702331700001902358700001902377700002202396700001802418700002202436700003802458700002002496700001702516700002302533700002002556700001702576700002202593700002602615700002502641700002802666700002502694700002402719700002002743700002202763700001802785700001902803700001602822700002102838700002202859700001902881700001302900700002002913700001402933700002602947700001602973700003702989700002003026700002303046700002403069700001703093700001403110700002103124700002003145700001903165700002103184700002103205700002203226700002403248700001703272700002003289700002103309700001803330700001803348700002103366700002003387700001903407700002403426700002403450700002403474700001803498700002303516700002003539700001903559700002603578700001803604700002503622700001903647700002603666700001803692700002103710700001903731700002803750700002003778700001803798700001603816700002103832700002003853700002303873700002103896700001503917700002003932700002203952700002203974700003003996700002404026700002404050700002804074700001804102700002304120700001204143700002504155700002704180700001804207700002204225700002004247700002304267700001904290700001604309700002404325700001804349700001704367700002004384700002504404700002204429700002304451700002004474700002404494700002204518700001804540700002304558700003004581700001904611700001804630700001704648700002504665700002104690700002204711700002404733700002204757700002304779700001404802700001804816700002104834700001504855700001704870700001504887700002504902700002204927700001804949700001804967700001804985700002405003700001905027700002005046700001705066700001605083700002305099700002205122700002405144700001705168700002205185700002305207700001505230700002905245700002905274700002005303700002405323700001805347700002405365700002205389700002305411700002605434700001905460700002005479700002105499700001905520700001605539700001905555700002505574700002105599700002105620700002205641700001905663700001905682700001805701700002605719700002605745700002305771700001805794700002005812700002405832700002105856700002005877700002705897700002305924700002605947700002205973700001805995700002806013700002506041700002706066700002006093700001806113700002006131700002006151700002206171700003006193700002006223700002406243700002006267700002106287700001406308700002106322700002806343700002306371700002306394700002006417700002006437700002506457700001906482700001906501700002506520700001806545700001906563700002706582700002206609700002106631700002006652700002306672700002006695700002506715700002806740700002206768700002206790700002406812700002106836700002206857700002606879700002006905700002206925700001706947700002006964700002006984700002607004700002407030700001907054700002507073700001607098700002807114700001907142700001807161700001707179700001407196700001607210700002707226700002507253700002107278700002007299700002207319700002907341700002107370700002507391700002407416700002107440700001807461700002107479700002707500700002307527700002107550700001607571700002307587700002007610700002207630700002807652700002007680700001907700700002207719700001807741700002407759700001807783700002207801700002307823700002207846700002207868700002307890700002507913700002207938700002107960700002107981700001808002700001908020700001808039700002508057700002108082700002208103700002308125700002208148700002308170700002208193700001608215700002408231700002008255700002208275700002008297700001508317700002008332700002108352700001908373700002008392700002008412700002508432700002408457700002408481700001908505700001908524700001908543700002108562700001908583700002408602700001908626700001808645700001908663700002808682700001608710700002108726700001908747700001908766700001908785700002408804700002008828700002208848700002208870700002208892700002208914700002108936700002008957700002108977700002508998700002609023700002409049700001909073700002009092700002609112700001709138700002909155700001909184700001809203700002609221700001909247700002209266700001909288700002409307700001909331700002609350700002309376700002309399700002009422700001909442700002609461700002009487700002209507700001609529700002709545700002709572700001909599700002209618700002509640700002409665700002109689700002309710700001709733700001609750700002309766700002209789700001809811700002209829700002509851700002109876700003209897700002209929700002409951700001909975700001909994700002310013700002010036700001910056700001710075700001810092700001210110700002210122700002310144700001910167700002710186700002810213700002210241700002310263700002010286700002310306700001710329700002010346700002210366700002210388700002110410700001610431700002010447700002110467700002010488700001910508700002110527856003610548 2019 eng d a2041-172300aAssociations of autozygosity with a broad range of human phenotypes.0 aAssociations of autozygosity with a broad range of human phenoty c2019 Oct 31 a49570 v103 aIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
1 aClark, David, W1 aOkada, Yukinori1 aMoore, Kristjan, H S1 aMason, Dan1 aPirastu, Nicola1 aGandin, Ilaria1 aMattsson, Hannele1 aBarnes, Catriona, L K1 aLin, Kuang1 aZhao, Jing Hua1 aDeelen, Patrick1 aRohde, Rebecca1 aSchurmann, Claudia1 aGuo, Xiuqing1 aGiulianini, Franco1 aZhang, Weihua1 aMedina-Gómez, Carolina1 aKarlsson, Robert1 aBao, Yanchun1 aBartz, Traci, M1 aBaumbach, Clemens1 aBiino, Ginevra1 aBixley, Matthew, J1 aBrumat, Marco1 aChai, Jin-Fang1 aCorre, Tanguy1 aCousminer, Diana, L1 aDekker, Annelot, M1 aEccles, David, A1 avan Eijk, Kristel, R1 aFuchsberger, Christian1 aGao, He1 aGermain, Marine1 aGordon, Scott, D1 ade Haan, Hugoline, G1 aHarris, Sarah, E1 aHofer, Edith1 aHuerta-Chagoya, Alicia1 aIgartua, Catherine1 aJansen, Iris, E1 aJia, Yucheng1 aKacprowski, Tim1 aKarlsson, Torgny1 aKleber, Marcus, E1 aLi, Shengchao, Alfred1 aLi-Gao, Ruifang1 aMahajan, Anubha1 aMatsuda, Koichi1 aMeidtner, Karina1 aMeng, Weihua1 aMontasser, May, E1 avan der Most, Peter, J1 aMunz, Matthias1 aNutile, Teresa1 aPalviainen, Teemu1 aPrasad, Gauri1 aPrasad, Rashmi, B1 aPriyanka, Tallapragada, Divya Sri1 aRizzi, Federica1 aSalvi, Erika1 aSapkota, Bishwa, R1 aShriner, Daniel1 aSkotte, Line1 aSmart, Melissa, C1 aSmith, Albert, Vernon1 avan der Spek, Ashley1 aSpracklen, Cassandra, N1 aStrawbridge, Rona, J1 aTajuddin, Salman, M1 aTrompet, Stella1 aTurman, Constance1 aVerweij, Niek1 aViberti, Clara1 aWang, Lihua1 aWarren, Helen, R1 aWootton, Robyn, E1 aYanek, Lisa, R1 aYao, Jie1 aYousri, Noha, A1 aZhao, Wei1 aAdeyemo, Adebowale, A1 aAfaq, Saima1 aAguilar-Salinas, Carlos, Alberto1 aAkiyama, Masato1 aAlbert, Matthew, L1 aAllison, Matthew, A1 aAlver, Maris1 aAung, Tin1 aAzizi, Fereidoun1 aBentley, Amy, R1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBorja, Judith, B1 ade Borst, Gert, J1 aBottinger, Erwin, P1 aBroer, Linda1 aCampbell, Harry1 aChanock, Stephen1 aChee, Miao-Li1 aChen, Guanjie1 aChen, Yii-der, I1 aChen, Zhengming1 aChiu, Yen-Feng1 aCocca, Massimiliano1 aCollins, Francis, S1 aConcas, Maria, Pina1 aCorley, Janie1 aCugliari, Giovanni1 avan Dam, Rob, M1 aDamulina, Anna1 aDaneshpour, Maryam, S1 aDay, Felix, R1 aDelgado, Graciela, E1 aDhana, Klodian1 aDoney, Alexander, S F1 aDörr, Marcus1 aDoumatey, Ayo, P1 aDzimiri, Nduna1 aEbenesersdóttir, Sunna1 aElliott, Joshua1 aElliott, Paul1 aEwert, Ralf1 aFelix, Janine, F1 aFischer, Krista1 aFreedman, Barry, I1 aGirotto, Giorgia1 aGoel, Anuj1 aGögele, Martin1 aGoodarzi, Mark, O1 aGraff, Mariaelisa1 aGranot-Hershkovitz, Einat1 aGrodstein, Francine1 aGuarrera, Simonetta1 aGudbjartsson, Daniel, F1 aGuity, Kamran1 aGunnarsson, Bjarni1 aGuo, Yu1 aHagenaars, Saskia, P1 aHaiman, Christopher, A1 aHalevy, Avner1 aHarris, Tamara, B1 aHedayati, Mehdi1 avan Heel, David, A1 aHirata, Makoto1 aHöfer, Imo1 aHsiung, Chao, Agnes1 aHuang, Jinyan1 aHung, Yi-Jen1 aIkram, Arfan, M1 aJagadeesan, Anuradha1 aJousilahti, Pekka1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerrison, Nicola, D1 aKessler, Thorsten1 aKhaw, Kay-Tee1 aKhor, Chiea, Chuen1 ade Kleijn, Dominique, P V1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKraft, Peter1 aKrämer, Bernhard, K1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLawlor, Deborah, A1 aLee, I-Te1 aLee, Wen-Jane1 aLerch, Markus, M1 aLi, Liming1 aLiu, Jianjun1 aLoh, Marie1 aLondon, Stephanie, J1 aLoomis, Stephanie1 aLu, Yingchang1 aLuan, Jian'an1 aMägi, Reedik1 aManichaikul, Ani, W1 aManunta, Paolo1 aMásson, Gísli1 aMatoba, Nana1 aMei, Xue, W1 aMeisinger, Christa1 aMeitinger, Thomas1 aMezzavilla, Massimo1 aMilani, Lili1 aMillwood, Iona, Y1 aMomozawa, Yukihide1 aMoore, Amy1 aMorange, Pierre-Emmanuel1 aMoreno-Macias, Hortensia1 aMori, Trevor, A1 aMorrison, Alanna, C1 aMuka, Taulant1 aMurakami, Yoshinori1 aMurray, Alison, D1 ade Mutsert, Renée1 aMychaleckyj, Josyf, C1 aNalls, Mike, A1 aNauck, Matthias1 aNeville, Matt, J1 aNolte, Ilja, M1 aOng, Ken, K1 aOrozco, Lorena1 aPadmanabhan, Sandosh1 aPálsson, Gunnar1 aPankow, James, S1 aPattaro, Cristian1 aPattie, Alison1 aPolasek, Ozren1 aPoulter, Neil1 aPramstaller, Peter, P1 aQuintana-Murci, Lluis1 aRäikkönen, Katri1 aRalhan, Sarju1 aRao, Dabeeru, C1 avan Rheenen, Wouter1 aRich, Stephen, S1 aRidker, Paul, M1 aRietveld, Cornelius, A1 aRobino, Antonietta1 avan Rooij, Frank, J A1 aRuggiero, Daniela1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSabater-Lleal, Maria1 aSala, Cinzia, Felicita1 aSalomaa, Veikko1 aSandow, Kevin1 aSchmidt, Helena1 aScott, Laura, J1 aScott, William, R1 aSedaghati-Khayat, Bahareh1 aSennblad, Bengt1 avan Setten, Jessica1 aSever, Peter, J1 aSheu, Wayne, H-H1 aShi, Yuan1 aShrestha, Smeeta1 aShukla, Sharvari, Rahul1 aSigurdsson, Jon, K1 aSikka, Timo, Tonis1 aSingh, Jai, Rup1 aSmith, Blair, H1 aStančáková, Alena1 aStanton, Alice1 aStarr, John, M1 aStefansdottir, Lilja1 aStraker, Leon1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSwertz, Morris, A1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTerzikhan, Natalie1 aTham, Yih-Chung1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTillander, Annika1 aTracy, Russell, P1 aTusié-Luna, Teresa1 aTzoulaki, Ioanna1 aVaccargiu, Simona1 aVangipurapu, Jagadish1 aVeldink, Jan, H1 aVitart, Veronique1 aVölker, Uwe1 aVuoksimaa, Eero1 aWakil, Salma, M1 aWaldenberger, Melanie1 aWander, Gurpreet, S1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWild, Sarah1 aYajnik, Chittaranjan, S1 aYuan, Jian-Min1 aZeng, Lingyao1 aZhang, Liang1 aZhou, Jie1 aAmin, Najaf1 aAsselbergs, Folkert, W1 aBakker, Stephan, J L1 aBecker, Diane, M1 aLehne, Benjamin1 aBennett, David, A1 avan den Berg, Leonard, H1 aBerndt, Sonja, I1 aBharadwaj, Dwaipayan1 aBielak, Lawrence, F1 aBochud, Murielle1 aBoehnke, Mike1 aBouchard, Claude1 aBradfield, Jonathan, P1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarmi, Shai1 aCaulfield, Mark, J1 aCesarini, David1 aChambers, John, C1 aChandak, Giriraj, Ratan1 aCheng, Ching-Yu1 aCiullo, Marina1 aCornelis, Marilyn1 aCusi, Daniele1 aSmith, George Davey1 aDeary, Ian, J1 aDorajoo, Rajkumar1 aDuijn, Cornelia, M1 aEllinghaus, David1 aErdmann, Jeanette1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aEvans, Michele, K1 aFaul, Jessica, D1 aFeenstra, Bjarke1 aFeitosa, Mary1 aFoisy, Sylvain1 aFranke, Andre1 aFriedlander, Yechiel1 aGasparini, Paolo1 aGieger, Christian1 aGonzalez, Clicerio1 aGoyette, Philippe1 aGrant, Struan, F A1 aGriffiths, Lyn, R1 aGroop, Leif1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHakonarson, Hakon1 aHamsten, Anders1 aHarst, Pim1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHochner, Hagit1 aHuikuri, Heikki1 aHunt, Steven, C1 aJaddoe, Vincent, W V1 aDe Jager, Philip, L1 aJohannesson, Magnus1 aJohansson, Asa1 aJonas, Jost, B1 aJukema, Wouter1 aJunttila, Juhani1 aKaprio, Jaakko1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKumari, Meena1 aLaakso, Markku1 avan der Laan, Sander, W1 aLahti, Jari1 aLaudes, Matthias1 aLea, Rodney, A1 aLieb, Wolfgang1 aLumley, Thomas1 aMartin, Nicholas, G1 aMärz, Winfried1 aMatullo, Giuseppe1 aMcCarthy, Mark, I1 aMedland, Sarah, E1 aMerriman, Tony, R1 aMetspalu, Andres1 aMeyer, Brian, F1 aMohlke, Karen, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis1 aMunroe, Patricia, B1 aNorth, Kari, E1 aNyholt, Dale, R1 aO'Connell, Jeffery, R1 aOber, Carole1 aOldehinkel, Albertine, J1 aPalmas, Walter1 aPalmer, Colin1 aPasterkamp, Gerard, G1 aPatin, Etienne1 aPennell, Craig, E1 aPerusse, Louis1 aPeyser, Patricia, A1 aPirastu, Mario1 aPolderman, Tinca, J C1 aPorteous, David, J1 aPosthuma, Danielle1 aPsaty, Bruce, M1 aRioux, John, D1 aRivadeneira, Fernando1 aRotimi, Charles1 aRotter, Jerome, I1 aRudan, Igor1 aRuijter, Hester, M den1 aSanghera, Dharambir, K1 aSattar, Naveed1 aSchmidt, Reinhold1 aSchulze, Matthias, B1 aSchunkert, Heribert1 aScott, Robert, A1 aShuldiner, Alan, R1 aSim, Xueling1 aSmall, Neil1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aTai, E-Shyong1 aTeumer, Alexander1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTrégouët, David-Alexandre1 aTuomi, Tiinamaija1 aVollenweider, Peter1 aWang, Carol, A1 aWeir, David, R1 aWhitfield, John, B1 aWijmenga, Cisca1 aWong, Tien-Yin1 aWright, John1 aYang, Jingyun1 aYu, Lei1 aZemel, Babette, S1 aZonderman, Alan, B1 aPerola, Markus1 aMagnusson, Patrik, K E1 aUitterlinden, André, G1 aKooner, Jaspal, S1 aChasman, Daniel, I1 aLoos, Ruth, J F1 aFranceschini, Nora1 aFranke, Lude1 aHaley, Chris, S1 aHayward, Caroline1 aWalters, Robin, G1 aPerry, John, R B1 aEsko, Tõnu1 aHelgason, Agnar1 aStefansson, Kari1 aJoshi, Peter, K1 aKubo, Michiaki1 aWilson, James, F uhttps://chs-nhlbi.org/node/819811242nas a2203601 4500008004100000022001400041245008000055210006900135260001300204300001400217490000700231520105900238100002601297700002201323700002101345700002201366700001901388700002001407700001901427700003301446700002001479700002801499700002101527700001901548700001701567700002201584700001701606700002201623700002501645700001801670700001901688700001601707700001301723700001501736700001701751700002001768700002601788700002901814700002001843700002301863700002501886700001701911700001701928700002501945700001601970700002101986700002302007700002202030700002202052700002102074700001802095700002202113700002002135700002102155700002202176700002002198700002002218700002902238700001902267700002102286700002102307700001602328700001802344700002102362700002002383700002302403700002202426700001902448700002002467700002102487700002402508700002202532700002102554700002202575700002502597700001802622700002902640700001602669700001702685700001802702700002902720700002802749700002102777700001602798700002202814700001702836700002302853700002102876700002302897700002602920700002302946700002102969700002602990700002003016700002303036700001903059700001903078700003303097700002203130700001503152700002303167700002003190700002103210700001603231700002103247700001903268700002203287700002203309700002103331700002003352700002703372700002003399700002303419700002003442700002503462700001703487700002503504700002303529700002303552700002203575700002203597700002003619700001703639700001903656700001703675700002703692700002203719700002403741700002303765700002203788700003403810700002103844700002203865700002403887700002203911700002203933700002403955700002703979700002004006700001304026700002404039700001904063700002304082700001904105700001904124700001704143700002504160700002804185700002604213700002404239700002104263700002404284700001904308700002604327700002404353700002104377700002004398700002304418700002104441700003304462700002404495700002304519700002104542700002004563700001804583700001904601700002604620700002004646700001904666700002804685700002104713700001904734700001904753700002504772700001804797700002004815700002004835700002504855700002304880700002304903700002404926700002004950700003004970700001705000700002705017700003405044700001605078700002005094700002105114700002605135700002205161700002905183700001905212700002205231700002405253700002605277700002205303700002205325700001305347700001905360700002005379700001905399700002405418700002505442700002205467700001705489700002205506700003005528700002005558700002205578700002805600700002605628700002005654700002005674700002505694700002105719700001805740700002405758700002705782700001805809700002305827700002405850700002505874700001805899700002205917700002705939700002105966700002305987700002206010700002106032700002106053700002306074700002006097700002106117700002006138700002106158700001806179700002206197700002806219700002306247700002106270700002206291700002306313700002206336700002006358700002306378700002206401700002006423700001806443700002406461700001706485700001806502700001906520700002406539700001706563700001806580700002306598700002006621700001906641700002406660700002406684700002306708700002006731700002206751700002506773700002606798700002406824700002806848700002106876700002106897700001906918700002206937700002106959700002906980700002607009700002407035700002407059700002307083700001907106700002407125700002107149700002007170700002207190700001907212700002307231700002207254700002307276700002007299700002007319700002307339700002207362700002107384700002407405700002107429700002307450700002407473700002207497700002307519700002207542700002007564700002007584856003607604 2019 eng d a1546-171800aGenetic architecture of subcortical brain structures in 38,851 individuals.0 aGenetic architecture of subcortical brain structures in 38851 in c2019 Nov a1624-16360 v513 aSubcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
1 aSatizabal, Claudia, L1 aAdams, Hieab, H H1 aHibar, Derrek, P1 aWhite, Charles, C1 aKnol, Maria, J1 aStein, Jason, L1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aJahanshad, Neda1 aRoshchupkin, Gennady, V1 aSmith, Albert, V1 aBis, Joshua, C1 aJian, Xueqiu1 aLuciano, Michelle1 aHofer, Edith1 aTeumer, Alexander1 avan der Lee, Sven, J1 aYang, Jingyun1 aYanek, Lisa, R1 aLee, Tom, V1 aLi, Shuo1 aHu, Yanhui1 aKoh, Jia, Yu1 aEicher, John, D1 aDesrivières, Sylvane1 aArias-Vasquez, Alejandro1 aChauhan, Ganesh1 aAthanasiu, Lavinia1 aRentería, Miguel, E1 aKim, Sungeun1 aHoehn, David1 aArmstrong, Nicola, J1 aChen, Qiang1 aHolmes, Avram, J1 aBraber, Anouk, den1 aKloszewska, Iwona1 aAndersson, Micael1 aEspeseth, Thomas1 aGrimm, Oliver1 aAbramovic, Lucija1 aAlhusaini, Saud1 aMilaneschi, Yuri1 aPapmeyer, Martina1 aAxelsson, Tomas1 aEhrlich, Stefan1 aRoiz-Santiañez, Roberto1 aKraemer, Bernd1 aHåberg, Asta, K1 aJones, Hannah, J1 aPike, Bruce1 aStein, Dan, J1 aStevens, Allison1 aBralten, Janita1 aVernooij, Meike, W1 aHarris, Tamara, B1 aFilippi, Irina1 aWitte, Veronica1 aGuadalupe, Tulio1 aWittfeld, Katharina1 aMosley, Thomas, H1 aBecker, James, T1 aDoan, Nhat, Trung1 aHagenaars, Saskia, P1 aSaba, Yasaman1 aCuellar-Partida, Gabriel1 aAmin, Najaf1 aHilal, Saima1 aNho, Kwangsik1 aMirza-Schreiber, Nazanin1 aArfanakis, Konstantinos1 aBecker, Diane, M1 aAmes, David1 aGoldman, Aaron, L1 aLee, Phil, H1 aBoomsma, Dorret, I1 aLovestone, Simon1 aGiddaluru, Sudheer1 aLe Hellard, Stephanie1 aMattheisen, Manuel1 aBohlken, Marc, M1 aKasperaviciute, Dalia1 aSchmaal, Lianne1 aLawrie, Stephen, M1 aAgartz, Ingrid1 aWalton, Esther1 aTordesillas-Gutierrez, Diana1 aDavies, Gareth, E1 aShin, Jean1 aIpser, Jonathan, C1 aVinke, Louis, N1 aHoogman, Martine1 aJia, Tianye1 aBurkhardt, Ralph1 aKlein, Marieke1 aCrivello, Fabrice1 aJanowitz, Deborah1 aCarmichael, Owen1 aHaukvik, Unn, K1 aAribisala, Benjamin, S1 aSchmidt, Helena1 aStrike, Lachlan, T1 aCheng, Ching-Yu1 aRisacher, Shannon, L1 aPütz, Benno1 aFleischman, Debra, A1 aAssareh, Amelia, A1 aMattay, Venkata, S1 aBuckner, Randy, L1 aMecocci, Patrizia1 aDale, Anders, M1 aCichon, Sven1 aBoks, Marco, P1 aMatarin, Mar1 aPenninx, Brenda, W J H1 aCalhoun, Vince, D1 aChakravarty, Mallar1 aMarquand, Andre, F1 aMacare, Christine1 aMasouleh, Shahrzad, Kharabian1 aOosterlaan, Jaap1 aAmouyel, Philippe1 aHegenscheid, Katrin1 aRotter, Jerome, I1 aSchork, Andrew, J1 aLiewald, David, C M1 ade Zubicaray, Greig, I1 aWong, Tien, Yin1 aShen, Li1 aSämann, Philipp, G1 aBrodaty, Henry1 aRoffman, Joshua, L1 aGeus, Eco, J C1 aTsolaki, Magda1 aErk, Susanne1 avan Eijk, Kristel, R1 aCavalleri, Gianpiero, L1 avan der Wee, Nic, J A1 aMcIntosh, Andrew, M1 aGollub, Randy, L1 aBulayeva, Kazima, B1 aBernard, Manon1 aRichards, Jennifer, S1 aHimali, Jayandra, J1 aLoeffler, Markus1 aRommelse, Nanda1 aHoffmann, Wolfgang1 aWestlye, Lars, T1 aHernández, Maria, C Valdés1 aHansell, Narelle, K1 avan Erp, Theo, G M1 aWolf, Christiane1 aKwok, John, B J1 aVellas, Bruno1 aHeinz, Andreas1 aLoohuis, Loes, M Olde1 aDelanty, Norman1 aHo, Beng-Choon1 aChing, Christopher, R K1 aShumskaya, Elena1 aSingh, Baljeet1 aHofman, Albert1 avan der Meer, Dennis1 aHomuth, Georg1 aPsaty, Bruce, M1 aBastin, Mark, E1 aMontgomery, Grant, W1 aForoud, Tatiana, M1 aReppermund, Simone1 aHottenga, Jouke-Jan1 aSimmons, Andrew1 aMeyer-Lindenberg, Andreas1 aCahn, Wiepke1 aWhelan, Christopher, D1 avan Donkelaar, Marjolein, M J1 aYang, Qiong1 aHosten, Norbert1 aGreen, Robert, C1 aThalamuthu, Anbupalam1 aMohnke, Sebastian1 aPol, Hilleke, E Hulshoff1 aLin, Honghuang1 aJack, Clifford, R1 aSchofield, Peter, R1 aMühleisen, Thomas, W1 aMaillard, Pauline1 aPotkin, Steven, G1 aWen, Wei1 aFletcher, Evan1 aToga, Arthur, W1 aGruber, Oliver1 aHuentelman, Matthew1 aSmith, George, Davey1 aLauner, Lenore, J1 aNyberg, Lars1 aJönsson, Erik, G1 aCrespo-Facorro, Benedicto1 aKoen, Nastassja1 aGreve, Douglas, N1 aUitterlinden, André, G1 aWeinberger, Daniel, R1 aSteen, Vidar, M1 aFedko, Iryna, O1 aGroenewold, Nynke, A1 aNiessen, Wiro, J1 aToro, Roberto1 aTzourio, Christophe1 aLongstreth, William, T1 aIkram, Kamran1 aSmoller, Jordan, W1 avan Tol, Marie-Jose1 aSussmann, Jessika, E1 aPaus, Tomáš1 aLemaître, Hervé1 aSchroeter, Matthias, L1 aMazoyer, Bernard1 aAndreassen, Ole, A1 aHolsboer, Florian1 aDepondt, Chantal1 aVeltman, Dick, J1 aTurner, Jessica, A1 aPausova, Zdenka1 aSchumann, Gunter1 avan Rooij, Daan1 aDjurovic, Srdjan1 aDeary, Ian, J1 aMcMahon, Katie, L1 aMüller-Myhsok, Bertram1 aBrouwer, Rachel, M1 aSoininen, Hilkka1 aPandolfo, Massimo1 aWassink, Thomas, H1 aCheung, Joshua, W1 aWolfers, Thomas1 aMartinot, Jean-Luc1 aZwiers, Marcel, P1 aNauck, Matthias1 aMelle, Ingrid1 aMartin, Nicholas, G1 aKanai, Ryota1 aWestman, Eric1 aKahn, René, S1 aSisodiya, Sanjay, M1 aWhite, Tonya1 aSaremi, Arvin1 avan Bokhoven, Hans1 aBrunner, Han, G1 aVölzke, Henry1 aWright, Margaret, J1 aEnt, Dennis, van 't1 aNöthen, Markus, M1 aOphoff, Roel, A1 aBuitelaar, Jan, K1 aFernández, Guillén1 aSachdev, Perminder, S1 aRietschel, Marcella1 avan Haren, Neeltje, E M1 aFisher, Simon, E1 aBeiser, Alexa, S1 aFrancks, Clyde1 aSaykin, Andrew, J1 aMather, Karen, A1 aRomanczuk-Seiferth, Nina1 aHartman, Catharina, A1 aDeStefano, Anita, L1 aHeslenfeld, Dirk, J1 aWeiner, Michael, W1 aWalter, Henrik1 aHoekstra, Pieter, J1 aNyquist, Paul, A1 aFranke, Barbara1 aBennett, David, A1 aGrabe, Hans, J1 aJohnson, Andrew, D1 aChen, Christopher1 aDuijn, Cornelia, M1 aLopez, Oscar, L1 aFornage, Myriam1 aWardlaw, Joanna, M1 aSchmidt, Reinhold1 aDeCarli, Charles1 aDe Jager, Philip, L1 aVillringer, Arno1 aDebette, Stephanie1 aGudnason, Vilmundur1 aMedland, Sarah, E1 aShulman, Joshua, M1 aThompson, Paul, M1 aSeshadri, Sudha1 aIkram, Arfan, M uhttps://chs-nhlbi.org/node/820617696nas a2205797 4500008004100000022001400041245014000055210006900195260001300264300001200277490000700289520123800296100002101534700002801555700001801583700001901601700002101620700001701641700001701658700002101675700002501696700002601721700002401747700001901771700002201790700002001812700002201832700002701854700002601881700002901907700002301936700001801959700002101977700001701998700002102015700002002036700002102056700001902077700002502096700002202121700001802143700001702161700002102178700002802199700001902227700002802246700002102274700002402295700001702319700002102336700001502357700001902372700002002391700001702411700001302428700002102441700001702462700002102479700001902500700002202519700002002541700001802561700003102579700001702610700002302627700002302650700003102673700002402704700002402728700002702752700001802779700001802797700001902815700002302834700002102857700002402878700001702902700002402919700001802943700001902961700002102980700001803001700002303019700002403042700002203066700001803088700002203106700002803128700002003156700002003176700002103196700002203217700002003239700002503259700002303284700002203307700001203329700002503341700001803366700002303384700002503407700002203432700002103454700003003475700002103505700002303526700002303549700002703572700002103599700001903620700002503639700002303664700001803687700002903705700002303734700002103757700002003778700002103798700002303819700002603842700001803868700001303886700002303899700001903922700002003941700002203961700001803983700002304001700001804024700001604042700001904058700002104077700001604098700002104114700001604135700002104151700002204172700002204194700002604216700002004242700001904262700002004281700002504301700001804326700002204344700002304366700002404389700001804413700002004431700002304451700002304474700002404497700002604521700002404547700002504571700002104596700002204617700002404639700002104663700002004684700002204704700002204726700002004748700001904768700001904787700002904806700002204835700002004857700003204877700002104909700001504930700001804945700002304963700002804986700001905014700001905033700002105052700001805073700001705091700001905108700002105127700002405148700002005172700002305192700002205215700002505237700001705262700002305279700002205302700002105324700002205345700002005367700002205387700002305409700002105432700002005453700001905473700002005492700002105512700001905533700002605552700002005578700002305598700001905621700001905640700002705659700002105686700002305707700002105730700002005751700002105771700002405792700002005816700002105836700002205857700002405879700002005903700001905923700001605942700002005958700002005978700002105998700002206019700002606041700002306067700002306090700002106113700002206134700001806156700002106174700002206195700002206217700002506239700001606264700002206280700001506302700002906317700002006346700001806366700002006384700002206404700001906426700002506445700002106470700002006491700001806511700001106529700001806540700002806558700002006586700001906606700002106625700002006646700002306666700003006689700002006719700001906739700002206758700001906780700001906799700001806818700002306836700002106859700002406880700001806904700001906922700001906941700002506960700002106985700001707006700002107023700001607044700002107060700002007081700002407101700002207125700002107147700002307168700002307191700002707214700002307241700002607264700002207290700002107312700002007333700001607353700001607369700002507385700001707410700002007427700001807447700002007465700002407485700002207509700001807531700002107549700002107570700001607591700001807607700002007625700001807645700002007663700001607683700002207699700002407721700001807745700002107763700002307784700001607807700002007823700002807843700002507871700001807896700002407914700002207938700002907960700001807989700002208007700002108029700002108050700002408071700002108095700002308116700002108139700002108160700002408181700002108205700002208226700001908248700002308267700002008290700001808310700002908328700002008357700001808377700002108395700002608416700002108442700002208463700002208485700002008507700002508527700002108552700001908573700001808592700002208610700002208632700002208654700002508676700002208701700001908723700002208742700001608764700002008780700002108800700001908821700001808840700002108858700001908879700002308898700002308921700001808944700002108962700002608983700001509009700002609024700002009050700002309070700001809093700002509111700002009136700001909156700002209175700001709197700002109214700001909235700002209254700002009276700002309296700002709319700002109346700001709367700002409384700002109408700001909429700002209448700002209470700001609492700002409508700002209532700002409554700002309578700001809601700002309619700002109642700002209663700002109685700002109706700002509727700001909752700002209771700002509793700002209818700002909840700002409869700002209893700002609915700002209941700003009963700002409993700002510017700002110042700002410063700002310087700001710110700001210127700001810139700002110157700002310178700001910201700001910220700001910239700001710258700001810275700002310293700002210316700001810338700001710356700002010373700002210393700002510415700002110440700002010461700002010481700002010501700002110521700002710542700002210569700001610591700002710607700001910634700002310653700001510676700002210691700002310713700003010736700002010766700002010786700002310806700001910829700002310848700001910871700002010890700002210910700002010932700001610952700002210968700002310990700003111013700002611044700002411070700001811094700002411112700002711136700002111163700002411184700002011208700002811228700002011256700002111276700001811297700001811315700002311333700002211356700002011378700002011398700002311418700002811441700002611469700003111495710005011526710005411576710008611630710014611716856003611862 2019 eng d a1546-171800aGenetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.0 aGenetic metaanalysis of diagnosed Alzheimers disease identifies c2019 Mar a414-4300 v513 aRisk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
1 aKunkle, Brian, W1 aGrenier-Boley, Benjamin1 aSims, Rebecca1 aBis, Joshua, C1 aDamotte, Vincent1 aNaj, Adam, C1 aBoland, Anne1 aVronskaya, Maria1 avan der Lee, Sven, J1 aAmlie-Wolf, Alexandre1 aBellenguez, Céline1 aFrizatti, Aura1 aChouraki, Vincent1 aMartin, Eden, R1 aSleegers, Kristel1 aBadarinarayan, Nandini1 aJakobsdottir, Johanna1 aHamilton-Nelson, Kara, L1 aMoreno-Grau, Sonia1 aOlaso, Robert1 aRaybould, Rachel1 aChen, Yuning1 aKuzma, Amanda, B1 aHiltunen, Mikko1 aMorgan, Taniesha1 aAhmad, Shahzad1 aVardarajan, Badri, N1 aEpelbaum, Jacques1 aHoffmann, Per1 aBoada, Merce1 aBeecham, Gary, W1 aGarnier, Jean-Guillaume1 aHarold, Denise1 aFitzpatrick, Annette, L1 aValladares, Otto1 aMoutet, Marie-Laure1 aGerrish, Amy1 aSmith, Albert, V1 aQu, Liming1 aBacq, Delphine1 aDenning, Nicola1 aJian, Xueqiu1 aZhao, Yi1 aDel Zompo, Maria1 aFox, Nick, C1 aChoi, Seung-Hoan1 aMateo, Ignacio1 aHughes, Joseph, T1 aAdams, Hieab, H1 aMalamon, John1 aSanchez-Garcia, Florentino1 aPatel, Yogen1 aBrody, Jennifer, A1 aDombroski, Beth, A1 aNaranjo, Maria, Candida De1 aDaniilidou, Makrina1 aEiriksdottir, Gudny1 aMukherjee, Shubhabrata1 aWallon, David1 aUphill, James1 aAspelund, Thor1 aCantwell, Laura, B1 aGarzia, Fabienne1 aGalimberti, Daniela1 aHofer, Edith1 aButkiewicz, Mariusz1 aFin, Bertrand1 aScarpini, Elio1 aSarnowski, Chloe1 aBush, Will, S1 aMeslage, Stéphane1 aKornhuber, Johannes1 aWhite, Charles, C1 aSong, Yuenjoo1 aBarber, Robert, C1 aEngelborghs, Sebastiaan1 aSordon, Sabrina1 aVoijnovic, Dina1 aAdams, Perrie, M1 aVandenberghe, Rik1 aMayhaus, Manuel1 aCupples, Adrienne, L1 aAlbert, Marilyn, S1 aDe Deyn, Peter, P1 aGu, Wei1 aHimali, Jayanadra, J1 aBeekly, Duane1 aSquassina, Alessio1 aHartmann, Annette, M1 aOrellana, Adelina1 aBlacker, Deborah1 aRodriguez-Rodriguez, Eloy1 aLovestone, Simon1 aGarcia, Melissa, E1 aDoody, Rachelle, S1 aMunoz-Fernadez, Carmen1 aSussams, Rebecca1 aLin, Honghuang1 aFairchild, Thomas, J1 aBenito, Yolanda, A1 aHolmes, Clive1 aKaramujić-Čomić, Hata1 aFrosch, Matthew, P1 aThonberg, Håkan1 aMaier, Wolfgang1 aRoschupkin, Gena1 aGhetti, Bernardino1 aGiedraitis, Vilmantas1 aKawalia, Amit1 aLi, Shuo1 aHuebinger, Ryan, M1 aKilander, Lena1 aMoebus, Susanne1 aHernandez, Isabel1 aKamboh, Ilyas1 aBrundin, RoseMarie1 aTurton, James1 aYang, Qiong1 aKatz, Mindy, J1 aConcari, Letizia1 aLord, Jenny1 aBeiser, Alexa, S1 aKeene, Dirk1 aHelisalmi, Seppo1 aKloszewska, Iwona1 aKukull, Walter, A1 aKoivisto, Anne, Maria1 aLynch, Aoibhinn1 aTarraga, Lluis1 aLarson, Eric, B1 aHaapasalo, Annakaisa1 aLawlor, Brian1 aMosley, Thomas, H1 aLipton, Richard, B1 aSolfrizzi, Vincenzo1 aGill, Michael1 aLongstreth, W T1 aMontine, Thomas, J1 aFrisardi, Vincenza1 aDiez-Fairen, Monica1 aRivadeneira, Fernando1 aPetersen, Ronald, C1 aDeramecourt, Vincent1 aAlvarez, Ignacio1 aSalani, Francesca1 aCiaramella, Antonio1 aBoerwinkle, Eric1 aReiman, Eric, M1 aFiévet, Nathalie1 aRotter, Jerome, I1 aReisch, Joan, S1 aHanon, Olivier1 aCupidi, Chiara1 aUitterlinden, A, G Andre1 aRoyall, Donald, R1 aDufouil, Carole1 aMaletta, Raffaele, Giovanni1 ade Rojas, Itziar1 aSano, Mary1 aBrice, Alexis1 aCecchetti, Roberta1 aSt George-Hyslop, Peter1 aRitchie, Karen1 aTsolaki, Magda1 aTsuang, Debby, W1 aDubois, Bruno1 aCraig, David1 aWu, Chuang-Kuo1 aSoininen, Hilkka1 aAvramidou, Despoina1 aAlbin, Roger, L1 aFratiglioni, Laura1 aGermanou, Antonia1 aApostolova, Liana, G1 aKeller, Lina1 aKoutroumani, Maria1 aArnold, Steven, E1 aPanza, Francesco1 aGkatzima, Olymbia1 aAsthana, Sanjay1 aHannequin, Didier1 aWhitehead, Patrice1 aAtwood, Craig, S1 aCaffarra, Paolo1 aHampel, Harald1 aQuintela, Inés1 aCarracedo, Angel1 aLannfelt, Lars1 aRubinsztein, David, C1 aBarnes, Lisa, L1 aPasquier, Florence1 aFrölich, Lutz1 aBarral, Sandra1 aMcGuinness, Bernadette1 aBeach, Thomas, G1 aJohnston, Janet, A1 aBecker, James, T1 aPassmore, Peter1 aBigio, Eileen, H1 aSchott, Jonathan, M1 aBird, Thomas, D1 aWarren, Jason, D1 aBoeve, Bradley, F1 aLupton, Michelle, K1 aBowen, James, D1 aProitsi, Petra1 aBoxer, Adam1 aPowell, John, F1 aBurke, James, R1 aKauwe, John, S K1 aBurns, Jeffrey, M1 aMancuso, Michelangelo1 aBuxbaum, Joseph, D1 aBonuccelli, Ubaldo1 aCairns, Nigel, J1 aMcQuillin, Andrew1 aCao, Chuanhai1 aLivingston, Gill1 aCarlson, Chris, S1 aBass, Nicholas, J1 aCarlsson, Cynthia, M1 aHardy, John1 aCarney, Regina, M1 aBras, Jose1 aCarrasquillo, Minerva, M1 aGuerreiro, Rita1 aAllen, Mariet1 aChui, Helena, C1 aFisher, Elizabeth1 aMasullo, Carlo1 aCrocco, Elizabeth, A1 aDeCarli, Charles1 aBisceglio, Gina1 aDick, Malcolm1 aMa, Li1 aDuara, Ranjan1 aGraff-Radford, Neill, R1 aEvans, Denis, A1 aHodges, Angela1 aFaber, Kelley, M1 aScherer, Martin1 aFallon, Kenneth, B1 aRiemenschneider, Matthias1 aFardo, David, W1 aHeun, Reinhard1 aFarlow, Martin, R1 aKölsch, Heike1 aFerris, Steven1 aLeber, Markus1 aForoud, Tatiana, M1 aHeuser, Isabella1 aGalasko, Douglas, R1 aGiegling, Ina1 aGearing, Marla1 aHüll, Michael1 aGeschwind, Daniel, H1 aGilbert, John, R1 aMorris, John1 aGreen, Robert, C1 aMayo, Kevin1 aGrowdon, John, H1 aFeulner, Thomas1 aHamilton, Ronald, L1 aHarrell, Lindy, E1 aDrichel, Dmitriy1 aHonig, Lawrence, S1 aCushion, Thomas, D1 aHuentelman, Matthew, J1 aHollingworth, Paul1 aHulette, Christine, M1 aHyman, Bradley, T1 aMarshall, Rachel1 aJarvik, Gail, P1 aMeggy, Alun1 aAbner, Erin1 aMenzies, Georgina, E1 aJin, Lee-Way1 aLeonenko, Ganna1 aReal, Luis, M1 aJun, Gyungah, R1 aBaldwin, Clinton, T1 aGrozeva, Detelina1 aKarydas, Anna1 aRusso, Giancarlo1 aKaye, Jeffrey, A1 aKim, Ronald1 aJessen, Frank1 aKowall, Neil, W1 aVellas, Bruno1 aKramer, Joel, H1 aVardy, Emma1 aLaFerla, Frank, M1 aJöckel, Karl-Heinz1 aLah, James, J1 aDichgans, Martin1 aLeverenz, James, B1 aMann, David1 aLevey, Allan, I1 aPickering-Brown, Stuart1 aLieberman, Andrew, P1 aKlopp, Norman1 aLunetta, Kathryn, L1 aWichmann, H-Erich1 aLyketsos, Constantine, G1 aMorgan, Kevin1 aMarson, Daniel, C1 aBrown, Kristelle1 aMartiniuk, Frank1 aMedway, Christopher1 aMash, Deborah, C1 aNöthen, Markus, M1 aMasliah, Eliezer1 aHooper, Nigel, M1 aMcCormick, Wayne, C1 aDaniele, Antonio1 aMcCurry, Susan, M1 aBayer, Anthony1 aMcDavid, Andrew, N1 aGallacher, John1 aMcKee, Ann, C1 avan den Bussche, Hendrik1 aMesulam, Marsel1 aBrayne, Carol1 aMiller, Bruce, L1 aRiedel-Heller, Steffi1 aMiller, Carol, A1 aMiller, Joshua, W1 aAl-Chalabi, Ammar1 aMorris, John, C1 aShaw, Christopher, E1 aMyers, Amanda, J1 aWiltfang, Jens1 aO'Bryant, Sid1 aOlichney, John, M1 aAlvarez, Victoria1 aParisi, Joseph, E1 aSingleton, Andrew, B1 aPaulson, Henry, L1 aCollinge, John1 aPerry, William, R1 aMead, Simon1 aPeskind, Elaine1 aCribbs, David, H1 aRossor, Martin1 aPierce, Aimee1 aRyan, Natalie, S1 aPoon, Wayne, W1 aNacmias, Benedetta1 aPotter, Huntington1 aSorbi, Sandro1 aQuinn, Joseph, F1 aSacchinelli, Eleonora1 aRaj, Ashok1 aSpalletta, Gianfranco1 aRaskind, Murray1 aCaltagirone, Carlo1 aBossù, Paola1 aOrfei, Maria, Donata1 aReisberg, Barry1 aClarke, Robert1 aReitz, Christiane1 aSmith, David1 aRingman, John, M1 aWarden, Donald1 aRoberson, Erik, D1 aWilcock, Gordon1 aRogaeva, Ekaterina1 aBruni, Amalia, Cecilia1 aRosen, Howard, J1 aGallo, Maura1 aRosenberg, Roger, N1 aBen-Shlomo, Yoav1 aSager, Mark, A1 aMecocci, Patrizia1 aSaykin, Andrew, J1 aPastor, Pau1 aCuccaro, Michael, L1 aVance, Jeffery, M1 aSchneider, Julie, A1 aSchneider, Lori, S1 aSlifer, Susan1 aSeeley, William, W1 aSmith, Amanda, G1 aSonnen, Joshua, A1 aSpina, Salvatore1 aStern, Robert, A1 aSwerdlow, Russell, H1 aTang, Mitchell1 aTanzi, Rudolph, E1 aTrojanowski, John, Q1 aTroncoso, Juan, C1 aVan Deerlin, Vivianna, M1 aVan Eldik, Linda, J1 aVinters, Harry, V1 aVonsattel, Jean, Paul1 aWeintraub, Sandra1 aWelsh-Bohmer, Kathleen, A1 aWilhelmsen, Kirk, C1 aWilliamson, Jennifer1 aWingo, Thomas, S1 aWoltjer, Randall, L1 aWright, Clinton, B1 aYu, Chang-En1 aYu, Lei1 aSaba, Yasaman1 aPilotto, Alberto1 aBullido, María, J1 aPeters, Oliver1 aCrane, Paul, K1 aBennett, David1 aBosco, Paola1 aCoto, Eliecer1 aBoccardi, Virginia1 aDe Jager, Phil, L1 aLleo, Alberto1 aWarner, Nick1 aLopez, Oscar, L1 aIngelsson, Martin1 aDeloukas, Panagiotis1 aCruchaga, Carlos1 aGraff, Caroline1 aGwilliam, Rhian1 aFornage, Myriam1 aGoate, Alison, M1 aSánchez-Juan, Pascual1 aKehoe, Patrick, G1 aAmin, Najaf1 aErtekin-Taner, Nilifur1 aBerr, Claudine1 aDebette, Stephanie1 aLove, Seth1 aLauner, Lenore, J1 aYounkin, Steven, G1 aDartigues, Jean-François1 aCorcoran, Chris1 aIkram, Arfan, M1 aDickson, Dennis, W1 aNicolas, Gaël1 aCampion, Dominique1 aTschanz, JoAnn1 aSchmidt, Helena1 aHakonarson, Hakon1 aClarimon, Jordi1 aMunger, Ron1 aSchmidt, Reinhold1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aO'Donovan, Michael, C1 aDeStefano, Anita, L1 aJones, Lesley1 aHaines, Jonathan, L1 aDeleuze, Jean-Francois1 aOwen, Michael, J1 aGudnason, Vilmundur1 aMayeux, Richard1 aEscott-Price, Valentina1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aRuiz, Agustin1 aDuijn, Cornelia, M1 aHolmans, Peter, A1 aSeshadri, Sudha1 aWilliams, Julie1 aAmouyel, Phillippe1 aSchellenberg, Gerard, D1 aLambert, Jean-Charles1 aPericak-Vance, Margaret, A1 aAlzheimer Disease Genetics Consortium (ADGC),1 aEuropean Alzheimer’s Disease Initiative (EADI),1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE),1 aGenetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), uhttps://chs-nhlbi.org/node/797704831nas 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/937210550nas a2203325 4500008004100000022001400041245010600055210006900161260001600230520134200246100002201588700002201610700002001632700001701652700002301669700001901692700002101711700001901732700001701751700002301768700002001791700001701811700002001828700002501848700002301873700001701896700002101913700002401934700002101958700002001979700002001999700002402019700001502043700002202058700002002080700002202100700002002122700002102142700002402163700002502187700002202212700001702234700002202251700002002273700001302293700001902306700001902325700001502344700001502359700002302374700002102397700002502418700001402443700002802457700001802485700002102503700002902524700002202553700002102575700002202596700001902618700001802637700002802655700001702683700001902700700001902719700001902738700001902757700002102776700001702797700002502814700002302839700002202862700002702884700002002911700001702931700001802948700001702966700001902983700001803002700001903020700001603039700001603055700001903071700001903090700001403109700002503123700002103148700002103169700002103190700002203211700002803233700002203261700002103283700001803304700002603322700002303348700002103371700002003392700002403412700001503436700002203451700002203473700002103495700002103516700002403537700002103561700002503582700002103607700002303628700001903651700002003670700001603690700002203706700002003728700002003748700001903768700002103787700002303808700002003831700002103851700001903872700002303891700002503914700002203939700002303961700002803984700001904012700002504031700001804056700002404074700002104098700002604119700001904145700002204164700001904186700002304205700002404228700002204252700002004274700002404294700001304318700002004331700001704351700001504368700001504383700001504398700001804413700002404431700002304455700002204478700002104500700002104521700001704542700002104559700002204580700002404602700001904626700002004645700002704665700002204692700002304714700002604737700001704763700002304780700002004803700002404823700001904847700001804866700002204884700002304906700002004929700001904949700002104968700002304989700002605012700001905038700001605057700002405073700002505097700002205122700001705144700001405161700002005175700001605195700002005211700002305231700002005254700001905274700002405293700001805317700002005335700001905355700002105374700002805395700002205423700002205445700002605467700001605493700001605509700001405525700001705539700002405556700002005580700002405600700001305624700001305637700001705650700001905667700001405686700002305700700002105723700002105744700002205765700002205787700001805809700001605827700002005843700002005863700002305883700002205906700002105928700002205949700002305971700002305994700001906017700002206036700001906058700001906077700002206096700002706118700002006145700002606165700002106191700002206212700001706234700001706251700001506268700002606283700001906309700002506328700001806353700001906371700003006390700001506420700001806435700001906453700002106472700002206493700002406515700001806539700001706557700002006574700002006594700002006614700002406634700001806658700002306676700002906699700002006728700002106748700001806769700002206787700002306809700001906832700002006851700001706871700002206888700002106910700002506931700002406956700001806980700002306998700002507021700002007046700002407066710002407090710007407114856003607188 2019 eng d a1476-625600aMulti-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.0 aMultiAncestry GenomeWide Association Study of Lipid Levels Incor c2019 Jan 293 aAn individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
1 ade Vries, Paul, S1 aBrown, Michael, R1 aBentley, Amy, R1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aSchwander, Karen1 aKraja, Aldi, T1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDeng, Xuan1 aDorajoo, Rajkumar1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aEvangelou, Evangelos1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLee, Joseph, H1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aRiaz, Muhammad1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aConnell, John, M1 ade Faire, Ulf1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDing, Jingzhong1 aDominiczak, Anna, F1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGrabe, Hans, J1 aGrove, Megan, L1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJacobs, David, R1 aJohnson, Craig1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Steve, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLemaitre, Rozenn, N1 aLi, Yize1 aLiang, Jingjing1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMukamal, Kenneth, J1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRice, Treva, K1 aRich, Stephen, S1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTan, Nicholas1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 avan Heemst, Diana1 aVuckovic, Dragana1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Yujie1 aWang, Zhe1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aPenninx, Brenda1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aZheng, Wei1 aElliott, Paul1 aNorth, Kari, E1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aLiu, Ching-Ti1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aKardia, Sharon, L R1 aZhu, Xiaofeng1 aRotimi, Charles, N1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLiu, Jingmin1 aRotter, Jerome, I1 aGauderman, James1 aProvince, Michael, A1 aMunroe, Patricia, B1 aRice, Kenneth1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aMorrison, Alanna, C1 aInterAct Consortium1 aLifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study) uhttps://chs-nhlbi.org/node/797011178nas a2203793 4500008004100000022001400041245013500055210006900190260001300259300001200272490000700284520073900291100002001030700001701050700002201067700002301089700001901112700001901131700002101150700002301171700001501194700001501209700001701224700001701241700001801258700002001276700001701296700002001313700002501333700002301358700001701381700002101398700002401419700002101443700001701464700001801481700002001499700002001519700002001539700002201559700002201581700002001603700002101623700002401644700001401668700002201682700001701704700002201721700002001743700001301763700001901776700002501795700001501820700001501835700002301850700002101873700002501894700001401919700002801933700001801961700001701979700002101996700002902017700002202046700002102068700001902089700001902108700001802127700002802145700001702173700001902190700001902209700001602228700001902244700002302263700001902286700001902305700002102324700001702345700002502362700002302387700002202410700002702432700002002459700002002479700001702499700001802516700001702534700002102551700001902572700001802591700001902609700002302628700001602651700001602667700001902683700001902702700002302721700001402744700002502758700001702783700002402800700002102824700002402845700002102869700001802890700001902908700002102927700002202948700002802970700002202998700002303020700002403043700002103067700002603088700002103114700002203135700001803157700001503175700002203190700002203212700002103234700002003255700002103275700002403296700002503320700001903345700001203364700002103376700002003397700001903417700002303436700001903459700001603478700002203494700002003516700002003536700001903556700002103575700002003596700001703616700001903633700001903652700002303671700002103694700002203715700002303737700002803760700001903788700001803807700002403825700002103849700002803870700001903898700002203917700001903939700002303958700002403981700002204005700002004027700001904047700001304066700002004079700001504099700001804114700001704132700001504149700001504164700002004179700001504199700001604214700001804230700002004248700002404268700002304292700002204315700002104337700002104358700001704379700002104396700002304417700002204440700002204462700001904484700002004503700002704523700001904550700002604569700002604595700002704621700002304648700002004671700002404691700001904715700001804734700002304752700002004775700002004795700001904815700002104834700002604855700001904881700002404900700001604924700002404940700002504964700002204989700001705011700001405028700002005042700001605062700002305078700002005101700001905121700002405140700002605164700002305190700001405213700002005227700001905247700002105266700002205287700002305309700002805332700002205360700002605382700001705408700001405425700001605439700001705455700002705472700002005499700002405519700001305543700001905556700001705575700001905592700001405611700002305625700002105648700002105669700002205690700002205712700002305734700001805757700001805775700001805793700001605811700002005827700002005847700002305867700002205890700002105912700002205933700002305955700002705978700002306005700002506028700001906053700002206072700001906094700002106113700001406134700002206148700002706170700002906197700002706226700002606253700002106279700001906300700002206319700001706341700001706358700001506375700002606390700001906416700001906435700002506454700001806479700001906497700003006516700001706546700002406563700001506587700002106602700002206623700002406645700002406669700001706693700002006710700002006730700002006750700002906770700002006799700002506819700002106844700001806865700002206883700002306905700001906928700002006947700002006967700002306987700002207010700001807032700002107050700002107071700001807092700002407110700002407134700002007158700002307178700002507201710002907226710002907255710004307284710002107327856003607348 2019 eng d a1546-171800aMulti-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.0 aMultiancestry genomewide genesmoking interaction study of 387272 c2019 Apr a636-6480 v513 aThe concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
1 aBentley, Amy, R1 aSung, Yun, J1 aBrown, Michael, R1 aWinkler, Thomas, W1 aKraja, Aldi, T1 aNtalla, Ioanna1 aSchwander, Karen1 aChasman, Daniel, I1 aLim, Elise1 aDeng, Xuan1 aGuo, Xiuqing1 aLiu, Jingmin1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aBaker, Jenna1 aChen, Guanjie1 aAschard, Hugues1 aBartz, Traci, M1 aDing, Jingzhong1 aDorajoo, Rajkumar1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aZhao, Wei1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aHung, Yi-Jen1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLeander, Karin1 aLin, Keng-Hung1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aPrins, Bram1 aRiaz, Muhammad1 aRobino, Antonietta1 aSaid, Abdullah1 aSchupf, Nicole1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Tzung-Dau1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aXiang, Yong-Bing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAdeyemo, Adebowale1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aArzumanyan, Zorayr1 aAung, Tin1 aBallantyne, Christie1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBroeckel, Ulrich1 aBrown, Morris1 aCade, Brian, E1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aChristensen, Kaare1 aConcas, Maria, Pina1 aConnell, John, M1 aFuentes, Lisa, de Las1 ade Silva, Janaka1 ade Vries, Paul, S1 aDoumatey, Ayo1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFloyd, James, S1 aForouhi, Nita, G1 aForrester, Terrence1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGharib, Sina, A1 aGigante, Bruna1 aGiulianini, Franco1 aGrabe, Hans, J1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aIkram, Arfan, M1 aJia, Yucheng1 aJoehanes, Roby1 aJohnson, Craig1 aJonas, Jost, Bruno1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLiang, Jingjing1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLohman, Kurt, K1 aLouie, Tin1 aLuzzi, Anna1 aMägi, Reedik1 aMahajan, Anubha1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMurray, Alison, D1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRenstrom, Frida1 aRice, Treva, K1 aRich, Stephen, S1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTiemeier, Henning1 aTurner, Stephen, T1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Heming1 aWang, Lan1 aWang, Lihua1 aBin Wei, Wen1 aWilliams, Christine, A1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYoung, Kristin1 aYu, Caizheng1 aYuan, Jian-Min1 aZhou, Jie1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aCooper, Richard, S1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aJuang, Jyh-Ming, Jimmy1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLaurie, Cathy, C1 aLee, I-Te1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aRedline, Susan1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Jun-Sing1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZeggini, Eleftheria1 aZheng, Wei1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aProvince, Michael, A1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aFranceschini, Nora1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aCOGENT-Kidney Consortium1 aEPIC-InterAct Consortium1 aUnderstanding Society Scientific Group1 aLifelines Cohort uhttps://chs-nhlbi.org/node/800510097nas 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/797604618nas 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/862506570nas a2201753 4500008004100000022001400041245007100055210006900126260001200195300001200207490000800219520164100227100002301868700002501891700002601916700002201942700001701964700002401981700002002005700001902025700002602044700001902070700001602089700002002105700002902125700002702154700001602181700002202197700002002219700002002239700002502259700002402284700001902308700002002327700001902347700002002366700002402386700002002410700002602430700002702456700002502483700002402508700001402532700002202546700002302568700002102591700002302612700001902635700002302654700001702677700002302694700001802717700002102735700001902756700002302775700002502798700002202823700002402845700002402869700001902893700002702912700001902939700001702958700002202975700001902997700002103016700001903037700002203056700001903078700001903097700002003116700002203136700002203158700002503180700001903205700002103224700002303245700002103268700002303289700002303312700002203335700001903357700001803376700002203394700002103416700002203437700002103459700002103480700002003501700001903521700002003540700002203560700001803582700002203600700002003622700001703642700001703659700001603676700001503692700002703707700002303734700001703757700002403774700002103798700002003819700002103839700002403860700002503884700002403909700002303933700002503956700002303981700002104004700001904025700002004044700001904064700002804083700001804111700002104129700002104150700002304171700001804194700002004212700002304232700001804255700002404273700002104297700002504318700002104343700001704364700001704381700001804398700002104416700002204437700002104459700001704480700002204497700002004519700002304539700002304562700002504585700002404610700002204634700002304656700002204679700002304701710005604724856003604780 2020 eng d a1476-468700aInherited causes of clonal haematopoiesis in 97,691 whole genomes.0 aInherited causes of clonal haematopoiesis in 97691 whole genomes c2020 10 a763-7680 v5863 aAge is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
1 aBick, Alexander, G1 aWeinstock, Joshua, S1 aNandakumar, Satish, K1 aFulco, Charles, P1 aBao, Erik, L1 aZekavat, Seyedeh, M1 aSzeto, Mindy, D1 aLiao, Xiaotian1 aLeventhal, Matthew, J1 aNasser, Joseph1 aChang, Kyle1 aLaurie, Cecelia1 aBurugula, Bala, Bharathi1 aGibson, Christopher, J1 aLin, Amy, E1 aTaub, Margaret, A1 aAguet, Francois1 aArdlie, Kristin1 aMitchell, Braxton, D1 aBarnes, Kathleen, C1 aMoscati, Arden1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aSilverman, Edwin, K1 aWeiss, Scott, T1 aPalmer, Nicholette, D1 aVasan, Ramachandran, S1 aBurchard, Esteban, G1 aKardia, Sharon, L R1 aHe, Jiang1 aKaplan, Robert, C1 aSmith, Nicholas, L1 aArnett, Donna, K1 aSchwartz, David, A1 aCorrea, Adolfo1 ade Andrade, Mariza1 aGuo, Xiuqing1 aKonkle, Barbara, A1 aCuster, Brian1 aPeralta, Juan, M1 aGui, Hongsheng1 aMeyers, Deborah, A1 aMcGarvey, Stephen, T1 aChen, Ida Yii-Der1 aShoemaker, Benjamin1 aPeyser, Patricia, A1 aBroome, Jai, G1 aGogarten, Stephanie, M1 aWang, Fei, Fei1 aWong, Quenna1 aMontasser, May, E1 aDaya, Michelle1 aKenny, Eimear, E1 aNorth, Kari, E1 aLauner, Lenore, J1 aCade, Brian, E1 aBis, Joshua, C1 aCho, Michael, H1 aLasky-Su, Jessica1 aBowden, Donald, W1 aCupples, Adrienne, L1 aC Y Mak, Angel1 aBecker, Lewis, C1 aSmith, Jennifer, A1 aKelly, Tanika, N1 aAslibekyan, Stella1 aHeckbert, Susan, R1 aTiwari, Hemant, K1 aYang, Ivana, V1 aHeit, John, A1 aLubitz, Steven, A1 aJohnsen, Jill, M1 aCurran, Joanne, E1 aWenzel, Sally, E1 aWeeks, Daniel, E1 aRao, Dabeeru, C1 aDarbar, Dawood1 aMoon, Jee-Young1 aTracy, Russell, P1 aButh, Erin, J1 aRafaels, Nicholas1 aLoos, Ruth, J F1 aDurda, Peter1 aLiu, Yongmei1 aHou, Lifang1 aLee, Jiwon1 aKachroo, Priyadarshini1 aFreedman, Barry, I1 aLevy, Daniel1 aBielak, Lawrence, F1 aHixson, James, E1 aFloyd, James, S1 aWhitsel, Eric, A1 aEllinor, Patrick, T1 aIrvin, Marguerite, R1 aFingerlin, Tasha, E1 aRaffield, Laura, M1 aArmasu, Sebastian, M1 aWheeler, Marsha, M1 aSabino, Ester, C1 aBlangero, John1 aWilliams, Keoki1 aLevy, Bruce, D1 aSheu, Wayne, Huey-Herng1 aRoden, Dan, M1 aBoerwinkle, Eric1 aManson, JoAnn, E1 aMathias, Rasika, A1 aDesai, Pinkal1 aTaylor, Kent, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aKooperberg, Charles1 aLaurie, Cathy, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aZhao, Hongyu1 aLange, Ethan1 aLange, Leslie1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aScheet, Paul1 aKitzman, Jacob, O1 aLander, Eric, S1 aEngreitz, Jesse, M1 aEbert, Benjamin, L1 aReiner, Alexander, P1 aJaiswal, Siddhartha1 aAbecasis, Goncalo1 aSankaran, Vijay, G1 aKathiresan, Sekar1 aNatarajan, Pradeep1 aNHLBI Trans-Omics for Precision Medicine Consortium uhttps://chs-nhlbi.org/node/862107958nas a2202377 4500008004100000022001400041245011500055210006900170260001600239300000900255490000700264520122900271100001901500700001801519700002501537700002401562700002701586700002201613700002201635700002101657700002201678700002301700700002001723700002101743700002201764700002101786700002201807700002401829700002101853700002001874700001801894700001901912700001601931700002401947700003201971700002902003700002002032700002902052700002602081700002002107700002002127700002202147700002602169700001602195700002002211700002102231700001902252700001502271700002502286700002202311700002702333700002202360700002202382700002402404700001802428700002002446700002502466700001802491700001702509700002302526700002102549700002502570700002202595700002302617700001902640700002302659700002602682700001702708700001802725700002702743700002602770700002202796700002802818700002302846700002602869700002002895700002002915700002102935700001802956700001702974700002302991700001903014700002403033700002203057700002203079700002103101700002403122700002003146700002403166700002303190700001903213700001303232700001803245700002203263700003003285700002003315700002603335700002103361700002403382700002203406700002703428700001503455700001803470700001903488700002303507700002203530700002403552700002303576700001803599700001803617700001903635700001803654700002403672700001803696700001903714700001903733700002303752700002003775700001803795700002203813700002603835700002703861700002203888700002603910700001403936700001903950700002503969700002003994700001804014700002204032700001704054700001804071700002204089700001604111700002504127700002004152700001704172700002304189700001804212700002204230700002004252700001304272700002304285700001804308700002904326700002104355700002104376700001404397700002304411700001504434700002304449700001704472700001904489700003204508700002404540700002204564700002304586700002004609700002304629700002404652700002804676700002204704700002404726700002404750700001904774700002504793700002104818700001904839700001904858700002104877700002004898700002404918700002204942700002704964700002204991700002105013700002305034700002005057700001705077700001905094700002405113700002205137700001905159700001905178700002905197700002005226700002805246700001605274700001905290700002505309700002805334700002805362700002405390700001905414700002105433700002405454700002005478700002205498700002405520856003605544 2020 eng d a2041-172300aMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.0 aMultiancestry GWAS of the electrocardiographic PR interval ident c2020 May 21 a25420 v113 aThe electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
1 aNtalla, Ioanna1 aWeng, Lu-Chen1 aCartwright, James, H1 aHall, Amelia, Weber1 aSveinbjornsson, Gardar1 aTucker, Nathan, R1 aChoi, Seung, Hoan1 aChaffin, Mark, D1 aRoselli, Carolina1 aBarnes, Michael, R1 aMifsud, Borbala1 aWarren, Helen, R1 aHayward, Caroline1 aMarten, Jonathan1 aCranley, James, J1 aConcas, Maria, Pina1 aGasparini, Paolo1 aBoutin, Thibaud1 aKolcic, Ivana1 aPolasek, Ozren1 aRudan, Igor1 aAraujo, Nathalia, M1 aLima-Costa, Maria, Fernanda1 aRibeiro, Antonio, Luiz P1 aSouza, Renan, P1 aTarazona-Santos, Eduardo1 aGiedraitis, Vilmantas1 aIngelsson, Erik1 aMahajan, Anubha1 aMorris, Andrew, P1 aM, Fabiola, del Greco1 aFoco, Luisa1 aGögele, Martin1 aHicks, Andrew, A1 aCook, James, P1 aLind, Lars1 aLindgren, Cecilia, M1 aSundström, Johan1 aNelson, Christopher, P1 aRiaz, Muhammad, B1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aUlivi, Sheila1 aKähönen, Mika1 aMishra, Pashupati, P1 aMononen, Nina1 aNikus, Kjell1 aCaulfield, Mark, J1 aDominiczak, Anna1 aPadmanabhan, Sandosh1 aMontasser, May, E1 aO'Connell, Jeff, R1 aRyan, Kathleen1 aShuldiner, Alan, R1 aAeschbacher, Stefanie1 aConen, David1 aRisch, Lorenz1 aThériault, Sébastien1 aHutri-Kähönen, Nina1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aRaitakari, Olli, T1 aBarnes, Catriona, L K1 aCampbell, Harry1 aJoshi, Peter, K1 aWilson, James, F1 aIsaacs, Aaron1 aKors, Jan, A1 aDuijn, Cornelia, M1 aHuang, Paul, L1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSmith, Albert, V1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aNadkarni, Girish, N1 aPreuss, Michael, H1 aCorrea, Adolfo1 aMei, Hao1 aWilson, James1 aMeitinger, Thomas1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aWaldenberger, Melanie1 aMangino, Massimo1 aSpector, Timothy, D1 aRienstra, Michiel1 avan de Vegte, Yordi, J1 aHarst, Pim1 aVerweij, Niek1 aKääb, Stefan1 aSchramm, Katharina1 aSinner, Moritz, F1 aStrauch, Konstantin1 aCutler, Michael, J1 aFatkin, Diane1 aLondon, Barry1 aOlesen, Morten1 aRoden, Dan, M1 aShoemaker, Benjamin1 aSmith, Gustav1 aBiggs, Mary, L1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aRice, Kenneth1 aSotoodehnia, Nona1 aDe Grandi, Alessandro1 aFuchsberger, Christian1 aPattaro, Cristian1 aPramstaller, Peter, P1 aFord, Ian1 aJukema, Wouter1 aMacfarlane, Peter, W1 aTrompet, Stella1 aDörr, Marcus1 aFelix, Stephan, B1 aVölker, Uwe1 aWeiss, Stefan1 aHavulinna, Aki, S1 aJula, Antti1 aSääksjärvi, Katri1 aSalomaa, Veikko1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aLin, Henry, J1 aRotter, Jerome, I1 aTaylor, Kent, D1 aYao, Jie1 ade Mutsert, Renée1 aMaan, Arie, C1 aMook-Kanamori, Dennis, O1 aNoordam, Raymond1 aCucca, Francesco1 aDing, Jun1 aLakatta, Edward, G1 aQian, Yong1 aTarasov, Kirill, V1 aLevy, Daniel1 aLin, Honghuang1 aNewton-Cheh, Christopher, H1 aLunetta, Kathryn, L1 aMurray, Alison, D1 aPorteous, David, J1 aSmith, Blair, H1 aStricker, Bruno, H1 aUitterlinden, Andre1 avan den Berg, Marten, E1 aHaessler, Jeffrey1 aJackson, Rebecca, D1 aKooperberg, Charles1 aPeters, Ulrike1 aReiner, Alexander, P1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBoerwinkle, Eric1 aEhret, Georg, B1 aSoliman, Elsayed, Z1 aAvery, Christy, L1 aGogarten, Stephanie, M1 aKerr, Kathleen, F1 aLaurie, Cathy, C1 aSeyerle, Amanda, A1 aStilp, Adrienne1 aAssa, Solmaz1 aSaid, Abdullah1 avan der Ende, Yldau1 aLambiase, Pier, D1 aOrini, Michele1 aRamirez, Julia1 aVan Duijvenboden, Stefan1 aArnar, David, O1 aGudbjartsson, Daniel, F1 aHolm, Hilma1 aSulem, Patrick1 aThorleifsson, Gudmar1 aThorolfsdottir, Rosa, B1 aThorsteinsdottir, Unnur1 aBenjamin, Emelia, J1 aTinker, Andrew1 aStefansson, Kari1 aEllinor, Patrick, T1 aJamshidi, Yalda1 aLubitz, Steven, A1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/836804156nas 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/898811212nas a2203445 4500008004100000022001400041245008000055210006900135260001300204300001200217490000800229520148100237100002301718700001801741700001901759700002701778700002401805700001601829700002501845700002301870700001801893700002601911700002901937700002401966700002601990700002302016700001902039700002202058700002002080700001802100700002202118700001502140700003102155700001902186700002802205700002302233700002002256700002002276700002302296700002002319700002502339700001502364700002102379700002502400700002202425700002502447700001802472700002302490700002102513700002402534700002602558700002502584700002602609700002302635700001802658700002602676700002802702700001902730700002102749700002102770700002102791700002202812700002302834700002102857700002302878700001702901700002102918700002102939700002002960700002202980700002003002700002403022700002903046700001903075700001803094700002103112700001603133700002003149700002003169700002103189700001803210700002403228700002403252700002303276700002403299700002303323700001603346700002303362700001703385700002103402700001603423700002303439700002103462700002003483700002303503700002503526700002803551700002403579700003103603700002203634700002103656700002103677700002803698700002403726700002003750700002703770700002303797700001403820700002203834700001603856700001203872700001903884700002303903700002003926700002303946700001403969700001803983700002304001700002404024700002704048700002004075700002004095700001904115700002404134700002704158700002104185700002204206700001804228700002404246700001704270700002304287700002104310700002304331700002404354700002404378700002204402700002104424700002304445700002304468700001604491700002104507700002104528700002204549700001804571700001704589700001504606700001804621700001804639700002704657700002104684700002004705700001804725700002104743700002404764700001804788700002204806700002204828700002304850700002204873700002004895700002104915700001704936700002004953700002504973700002904998700002105027700002205048700001905070700001905089700001705108700002105125700001905146700002005165700002205185700001905207700002205226700001905248700002305267700002305290700002005313700001905333700002305352700001905375700002005394700002005414700001805434700001705452700002105469700002005490700001905510700002305529700001905552700002405571700002105595700001605616700001705632700002205649700002005671700002605691700002105717700001805738700002205756700002105778700002405799700002505823700002605848700002605874700002305900700001905923700002305942700002105965700002005986700002306006700002106029700002406050700002006074700002206094700001906116700001906135700002606154700002406180700002606204700002506230700002006255700002106275700002206296700002806318700002506346700002106371700002106392700002506413700002206438700002106460700002806481700001806509700002206527700002206549700001706571700002406588700001906612700001406631700002506645700002506670700001906695700002106714700002106735700002306756700002106779700003006800700001706830700002006847700001406867700001906881700002006900700001506920700001706935700002106952700002006973700001806993700002907011700002707040700001607067700003107083700002207114700002107136700002407157700002207181700002407203700002307227700002307250700002107273700002107294700002507315700001507340700002407355700001607379700002107395700001707416700001707433700002107450710006007471710002307531710002607554710004707580710002607627710002707653710002407680710002607704856003607730 2021 eng d a1476-468700aGenetic insights into biological mechanisms governing human ovarian ageing.0 aGenetic insights into biological mechanisms governing human ovar c2021 Aug a393-3970 v5963 aReproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
1 aRuth, Katherine, S1 aDay, Felix, R1 aHussain, Jazib1 aMartínez-Marchal, Ana1 aAiken, Catherine, E1 aAzad, Ajuna1 aThompson, Deborah, J1 aKnoblochova, Lucie1 aAbe, Hironori1 aTarry-Adkins, Jane, L1 aGonzalez, Javier, Martin1 aFontanillas, Pierre1 aClaringbould, Annique1 aBakker, Olivier, B1 aSulem, Patrick1 aWalters, Robin, G1 aTerao, Chikashi1 aTuron, Sandra1 aHorikoshi, Momoko1 aLin, Kuang1 aOnland-Moret, Charlotte, N1 aSankar, Aditya1 aHertz, Emil, Peter Thra1 aTimshel, Pascal, N1 aShukla, Vallari1 aBorup, Rehannah1 aOlsen, Kristina, W1 aAguilera, Paula1 aFerrer-Roda, Mònica1 aHuang, Yan1 aStankovic, Stasa1 aTimmers, Paul, R H J1 aAhearn, Thomas, U1 aAlizadeh, Behrooz, Z1 aNaderi, Elnaz1 aAndrulis, Irene, L1 aArnold, Alice, M1 aAronson, Kristan, J1 aAugustinsson, Annelie1 aBandinelli, Stefania1 aBarbieri, Caterina, M1 aBeaumont, Robin, N1 aBecher, Heiko1 aBeckmann, Matthias, W1 aBenonisdottir, Stefania1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBojesen, Stig, E1 aBolla, Manjeet, K1 aBoomsma, Dorret, I1 aBowker, Nicholas1 aBrody, Jennifer, A1 aBroer, Linda1 aBuring, Julie, E1 aCampbell, Archie1 aCampbell, Harry1 aCastelao, Jose, E1 aCatamo, Eulalia1 aChanock, Stephen, J1 aChenevix-Trench, Georgia1 aCiullo, Marina1 aCorre, Tanguy1 aCouch, Fergus, J1 aCox, Angela1 aCrisponi, Laura1 aCross, Simon, S1 aCucca, Francesco1 aCzene, Kamila1 aSmith, George Davey1 ade Geus, Eco, J C N1 ade Mutsert, Renée1 aDe Vivo, Immaculata1 aDemerath, Ellen, W1 aDennis, Joe1 aDunning, Alison, M1 aDwek, Miriam1 aEriksson, Mikael1 aEsko, Tõnu1 aFasching, Peter, A1 aFaul, Jessica, D1 aFerrucci, Luigi1 aFranceschini, Nora1 aFrayling, Timothy, M1 aGago-Dominguez, Manuela1 aMezzavilla, Massimo1 aGarcía-Closas, Montserrat1 aGieger, Christian1 aGiles, Graham, G1 aGrallert, Harald1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aGuénel, Pascal1 aHaiman, Christopher, A1 aHåkansson, Niclas1 aHall, Per1 aHayward, Caroline1 aHe, Chunyan1 aHe, Wei1 aHeiss, Gerardo1 aHøffding, Miya, K1 aHopper, John, L1 aHottenga, Jouke, J1 aHu, Frank1 aHunter, David1 aIkram, Mohammad, A1 aJackson, Rebecca, D1 aJoaquim, Micaella, D R1 aJohn, Esther, M1 aJoshi, Peter, K1 aKarasik, David1 aKardia, Sharon, L R1 aKartsonaki, Christiana1 aKarlsson, Robert1 aKitahara, Cari, M1 aKolcic, Ivana1 aKooperberg, Charles1 aKraft, Peter1 aKurian, Allison, W1 aKutalik, Zoltán1 aLa Bianca, Martina1 aLachance, Genevieve1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLaven, Joop, S E1 aLawlor, Deborah, A1 aLe Marchand, Loïc1 aLi, Jingmei1 aLindblom, Annika1 aLindström, Sara1 aLindstrom, Tricia1 aLinet, Martha1 aLiu, Yongmei1 aLiu, Simin1 aLuan, Jian'an1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMannermaa, Arto1 aMarco, Brumat1 aMarten, Jonathan1 aMartin, Nicholas, G1 aMbarek, Hamdi1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMeisinger, Christa1 aMeitinger, Thomas1 aMenni, Cristina1 aMetspalu, Andres1 aMilani, Lili1 aMilne, Roger, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMulas, Antonella1 aMulligan, Anna, M1 aMurray, Alison1 aNalls, Mike, A1 aNewman, Anne1 aNoordam, Raymond1 aNutile, Teresa1 aNyholt, Dale, R1 aOlshan, Andrew, F1 aOlsson, Håkan1 aPainter, Jodie, N1 aPatel, Alpa, V1 aPedersen, Nancy, L1 aPerjakova, Natalia1 aPeters, Annette1 aPeters, Ulrike1 aPharoah, Paul, D P1 aPolasek, Ozren1 aPorcu, Eleonora1 aPsaty, Bruce, M1 aRahman, Iffat1 aRennert, Gad1 aRennert, Hedy, S1 aRidker, Paul, M1 aRing, Susan, M1 aRobino, Antonietta1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRossouw, Jacques1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aSala, Cinzia, F1 aSaloustros, Emmanouil1 aSandler, Dale, P1 aSanna, Serena1 aSawyer, Elinor, J1 aSarnowski, Chloe1 aSchlessinger, David1 aSchmidt, Marjanka, K1 aSchoemaker, Minouk, J1 aSchraut, Katharina, E1 aScott, Christopher1 aShekari, Saleh1 aShrikhande, Amruta1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSorice, Rossella1 aSouthey, Melissa, C1 aSpector, Tim, D1 aSpinelli, John, J1 aStampfer, Meir1 aStöckl, Doris1 avan Meurs, Joyce, B J1 aStrauch, Konstantin1 aStyrkarsdottir, Unnur1 aSwerdlow, Anthony, J1 aTanaka, Toshiko1 aTeras, Lauren, R1 aTeumer, Alexander1 aÞorsteinsdottir, Unnur1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTraglia, Michela1 aTroester, Melissa, A1 aTruong, Thérèse1 aTyrrell, Jessica1 aUitterlinden, André, G1 aUlivi, Sheila1 aVachon, Celine, M1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVölzke, Henry1 aWang, Qin1 aWareham, Nicholas, J1 aWeinberg, Clarice, R1 aWeir, David, R1 aWilcox, Amber, N1 aDijk, Ko Willems1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWolk, Alicja1 aWood, Andrew, R1 aZhao, Wei1 aZygmunt, Marek1 aChen, Zhengming1 aLi, Liming1 aFranke, Lude1 aBurgess, Stephen1 aDeelen, Patrick1 aPers, Tune, H1 aGrøndahl, Marie, Louise1 aAndersen, Claus, Yding1 aPujol, Anna1 aLopez-Contreras, Andres, J1 aDaniel, Jeremy, A1 aStefansson, Kari1 aChang-Claude, Jenny1 aSchouw, Yvonne, T1 aLunetta, Kathryn, L1 aChasman, Daniel, I1 aEaston, Douglas, F1 aVisser, Jenny, A1 aOzanne, Susan, E1 aNamekawa, Satoshi, H1 aSolc, Petr1 aMurabito, Joanne, M1 aOng, Ken, K1 aHoffmann, Eva, R1 aMurray, Anna1 aRoig, Ignasi1 aPerry, John, R B1 aBiobank-based Integrative Omics Study (BIOS) Consortium1 aeQTLGen Consortium1 aBioBank Japan Project1 aChina Kadoorie Biobank Collaborative Group1 akConFab Investigators1 aLifeLines Cohort Study1 aInterAct Consortium1 a23andMe Research Team uhttps://chs-nhlbi.org/node/883506233nas a2201609 4500008004100000022001400041245009500055210006900150260001600219520178500235100001702020700002102037700001902058700002102077700002302098700001502121700001802136700002002154700002202174700002002196700002802216700001802244700002202262700002402284700002102308700002002329700002002349700001502369700002502384700001702409700003102426700002002457700002302477700002302500700002102523700001702544700002002561700002102581700002702602700001902629700002402648700002602672700002102698700001802719700001702737700001902754700002802773700002002801700002402821700002202845700002202867700001902889700001402908700002102922700002102943700002502964700002002989700002203009700001803031700002203049700002003071700001903091700002303110700002003133700002803153700001603181700001503197700001703212700001403229700002003243700002303263700001903286700001603305700002003321700001703341700002103358700001903379700001303398700001703411700002203428700002403450700002903474700002003503700001503523700002303538700002403561700002203585700002003607700001803627700001703645700002103662700001903683700002103702700001603723700001503739700002603754700002003780700002403800700002203824700002103846700001703867700001803884700001703902700002203919700002203941700002003963700002603983700002204009700001904031700001504050700002004065700002204085700002404107700002404131700002604155700002004181700002004201700002304221700001804244700002104262700002204283700002104305700001804326700002404344700001804368700001904386700001604405700001904421700001804440700002004458700002704478700002104505700002004526700001904546700002204565856003604587 2021 eng d a1476-557800aMulti-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.0 aMultiancestry genomewide genesleep interactions identify novel l c2021 Apr 153 aLong and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
1 aWang, Heming1 aNoordam, Raymond1 aCade, Brian, E1 aSchwander, Karen1 aWinkler, Thomas, W1 aLee, Jiwon1 aSung, Yun, Ju1 aBentley, Amy, R1 aManning, Alisa, K1 aAschard, Hugues1 aKilpeläinen, Tuomas, O1 aIlkov, Marjan1 aBrown, Michael, R1 aHorimoto, Andrea, R1 aRichard, Melissa1 aBartz, Traci, M1 aVojinovic, Dina1 aLim, Elise1 aNierenberg, Jovia, L1 aLiu, Yongmei1 aChitrala, Kumaraswamynaidu1 aRankinen, Tuomo1 aMusani, Solomon, K1 aFranceschini, Nora1 aRauramaa, Rainer1 aAlver, Maris1 aZee, Phyllis, C1 aHarris, Sarah, E1 avan der Most, Peter, J1 aNolte, Ilja, M1 aMunroe, Patricia, B1 aPalmer, Nicholette, D1 aKuhnel, Brigitte1 aWeiss, Stefan1 aWen, Wanqing1 aHall, Kelly, A1 aLyytikäinen, Leo-Pekka1 aO'Connell, Jeff1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 ade Vries, Paul, S1 aArking, Dan, E1 aChen, Han1 aBoerwinkle, Eric1 aKrieger, Jose, E1 aSchreiner, Pamela, J1 aSidney, Stephen1 aShikany, James, M1 aRice, Kenneth1 aChen, Yii-Der Ida1 aGharib, Sina, A1 aBis, Joshua, C1 aLuik, Annemarie, I1 aIkram, Arfan, M1 aUitterlinden, André, G1 aAmin, Najaf1 aXu, Hanfei1 aLevy, Daniel1 aHe, Jiang1 aLohman, Kurt, K1 aZonderman, Alan, B1 aRice, Treva, K1 aSims, Mario1 aWilson, Gregory1 aSofer, Tamar1 aRich, Stephen, S1 aPalmas, Walter1 aYao, Jie1 aGuo, Xiuqing1 aRotter, Jerome, I1 aBiermasz, Nienke, R1 aMook-Kanamori, Dennis, O1 aMartin, Lisa, W1 aBarac, Ana1 aWallace, Robert, B1 aGottlieb, Daniel, J1 aKomulainen, Pirjo1 aHeikkinen, Sami1 aMägi, Reedik1 aMilani, Lili1 aMetspalu, Andres1 aStarr, John, M1 aMilaneschi, Yuri1 aWaken, R, J1 aGao, Chuan1 aWaldenberger, Melanie1 aPeters, Annette1 aStrauch, Konstantin1 aMeitinger, Thomas1 aRoenneberg, Till1 aVölker, Uwe1 aDörr, Marcus1 aShu, Xiao-Ou1 aMukherjee, Sutapa1 aHillman, David, R1 aKähönen, Mika1 aWagenknecht, Lynne, E1 aGieger, Christian1 aGrabe, Hans, J1 aZheng, Wei1 aPalmer, Lyle, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aMorrison, Alanna, C1 aPereira, Alexandre, C1 aFornage, Myriam1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLiu, Ching-Ti1 aKelly, Tanika, N1 aEvans, Michele, K1 aBouchard, Claude1 aFox, Ervin, R1 aKooperberg, Charles1 aZhu, Xiaofeng1 aLakka, Timo, A1 aEsko, Tõnu1 aNorth, Kari, E1 aDeary, Ian, J1 aSnieder, Harold1 aPenninx, Brenda, W J H1 aGauderman, James1 aRao, Dabeeru, C1 aRedline, Susan1 avan Heemst, Diana uhttps://chs-nhlbi.org/node/871403642nas a2200589 4500008004100000022001400041245009900055210006900154260001600223520192000239100002002159700001702179700002602196700002402222700002202246700001702268700002002285700002402305700001802329700002402347700001602371700002002387700002202407700002402429700002602453700002002479700002202499700002202521700002502543700002002568700002002588700002702608700002102635700002602656700002202682700002502704700001802729700002002747700002702767700002302794700001902817700002202836700001302858700002102871700002402892700001902916700002002935700002202955700001902977700002002996856003603016 2022 eng d a1875-890800aAssociations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis.0 aAssociations of Pulmonary Function with MRI Brain Volumes A Coor c2022 Oct 033 aBACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.
OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.
METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.
RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.
CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.
1 aFrenzel, Stefan1 aBis, Josh, C1 aGudmundsson, Elias, F1 aO'Donnell, Adrienne1 aSimino, Jeannette1 aYaqub, Amber1 aBartz, Traci, M1 aBrusselle, Guy, G O1 aBülow, Robin1 aDeCarli, Charles, S1 aEwert, Ralf1 aGharib, Sina, A1 aGhosh, Saptaparni1 aGireud-Goss, Monica1 aGottesman, Rebecca, F1 aIkram, Arfan, M1 aKnopman, David, S1 aLauner, Lenore, J1 aLondon, Stephanie, J1 aLongstreth, W T1 aLopez, Oscar, L1 avan Lent, Debora, Melo1 aO'Connor, George1 aSatizabal, Claudia, L1 aShrestha, Srishti1 aSigurdsson, Sigurdur1 aStubbe, Beate1 aTalluri, Rajesh1 aVasan, Ramachandran, S1 aVernooij, Meike, W1 aVölzke, Henry1 aWiggins, Kerri, L1 aYu, Bing1 aBeiser, Alexa, S1 aGudnason, Vilmundur1 aMosley, Thomas1 aPsaty, Bruce, M1 aWolters, Frank, J1 aGrabe, Hans, J1 aSeshadri, Sudha uhttps://chs-nhlbi.org/node/916312282nas 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/911204975nas a2200733 4500008004100000022001400041245010200055210006900157260001600226520287800242100001603120700001903136700001603155700001903171700001303190700002203203700002203225700002203247700001903269700001703288700001303305700002203318700002303340700002003363700002103383700002303404700002003427700002603447700002003473700001603493700002403509700002003533700002103553700002803574700002603602700002403628700003303652700002303685700002303708700002403731700001603755700001403771700002103785700001703806700001803823700001803841700002103859700002203880700002003902700002603922700002303948700002203971700002403993700002704017700001704044700001904061700002004080700002004100700002204120700002004142700002304162700002004185856003604205 2022 eng d a1460-215600aEpigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.0 aEpigenetic and integrative crossomics analyses of cerebral white c2022 Aug 093 aCerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.
1 aYang, Yunju1 aKnol, Maria, J1 aWang, Ruiqi1 aMishra, Aniket1 aLiu, Dan1 aLuciano, Michelle1 aTeumer, Alexander1 aArmstrong, Nicola1 aBis, Joshua, C1 aJhun, Min, A1 aLi, Shuo1 aAdams, Hieab, H H1 aAziz, Nasir, Ahmad1 aBastin, Mark, E1 aBourgey, Mathieu1 aBrody, Jennifer, A1 aFrenzel, Stefan1 aGottesman, Rebecca, F1 aHosten, Norbert1 aHou, Lifang1 aKardia, Sharon, L R1 aLohner, Valerie1 aMarquis, Pascale1 aManiega, Susana, Muñoz1 aSatizabal, Claudia, L1 aSorond, Farzaneh, A1 aHernández, Maria, C Valdés1 aDuijn, Cornelia, M1 aVernooij, Meike, W1 aWittfeld, Katharina1 aYang, Qiong1 aZhao, Wei1 aBoerwinkle, Eric1 aLevy, Daniel1 aDeary, Ian, J1 aJiang, Jiyang1 aMather, Karen, A1 aMosley, Thomas, H1 aPsaty, Bruce, M1 aSachdev, Perminder, S1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aDeCarli, Charles, S1 aBreteler, Monique, M B1 aIkram, Arfan1 aGrabe, Hans, J1 aWardlaw, Joanna1 aLongstreth, W T1 aLauner, Lenore, J1 aSeshadri, Sudha1 aDebette, Stephanie1 aFornage, Myriam uhttps://chs-nhlbi.org/node/918405288nas a2201585 4500008004100000022001400041245009100055210006900146260001600215520091300231100001601144700002101160700001601181700002001197700001901217700001601236700002501252700001801277700001901295700001901314700002101333700001801354700002101372700002001393700001601413700001801429700001801447700001701465700002401482700001901506700002101525700002801546700002201574700001401596700002001610700002101630700001901651700002401670700002401694700002301718700002701741700002001768700001901788700001901807700002101826700002101847700001901868700002201887700001801909700001801927700001301945700001601958700001301974700001701987700001702004700002502021700002102046700001902067700002002086700001902106700001802125700002402143700002702167700001902194700001902213700002302232700002502255700002102280700002402301700001902325700002602344700002402370700002602394700002102420700002202441700002102463700002302484700002002507700001702527700002202544700002602566700002002592700002302612700002502635700002102660700001702681700002202698700002402720700002002744700001302764700002002777700001202797700001602809700001402825700001602839700001602855700002202871700001902893700002302912700002202935700002202957700002002979700001902999700002403018700001603042700002103058700002303079700001903102700002003121700002103141700002003162700002903182700002603211700002203237700002003259700002403279700002003303700001903323700002003342700002003362700002003382700001903402700002103421700002403442700002603466700002303492700002303515700002203538700002203560700002303582700001803605700002003623700002303643856003603666 2022 eng d a1476-557800aGenome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.0 aGenomewide metaanalyses reveal novel loci for verbal shortterm m c2022 Aug 163 aUnderstanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
1 aLahti, Jari1 aTuominen, Samuli1 aYang, Qiong1 aPergola, Giulio1 aAhmad, Shahzad1 aAmin, Najaf1 aArmstrong, Nicola, J1 aBeiser, Alexa1 aBey, Katharina1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBressler, Jan1 aCampbell, Archie1 aCampbell, Harry1 aChen, Qiang1 aCorley, Janie1 aCox, Simon, R1 aDavies, Gail1 aDe Jager, Philip, L1 aDerks, Eske, M1 aFaul, Jessica, D1 aFitzpatrick, Annette, L1 aFohner, Alison, E1 aFord, Ian1 aFornage, Myriam1 aGerring, Zachary1 aGrabe, Hans, J1 aGrodstein, Francine1 aGudnason, Vilmundur1 aSimonsick, Eleanor1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKajantie, Eero1 aKaprio, Jaakko1 aKarell, Pauliina1 aKleineidam, Luca1 aKnol, Maria, J1 aKochan, Nicole, A1 aKwok, John, B1 aLeber, Markus1 aLam, Max1 aLee, Teresa1 aLi, Shuo1 aLoukola, Anu1 aLuck, Tobias1 aMarioni, Riccardo, E1 aMather, Karen, A1 aMedland, Sarah1 aMirza, Saira, S1 aNalls, Mike, A1 aNho, Kwangsik1 aO'Donnell, Adrienne1 aOldmeadow, Christopher1 aPainter, Jodie1 aPattie, Alison1 aReppermund, Simone1 aRisacher, Shannon, L1 aRose, Richard, J1 aSadashivaiah, Vijay1 aScholz, Markus1 aSatizabal, Claudia, L1 aSchofield, Peter, W1 aSchraut, Katharina, E1 aScott, Rodney, J1 aSimino, Jeannette1 aSmith, Albert, V1 aSmith, Jennifer, A1 aStott, David, J1 aSurakka, Ida1 aTeumer, Alexander1 aThalamuthu, Anbupalam1 aTrompet, Stella1 aTurner, Stephen, T1 avan der Lee, Sven, J1 aVillringer, Arno1 aVölker, Uwe1 aWilson, Robert, S1 aWittfeld, Katharina1 aVuoksimaa, Eero1 aXia, Rui1 aYaffe, Kristine1 aYu, Lei1 aZare, Habil1 aZhao, Wei1 aAmes, David1 aAttia, John1 aBennett, David, A1 aBrodaty, Henry1 aChasman, Daniel, I1 aGoldman, Aaron, L1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, L R1 aLencz, Todd1 aLoeffler, Markus1 aMattay, Venkata, S1 aPalotie, Aarno1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aRidker, Paul, M1 aRiedel-Heller, Steffi, G1 aSachdev, Perminder, S1 aSaykin, Andrew, J1 aScherer, Martin1 aSchofield, Peter, R1 aSidney, Stephen1 aStarr, John, M1 aTrollor, Julian1 aUlrich, William1 aWagner, Michael1 aWeir, David, R1 aWilson, James, F1 aWright, Margaret, J1 aWeinberger, Daniel, R1 aDebette, Stephanie1 aEriksson, Johan, G1 aMosley, Thomas, H1 aLauner, Lenore, J1 aDuijn, Cornelia, M1 aDeary, Ian, J1 aSeshadri, Sudha1 aRäikkönen, Katri uhttps://chs-nhlbi.org/node/916909141nas a2202533 4500008004100000022001400041245008200055210006900137260001600206520188300222100001902105700001802124700002202142700002202164700002002186700002202206700002502228700001802253700002202271700001802293700001402311700002502325700001602350700001802366700001902384700002002403700001502423700003202438700003302470700001802503700001802521700002002539700002202559700001802581700002002599700002802619700001702647700001702664700002902681700001602710700002702726700002202753700002402775700001802799700002802817700001902845700001902864700001902883700001702902700002202919700002502941700002002966700002002986700002203006700001903028700002203047700001903069700001603088700002003104700001503124700002003139700002103159700001803180700002203198700001903220700002103239700002403260700002503284700002203309700002403331700001403355700001303369700002103382700001603403700002203419700002303441700002603464700002003490700001903510700002303529700002003552700002303572700002003595700002303615700002303638700002103661700001603682700001703698700002203715700001803737700001703755700001403772700001503786700002103801700002003822700002503842700002203867700002503889700002603914700002303940700002203963700001903985700002804004700002504032700002004057700003104077700002104108700002004129700002004149700002104169700002104190700002204211700002004233700002104253700002904274700002004303700003304323700001904356700002604375700002404401700002104425700002304446700002104469700001804490700001604508700001604524700001904540700002304559700002804582700002204610700003204632700002004664700002404684700002604708700002104734700001604755700002204771700002204793700002104815700001604836700002304852700001604875700001604891700002004907700002204927700002204949700002404971700001904995700001905014700002105033700002005054700002005074700001905094700002205113700002405135700002505159700001705184700003205201700002305233700002305256700002005279700002505299700002105324700001605345700002605361700001805387700002405405700001605429700002205445700002505467700002505492700001805517700002605535700002105561700003005582700002005612700001905632700002105651700002105672700002305693700002305716700002205739700002905761700002205790700002305812700002005835700001805855700002005873700003005893700002205923700002305945700002305968700002505991700001706016700002306033700002106056700002306077710002306100710002206123710007406145710002106219710002406240710002306264710004106287710002606328710002106354710004706375710003106422710005206453710001806505710002206523710002606545856003606571 2022 eng d a1476-468700aStroke genetics informs drug discovery and risk prediction across ancestries.0 aStroke genetics informs drug discovery and risk prediction acros c2022 Sep 303 aPrevious genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
1 aMishra, Aniket1 aMalik, Rainer1 aHachiya, Tsuyoshi1 aJürgenson, Tuuli1 aNamba, Shinichi1 aPosner, Daniel, C1 aKamanu, Frederick, K1 aKoido, Masaru1 aLe Grand, Quentin1 aShi, Mingyang1 aHe, Yunye1 aGeorgakis, Marios, K1 aCaro, Ilana1 aKrebs, Kristi1 aLiaw, Yi-Ching1 aVaura, Felix, C1 aLin, Kuang1 aWinsvold, Bendik, Slagsvold1 aSrinivasasainagendra, Vinodh1 aParodi, Livia1 aBae, Hee-Joon1 aChauhan, Ganesh1 aChong, Michael, R1 aTomppo, Liisa1 aAkinyemi, Rufus1 aRoshchupkin, Gennady, V1 aHabib, Naomi1 aJee, Yon, Ho1 aThomassen, Jesper, Qvist1 aAbedi, Vida1 aCárcel-Márquez, Jara1 aNygaard, Marianne1 aLeonard, Hampton, L1 aYang, Chaojie1 aYonova-Doing, Ekaterina1 aKnol, Maria, J1 aLewis, Adam, J1 aJudy, Renae, L1 aAgo, Tetsuro1 aAmouyel, Philippe1 aArmstrong, Nicole, D1 aBakker, Mark, K1 aBartz, Traci, M1 aBennett, David, A1 aBis, Joshua, C1 aBordes, Constance1 aBørte, Sigrid1 aCain, Anael1 aRidker, Paul, M1 aCho, Kelly1 aChen, Zhengming1 aCruchaga, Carlos1 aCole, John, W1 aDe Jager, Phil, L1 ade Cid, Rafael1 aEndres, Matthias1 aFerreira, Leslie, E1 aGeerlings, Mirjam, I1 aGasca, Natalie, C1 aGudnason, Vilmundur1 aHata, Jun1 aHe, Jing1 aHeath, Alicia, K1 aHo, Yuk-Lam1 aHavulinna, Aki, S1 aHopewell, Jemma, C1 aHyacinth, Hyacinth, I1 aInouye, Michael1 aJacob, Mina, A1 aJeon, Christina, E1 aJern, Christina1 aKamouchi, Masahiro1 aKeene, Keith, L1 aKitazono, Takanari1 aKittner, Steven, J1 aKonuma, Takahiro1 aKumar, Amit1 aLacaze, Paul1 aLauner, Lenore, J1 aLee, Keon-Joo1 aLepik, Kaido1 aLi, Jiang1 aLi, Liming1 aManichaikul, Ani1 aMarkus, Hugh, S1 aMarston, Nicholas, A1 aMeitinger, Thomas1 aMitchell, Braxton, D1 aMontellano, Felipe, A1 aMorisaki, Takayuki1 aMosley, Thomas, H1 aNalls, Mike, A1 aNordestgaard, Børge, G1 aO'Donnell, Martin, J1 aOkada, Yukinori1 aOnland-Moret, Charlotte, N1 aOvbiagele, Bruce1 aPeters, Annette1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRosand, Jonathan1 aSabatine, Marc, S1 aSacco, Ralph, L1 aSaleheen, Danish1 aSandset, Else, Charlotte1 aSalomaa, Veikko1 aSargurupremraj, Muralidharan1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSchmidt, Carsten, O1 aShimizu, Atsushi1 aSmith, Nicholas, L1 aSloane, Kelly, L1 aSutoh, Yoichi1 aSun, Yan, V1 aTanno, Kozo1 aTiedt, Steffen1 aTatlisumak, Turgut1 aTorres-Aguila, Nuria, P1 aTiwari, Hemant, K1 aTrégouët, David-Alexandre1 aTrompet, Stella1 aTuladhar, Anil, Man1 aTybjærg-Hansen, Anne1 avan Vugt, Marion1 aVibo, Riina1 aVerma, Shefali, S1 aWiggins, Kerri, L1 aWennberg, Patrik1 aWoo, Daniel1 aWilson, Peter, W F1 aXu, Huichun1 aYang, Qiong1 aYoon, Kyungheon1 aMillwood, Iona, Y1 aGieger, Christian1 aNinomiya, Toshiharu1 aGrabe, Hans, J1 aJukema, Wouter1 aRissanen, Ina, L1 aStrbian, Daniel1 aKim, Young, Jin1 aChen, Pei-Hsin1 aMayerhofer, Ernst1 aHowson, Joanna, M M1 aIrvin, Marguerite, R1 aAdams, Hieab1 aWassertheil-Smoller, Sylvia1 aChristensen, Kaare1 aIkram, Mohammad, A1 aRundek, Tatjana1 aWorrall, Bradford, B1 aLathrop, Mark, G1 aRiaz, Moeen1 aSimonsick, Eleanor, M1 aKõrv, Janika1 aFrança, Paulo, H C1 aZand, Ramin1 aPrasad, Kameshwar1 aFrikke-Schmidt, Ruth1 ade Leeuw, Frank-Erik1 aLiman, Thomas1 aHaeusler, Karl, Georg1 aRuigrok, Ynte, M1 aHeuschmann, Peter, Ulrich1 aLongstreth, W T1 aJung, Keum, Ji1 aBastarache, Lisa1 aParé, Guillaume1 aDamrauer, Scott, M1 aChasman, Daniel, I1 aRotter, Jerome, I1 aAnderson, Christopher, D1 aZwart, John-Anker1 aNiiranen, Teemu, J1 aFornage, Myriam1 aLiaw, Yung-Po1 aSeshadri, Sudha1 aFernandez-Cadenas, Israel1 aWalters, Robin, G1 aRuff, Christian, T1 aOwolabi, Mayowa, O1 aHuffman, Jennifer, E1 aMilani, Lili1 aKamatani, Yoichiro1 aDichgans, Martin1 aDebette, Stephanie1 aCOMPASS Consortium1 aINVENT Consortium1 aDutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group1 aEstonian Biobank1 aPRECISEQ Consortium1 aFinnGen Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aMEGASTROKE Consortium1 aSIREN Consortium1 aChina Kadoorie Biobank Collaborative Group1 aVA Million Veteran Program1 aInternational Stroke Genetics Consortium (ISGC)1 aBiobank Japan1 aCHARGE Consortium1 aGIGASTROKE Consortium uhttps://chs-nhlbi.org/node/917206165nas a2200505 4500008004100000245012200041210006900163260001600232520464400248100003304892700002104925700001904946700001704965700002204982700001705004700001905021700001605040700001605056700002605072700002605098700001905124700002305143700002105166700002305187700002105210700002005231700002205251700001705273700002005290700002405310700002205334700002005356700002805376700002705404700002405431700001705455700002405472700002005496700002205516700002005538700002005558700002205578700002305600856003605623 2023 eng d00aComplexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.0 aComplexities of cerebral small vessel disease blood pressure and c2023 Aug 133 aIMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.
OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.
DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.
EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.
MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.
RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.
CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.
KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.
1 aSargurupremraj, Muralidharan1 aSoumaré, Aïcha1 aBis, Joshua, C1 aSurakka, Ida1 aJürgenson, Tuuli1 aJoly, Pierre1 aKnol, Maria, J1 aWang, Ruiqi1 aYang, Qiong1 aSatizabal, Claudia, L1 aGudjonsson, Alexander1 aMishra, Aniket1 aBouteloup, Vincent1 aPhuah, Chia-Ling1 aDuijn, Cornelia, M1 aCruchaga, Carlos1 aDufouil, Carole1 aChene, Geneviève1 aLopez, Oscar1 aPsaty, Bruce, M1 aTzourio, Christophe1 aAmouyel, Philippe1 aAdams, Hieab, H1 aJacqmin-Gadda, Hélène1 aIkram, Mohammad, Arfan1 aGudnason, Vilmundur1 aMilani, Lili1 aWinsvold, Bendik, S1 aHveem, Kristian1 aMatthews, Paul, M1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/950504607nas a2201201 4500008004100000022001400041245012100055210006900176260001300245300001400258490000700272520112800279100002001407700001901427700002101446700003201467700001601499700001501515700002301530700002801553700002001581700001701601700002401618700002201642700002201664700002101686700001801707700002801725700001701753700001701770700002001787700002001807700002801827700002001855700002101875700002801896700002401924700001701948700001901965700002101984700002002005700002302025700002102048700001702069700002402086700002402110700002202134700001902156700002302175700002202198700001902220700003302239700001802272700002202290700002302312700002002335700002002355700002602375700002102401700002902422700001702451700002102468700002102489700002002510700002902530700002102559700001602580700001802596700002502614700003002639700002202669700002702691700002002718700002302738700002402761700002402785700002202809700002002831700001802851700002102869700002002890700002102910700002202931700002302953700002302976700002002999700002003019700002803039700002303067700001903090700002303109700002003132700001903152700002203171700002803193700003003221700002403251700002403275700002103299700002803320700002103348856003603369 2023 eng d a1546-171800aMulti-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.0 aMultiancestry genomewide study identifies effector genes and dru c2023 Oct a1651-16640 v553 aCoronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.
1 aKavousi, Maryam1 aBos, Maxime, M1 aBarnes, Hanna, J1 aCardenas, Christian, L Lino1 aWong, Doris1 aLu, Haojie1 aHodonsky, Chani, J1 aLandsmeer, Lennart, P L1 aTurner, Adam, W1 aKho, Minjung1 aHasbani, Natalie, R1 ade Vries, Paul, S1 aBowden, Donald, W1 aChopade, Sandesh1 aDeelen, Joris1 aBenavente, Ernest, Diez1 aGuo, Xiuqing1 aHofer, Edith1 aHwang, Shih-Jen1 aLutz, Sharon, M1 aLyytikäinen, Leo-Pekka1 aSlenders, Lotte1 aSmith, Albert, V1 aStanislawski, Maggie, A1 avan Setten, Jessica1 aWong, Quenna1 aYanek, Lisa, R1 aBecker, Diane, M1 aBeekman, Marian1 aBudoff, Matthew, J1 aFeitosa, Mary, F1 aFinan, Chris1 aHilliard, Austin, T1 aKardia, Sharon, L R1 aKovacic, Jason, C1 aKral, Brian, G1 aLangefeld, Carl, D1 aLauner, Lenore, J1 aMalik, Shaista1 aHoesein, Firdaus, A A Mohame1 aMokry, Michal1 aSchmidt, Reinhold1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aTerry, James, G1 avan der Grond, Jeroen1 avan Meurs, Joyce1 aVliegenthart, Rozemarijn1 aXu, Jianzhao1 aYoung, Kendra, A1 aZilhão, Nuno, R1 aZweiker, Robert1 aAssimes, Themistocles, L1 aBecker, Lewis, C1 aBos, Daniel1 aCarr, Jeffrey1 aCupples, Adrienne, L1 ade Kleijn, Dominique, P V1 ade Winther, Menno1 aRuijter, Hester, M den1 aFornage, Myriam1 aFreedman, Barry, I1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aHokanson, John, E1 aIkram, Arfan, M1 aIšgum, Ivana1 aJacobs, David, R1 aKähönen, Mika1 aLange, Leslie, A1 aLehtimäki, Terho1 aPasterkamp, Gerard1 aRaitakari, Olli, T1 aSchmidt, Helena1 aSlagboom, Eline1 aUitterlinden, André, G1 aVernooij, Meike, W1 aBis, Joshua, C1 aFranceschini, Nora1 aPsaty, Bruce, M1 aPost, Wendy, S1 aRotter, Jerome, I1 aBjörkegren, Johan, L M1 aO'Donnell, Christopher, J1 aBielak, Lawrence, F1 aPeyser, Patricia, A1 aMalhotra, Rajeev1 avan der Laan, Sander, W1 aMiller, Clint, L uhttps://chs-nhlbi.org/node/950103043nas a2200361 4500008004100000022001400041245007400055210006900129260001600198520194700214100002002161700002702181700002202208700002802230700002302258700002302281700002702304700002902331700002102360700002302381700001902404700002202423700002802445700002602473700002102499700002102520700001802541700002002559700002002579700002202599700002402621856003602645 2023 eng d a1879-084400aProteomic prediction of incident heart failure and its main subtypes.0 aProteomic prediction of incident heart failure and its main subt c2023 Nov 083 aAIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables.
METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with nonparametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on NT-proBNP and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study (CHS).
CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to eight years, with predictor performance significantly improving for events occurring less than one year ahead, a finding replicated in an external cohort study. This article is protected by copyright. All rights reserved.
1 aEmilsson, Valur1 aJonsson, Brynjolfur, G1 aAustin, Thomas, R1 aGudmundsdottir, Valborg1 aAxelsson, Gisli, T1 aFrick, Elisabet, A1 aJonmundsson, Thorarinn1 aSteindorsdottir, Anna, E1 aLoureiro, Joseph1 aBrody, Jennifer, A1 aAspelund, Thor1 aLauner, Lenore, J1 aThorgeirsson, Gudmundur1 aKortekaas, Kirsten, A1 aLindeman, Jan, H1 aOrth, Anthony, P1 aLamb, John, R1 aPsaty, Bruce, M1 aKizer, Jorge, R1 aJennings, Lori, L1 aGudnason, Vilmundur uhttps://chs-nhlbi.org/node/9536