06326nas 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 a
Chronic 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/118304248nas a2200877 4500008004100000022001400041245015200055210006900207260001600276300001200292490000700304520170700311653001002018653002202028653000902050653001902059653001902078653001302097653004002110653001102150653001702161653003402178653001302212653001102225653001702236653000902253653001602262653001402278653003602292653001202328100001802340700002102358700001302379700002502392700002402417700002302441700001502464700002402479700001902503700002102522700002702543700002002570700002402590700002102614700002302635700001902658700002302677700002302700700001602723700002102739700002002760700001902780700002202799700002502821700002102846700002202867700002202889700001902911700001702930700002302947700002302970700002302993700001603016700002003032700002203052700002403074700002203098700002303120700002003143700001803163700002603181700001803207700001703225710009203242856003603334 2011 eng d a1460-208300aAssociation of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.0 aAssociation of genetic variation with systolic and diastolic blo c2011 Jun 01 a2273-840 v203 aThe prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
10aAdult10aAfrican Americans10aAged10aBlood Pressure10aCohort Studies10aDiastole10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aHypertension10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aYoung, Hunter, J1 aLi, Yali1 aDreisbach, Albert, W1 aKeating, Brendan, J1 aMusani, Solomon, K1 aLiu, Kiang1 aMorrison, Alanna, C1 aGanesh, Santhi1 aKutlar, Abdullah1 aRamachandran, Vasan, S1 aPolak, Josef, F1 aFabsitz, Richard, R1 aDries, Daniel, L1 aFarlow, Deborah, N1 aRedline, Susan1 aAdeyemo, Adebowale1 aHirschorn, Joel, N1 aSun, Yan, V1 aWyatt, Sharon, B1 aPenman, Alan, D1 aPalmas, Walter1 aRotter, Jerome, I1 aTownsend, Raymond, R1 aDoumatey, Ayo, P1 aTayo, Bamidele, O1 aMosley, Thomas, H1 aLyon, Helen, N1 aKang, Sun, J1 aRotimi, Charles, N1 aCooper, Richard, S1 aFranceschini, Nora1 aCurb, David1 aMartin, Lisa, W1 aEaton, Charles, B1 aKardia, Sharon, L R1 aTaylor, Herman, A1 aCaulfield, Mark, J1 aEhret, Georg, B1 aJohnson, Toby1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aLevy, Daniel1 aInternational Consortium for Blood Pressure Genome-wide Association Studies (ICBP-GWAS) uhttps://chs-nhlbi.org/node/127303940nas a2200757 4500008004100000022001400041245008100055210006900136260001300205300001200218490000700230520182400237653001002061653000902071653001102080653003802091653003402129653001302163653001102176653000902187653002702196653002302223653001602246653001402262653003602276100001902312700002202331700002102353700002202374700002902396700002302425700001602448700002302464700001602487700002302503700001802526700001202544700001902556700002102575700002202596700002302618700002802641700002302669700001902692700002202711700001602733700001602749700002202765700002202787700002102809700002102830700002602851700002002877700002102897700002502918700002102943700002402964700001902988700002703007700002103034700002403055700002203079700002203101700002303123856003603146 2011 eng d a1939-327X00aA bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium.0 abivariate genomewide approach to metabolic syndrome STAMPEED con c2011 Apr a1329-390 v603 aOBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
10aAdult10aAged10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMeta-Analysis as Topic10aMetabolic Syndrome10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide1 aKraja, Aldi, T1 aVaidya, Dhananjay1 aPankow, James, S1 aGoodarzi, Mark, O1 aAssimes, Themistocles, L1 aKullo, Iftikhar, J1 aSovio, Ulla1 aMathias, Rasika, A1 aSun, Yan, V1 aFranceschini, Nora1 aAbsher, Devin1 aLi, Guo1 aZhang, Qunyuan1 aFeitosa, Mary, F1 aGlazer, Nicole, L1 aHaritunians, Talin1 aHartikainen, Anna-Liisa1 aKnowles, Joshua, W1 aNorth, Kari, E1 aIribarren, Carlos1 aKral, Brian1 aYanek, Lisa1 aO'Reilly, Paul, F1 aMcCarthy, Mark, I1 aJaquish, Cashell1 aCouper, David, J1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aBecker, Lewis, C1 aProvince, Michael, A1 aBoerwinkle, Eric1 aQuertermous, Thomas1 aPalotie, Leena1 aJarvelin, Marjo-Riitta1 aBecker, Diane, M1 aKardia, Sharon, L R1 aRotter, Jerome, I1 aChen, Yii-Der Ida1 aBorecki, Ingrid, B uhttps://chs-nhlbi.org/node/127405938nas 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/127104453nas a2200889 4500008004100000022001400041245011700055210006900172260001300241300001300254490000600267520190600273653004202179653001002221653003902231653000902270653001202279653001102291653003002302653003202332653001702364653003402381653003102415653001102446653002802457653001102485653002802496653000902524653001602533653002202549653001402571653003602585653001402621100001802635700002202653700001802675700001902693700002302712700002302735700002002758700001702778700002402795700002002819700001902839700002002858700001802878700002102896700002902917700002102946700002202967700001802989700001603007700002303023700001203046700002403058700002503082700002303107700002303130700002303153700002303176700002203199700002203221700002303243700001703266700002403283700002203307700002403329700001803353700002503371700002503396700002303421700002503444700001503469700002103484710002203505856003603527 2011 eng d a1553-740400aGenetic association for renal traits among participants of African ancestry reveals new loci for renal function.0 aGenetic association for renal traits among participants of Afric c2011 Sep ae10022640 v73 aChronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
10aAdaptor Proteins, Vesicular Transport10aAdult10aAfrican Continental Ancestry Group10aAged10aAnimals10aFemale10aGene Knockdown Techniques10aGenetic Association Studies10aGenetic Loci10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKCNQ1 Potassium Channel10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aNeoplasm Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aZebrafish1 aLiu, Ching-Ti1 aGarnaas, Maija, K1 aTin, Adrienne1 aKöttgen, Anna1 aFranceschini, Nora1 aPeralta, Carmen, A1 ade Boer, Ian, H1 aLu, Xiaoning1 aAtkinson, Elizabeth1 aDing, Jingzhong1 aNalls, Michael1 aShriner, Daniel1 aCoresh, Josef1 aKutlar, Abdullah1 aBibbins-Domingo, Kirsten1 aSiscovick, David1 aAkylbekova, Ermeg1 aWyatt, Sharon1 aAstor, Brad1 aMychaleckjy, Josef1 aLi, Man1 aReilly, Muredach, P1 aTownsend, Raymond, R1 aAdeyemo, Adebowale1 aZonderman, Alan, B1 ade Andrade, Mariza1 aTurner, Stephen, T1 aMosley, Thomas, H1 aHarris, Tamara, B1 aRotimi, Charles, N1 aLiu, Yongmei1 aKardia, Sharon, L R1 aEvans, Michele, K1 aShlipak, Michael, G1 aKramer, Holly1 aFlessner, Michael, F1 aDreisbach, Albert, W1 aGoessling, Wolfram1 aCupples, Adrienne, L1 aKao, Linda1 aFox, Caroline, S1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/132707377nas a2201945 4500008004100000022001400041245014700055210006900202260001600271300001100287490000600298520192200304653001002226653001602236653000902252653002202261653001202283653002502295653003102320653001902351653004202370653001102412653003402423653001302457653001902470653001102489653002002500653000902520653001602529653003302545653001402578653003602592653001702628653001602645100002402661700002202685700002002707700001602727700002102743700001702764700002002781700002002801700002002821700001902841700001702860700002202877700002302899700002502922700001702947700002202964700002502986700002003011700001903031700002303050700002203073700001903095700002103114700001803135700002203153700001503175700002203190700002203212700002003234700002503254700002103279700002403300700001603324700001803340700002703358700002103385700002503406700001903431700001803450700002603468700002103494700002303515700001903538700002403557700002503581700002003606700001803626700003003644700002203674700002003696700002103716700002203737700001903759700002003778700001803798700002403816700001903840700001903859700001803878700002703896700001803923700002303941700002803964700002103992700001604013700001904029700001704048700002304065700001804088700002104106700001804127700002004145700001804165700002904183700002104212700002004233700003004253700001904283700002304302700002304325700001904348700002004367700002104387700001404408700002604422700002204448700002204470700002204492700002104514700002004535700002604555700002804581700001904609700002304628700001904651700002104670700002004691700001804711700002204729700001604751700002904767700002404796700002104820700002004841700001904861700002504880700002204905700002404927700002504951700001704976700002004993700002005013700001905033700001605052700002305068700002005091700002305111700001705134700002005151700002205171700002105193700003005214700001705244700002205261700002305283700002105306700001905327700002505346700002405371856003605395 2012 eng d a1942-326800aAssociation between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.0 aAssociation between chromosome 9p21 variants and the anklebrachi c2012 Feb 01 a100-120 v53 aBACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).
CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
10aAdult10aAge Factors10aAged10aAged, 80 and over10aAlleles10aAnkle Brachial Index10aChromosomes, Human, Pair 910aCohort Studies10aCyclin-Dependent Kinase Inhibitor p1510aFemale10aGenome-Wide Association Study10aGenotype10aHapMap Project10aHumans10aLogistic Models10aMale10aMiddle Aged10aPeripheral Vascular Diseases10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aSex Factors1 aMurabito, Joanne, M1 aWhite, Charles, C1 aKavousi, Maryam1 aSun, Yan, V1 aFeitosa, Mary, F1 aNambi, Vijay1 aLamina, Claudia1 aSchillert, Arne1 aCoassin, Stefan1 aBis, Joshua, C1 aBroer, Linda1 aCrawford, Dana, C1 aFranceschini, Nora1 aFrikke-Schmidt, Ruth1 aHaun, Margot1 aHolewijn, Suzanne1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aKiechl, Stefan1 aKollerits, Barbara1 aMontasser, May, E1 aNolte, Ilja, M1 aRudock, Megan, E1 aSenft, Andrea1 aTeumer, Alexander1 aHarst, Pim1 aVitart, Veronique1 aWaite, Lindsay, L1 aWood, Andrew, R1 aWassel, Christina, L1 aAbsher, Devin, M1 aAllison, Matthew, A1 aAmin, Najaf1 aArnold, Alice1 aAsselbergs, Folkert, W1 aAulchenko, Yurii1 aBandinelli, Stefania1 aBarbalic, Maja1 aBoban, Mladen1 aBrown-Gentry, Kristin1 aCouper, David, J1 aCriqui, Michael, H1 aDehghan, Abbas1 aHeijer, Martin, den1 aDieplinger, Benjamin1 aDing, Jingzhong1 aDörr, Marcus1 aEspinola-Klein, Christine1 aFelix, Stephan, B1 aFerrucci, Luigi1 aFolsom, Aaron, R1 aFraedrich, Gustav1 aGibson, Quince1 aGoodloe, Robert1 aGunjaca, Grgo1 aHaltmayer, Meinhard1 aHeiss, Gerardo1 aHofman, Albert1 aKieback, Arne1 aKiemeney, Lambertus, A1 aKolcic, Ivana1 aKullo, Iftikhar, J1 aKritchevsky, Stephen, B1 aLackner, Karl, J1 aLi, Xiaohui1 aLieb, Wolfgang1 aLohman, Kurt1 aMeisinger, Christa1 aMelzer, David1 aMohler, Emile, R1 aMudnic, Ivana1 aMueller, Thomas1 aNavis, Gerjan1 aOberhollenzer, Friedrich1 aOlin, Jeffrey, W1 aO'Connell, Jeff1 aO'Donnell, Christopher, J1 aPalmas, Walter1 aPenninx, Brenda, W1 aPetersmann, Astrid1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRantner, Barbara1 aRice, Ken1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSeldenrijk, Adrie1 aStadler, Marietta1 aSummerer, Monika1 aTanaka, Toshiko1 aTybjaerg-Hansen, Anne1 aUitterlinden, André, G1 aGilst, Wiek, H1 aVermeulen, Sita, H1 aWild, Sarah, H1 aWild, Philipp, S1 aWilleit, Johann1 aZeller, Tanja1 aZemunik, Tatijana1 aZgaga, Lina1 aAssimes, Themistocles, L1 aBlankenberg, Stefan1 aBoerwinkle, Eric1 aCampbell, Harry1 aCooke, John, P1 ade Graaf, Jacqueline1 aHerrington, David1 aKardia, Sharon, L R1 aMitchell, Braxton, D1 aMurray, Anna1 aMünzel, Thomas1 aNewman, Anne, B1 aOostra, Ben, A1 aRudan, Igor1 aShuldiner, Alan, R1 aSnieder, Harold1 aDuijn, Cornelia, M1 aVölker, Uwe1 aWright, Alan, F1 aWichmann, H-Erich1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aLiu, Yongmei1 aHayward, Caroline1 aBorecki, Ingrid, B1 aZiegler, Andreas1 aNorth, Kari, E1 aCupples, Adrienne, L1 aKronenberg, Florian uhttps://chs-nhlbi.org/node/135907422nas a2202413 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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/137707748nas a2202497 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2012 eng d a1546-171800aMeta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.0 aMetaanalyses identify 13 loci associated with age at menopause a c2012 Jan 22 a260-80 v443 aTo newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
10aAge Factors10aDNA Helicases10aDNA Polymerase gamma10aDNA Primase10aDNA Repair10aDNA Repair Enzymes10aDNA-Directed DNA Polymerase10aEuropean Continental Ancestry Group10aExodeoxyribonucleases10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aImmunity10aMenopause10aPolymorphism, Single Nucleotide10aProteins1 aStolk, Lisette1 aPerry, John, R B1 aChasman, Daniel, I1 aHe, Chunyan1 aMangino, Massimo1 aSulem, Patrick1 aBarbalic, Maja1 aBroer, Linda1 aByrne, Enda, M1 aErnst, Florian1 aEsko, Tõnu1 aFranceschini, Nora1 aGudbjartsson, Daniel, F1 aHottenga, Jouke-Jan1 aKraft, Peter1 aMcArdle, Patrick, F1 aPorcu, Eleonora1 aShin, So-Youn1 aSmith, Albert, V1 avan Wingerden, Sophie1 aZhai, Guangju1 aZhuang, Wei, V1 aAlbrecht, Eva1 aAlizadeh, Behrooz, Z1 aAspelund, Thor1 aBandinelli, Stefania1 aLauc, Lovorka, Barac1 aBeckmann, Jacques, S1 aBoban, Mladen1 aBoerwinkle, Eric1 aBroekmans, Frank, J1 aBurri, Andrea1 aCampbell, Harry1 aChanock, Stephen, J1 aChen, Constance1 aCornelis, Marilyn, C1 aCorre, Tanguy1 aCoviello, Andrea, D1 aD'Adamo, Pio1 aDavies, Gail1 ade Faire, Ulf1 aGeus, Eco, J C1 aDeary, Ian, J1 aDedoussis, George, V Z1 aDeloukas, Panagiotis1 aEbrahim, Shah1 aEiriksdottir, Gudny1 aEmilsson, Valur1 aEriksson, Johan, G1 aFauser, Bart, C J M1 aFerreli, Liana1 aFerrucci, Luigi1 aFischer, Krista1 aFolsom, Aaron, R1 aGarcia, Melissa, E1 aGasparini, Paolo1 aGieger, Christian1 aGlazer, Nicole1 aGrobbee, Diederick, E1 aHall, Per1 aHaller, Toomas1 aHankinson, Susan, E1 aHass, Merli1 aHayward, Caroline1 aHeath, Andrew, C1 aHofman, Albert1 aIngelsson, Erik1 aJanssens, Cecile, J W1 aJohnson, Andrew, D1 aKarasik, David1 aKardia, Sharon, L R1 aKeyzer, Jules1 aKiel, Douglas, P1 aKolcic, Ivana1 aKutalik, Zoltán1 aLahti, Jari1 aLai, Sandra1 aLaisk, Triin1 aLaven, Joop, S E1 aLawlor, Debbie, A1 aLiu, Jianjun1 aLopez, Lorna, M1 aLouwers, Yvonne, V1 aMagnusson, Patrik, K E1 aMarongiu, Mara1 aMartin, Nicholas, G1 aKlaric, Irena, Martinovic1 aMasciullo, Corrado1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMelzer, David1 aMooser, Vincent1 aNavarro, Pau1 aNewman, Anne, B1 aNyholt, Dale, R1 aOnland-Moret, Charlotte, N1 aPalotie, Aarno1 aParé, Guillaume1 aParker, Alex, N1 aPedersen, Nancy, L1 aPeeters, Petra, H M1 aPistis, Giorgio1 aPlump, Andrew, S1 aPolasek, Ozren1 aPop, Victor, J M1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRehnberg, Emil1 aRotter, Jerome, I1 aRudan, Igor1 aSala, Cinzia1 aSalumets, Andres1 aScuteri, Angelo1 aSingleton, Andrew1 aSmith, Jennifer, A1 aSnieder, Harold1 aSoranzo, Nicole1 aStacey, Simon, N1 aStarr, John, M1 aStathopoulou, Maria, G1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStyrkarsdottir, Unnur1 aSun, Yan, V1 aTenesa, Albert1 aThorand, Barbara1 aToniolo, Daniela1 aTryggvadottir, Laufey1 aTsui, Kim1 aUlivi, Sheila1 avan Dam, Rob, M1 aSchouw, Yvonne, T1 avan Gils, Carla, H1 avan Nierop, Peter1 aVink, Jacqueline, M1 aVisscher, Peter, M1 aVoorhuis, Marlies1 aWaeber, Gérard1 aWallaschofski, Henri1 aWichmann, Erich, H1 aWiden, Elisabeth1 avan Gent, Colette, J M Wijnan1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZemunik, Tatijana1 aZgaga, Lina1 aZillikens, Carola, M1 aZygmunt, Marek1 aArnold, Alice, M1 aBoomsma, Dorret, I1 aBuring, Julie, E1 aCrisponi, Laura1 aDemerath, Ellen, W1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHu, Frank, B1 aHunter, David, J1 aLauner, Lenore, J1 aMetspalu, Andres1 aMontgomery, Grant, W1 aOostra, Ben, A1 aRidker, Paul, M1 aSanna, Serena1 aSchlessinger, David1 aSpector, Tim, D1 aStefansson, Kari1 aStreeten, Elizabeth, A1 aThorsteinsdottir, Unnur1 aUda, Manuela1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aMurray, Anna1 aMurabito, Joanne, M1 aVisser, Jenny, A1 aLunetta, Kathryn, L1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/136007440nas a2202173 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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/628806047nas a2201393 4500008004100000022001400041245010400055210006900159260000900228300001300237490000600250520209200256653001402348653003902362653002602401653004002427653001102467653001702478653003402495653001102529653000902540653001202549653003602561653002002597100001802617700001902635700002002654700001802674700002302692700001902715700002402734700002102758700002202779700001502801700002802816700002502844700001602869700002202885700002202907700002302929700001802952700001202970700002802982700001803010700001503028700002403043700002403067700002803091700001903119700001703138700002503155700001603180700002203196700001903218700002003237700002303257700002203280700002803302700001703330700002003347700002303367700001503390700001703405700002003422700002103442700001803463700002203481700002303503700002303526700003103549700002203580700002003602700001703622700002803639700001403667700002403681700002403705700002203729700002103751700001803772700001403790700003203804700002503836700002403861700001703885700002403902700002103926700002103947700002803968700002203996700002004018700002104038700002104059700002704080700002204107700002304129700002104152700002404173700001704197700002404214700002304238700002204261700002104283700002504304700002304329700002204352700001904374700002204393700002104415700002804436700002304464700001804487700002204505700002504527700002504552700001904577700002104596856003604617 2013 eng d a1553-740400aGenome-wide association of body fat distribution in African ancestry populations suggests new loci.0 aGenomewide association of body fat distribution in African ances c2013 ae10036810 v93 aCentral obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
10aAdiposity10aAfrican Continental Ancestry Group10aBody Fat Distribution10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aObesity10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aLiu, Ching-Ti1 aMonda, Keri, L1 aTaylor, Kira, C1 aLange, Leslie1 aDemerath, Ellen, W1 aPalmas, Walter1 aWojczynski, Mary, K1 aEllis, Jaclyn, C1 aVitolins, Mara, Z1 aLiu, Simin1 aPapanicolaou, George, J1 aIrvin, Marguerite, R1 aXue, Luting1 aGriffin, Paula, J1 aNalls, Michael, A1 aAdeyemo, Adebowale1 aLiu, Jiankang1 aLi, Guo1 aRuiz-Narvaez, Edward, A1 aChen, Wei-Min1 aChen, Fang1 aHenderson, Brian, E1 aMillikan, Robert, C1 aAmbrosone, Christine, B1 aStrom, Sara, S1 aGuo, Xiuqing1 aAndrews, Jeanette, S1 aSun, Yan, V1 aMosley, Thomas, H1 aYanek, Lisa, R1 aShriner, Daniel1 aHaritunians, Talin1 aRotter, Jerome, I1 aSpeliotes, Elizabeth, K1 aSmith, Megan1 aRosenberg, Lynn1 aMychaleckyj, Josyf1 aNayak, Uma1 aSpruill, Ida1 aGarvey, Timothy1 aPettaway, Curtis1 aNyante, Sarah1 aBandera, Elisa, V1 aBritton, Angela, F1 aZonderman, Alan, B1 aRasmussen-Torvik, Laura, J1 aChen, Yii-Der Ida1 aDing, Jingzhong1 aLohman, Kurt1 aKritchevsky, Stephen, B1 aZhao, Wei1 aPeyser, Patricia, A1 aKardia, Sharon, L R1 aKabagambe, Edmond1 aBroeckel, Ulrich1 aChen, Guanjie1 aZhou, Jie1 aWassertheil-Smoller, Sylvia1 aNeuhouser, Marian, L1 aRampersaud, Evadnie1 aPsaty, Bruce1 aKooperberg, Charles1 aManson, JoAnn, E1 aKuller, Lewis, H1 aOchs-Balcom, Heather, M1 aJohnson, Karen, C1 aSucheston, Lara1 aOrdovas, Jose, M1 aPalmer, Julie, R1 aHaiman, Christopher, A1 aMcKnight, Barbara1 aHoward, Barbara, V1 aBecker, Diane, M1 aBielak, Lawrence, F1 aLiu, Yongmei1 aAllison, Matthew, A1 aGrant, Struan, F A1 aBurke, Gregory, L1 aPatel, Sanjay, R1 aSchreiner, Pamela, J1 aBorecki, Ingrid, B1 aEvans, Michele, K1 aTaylor, Herman1 aSale, Michèle, M1 aHoward, Virginia1 aCarlson, Christopher, S1 aRotimi, Charles, N1 aCushman, Mary1 aHarris, Tamara, B1 aReiner, Alexander, P1 aCupples, Adrienne, L1 aNorth, Kari, E1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/628709008nas a2202809 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2013 eng d a1546-171800aA meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.0 ametaanalysis identifies new loci associated with body mass index c2013 Jun a690-60 v453 aGenome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
10aAfrican Americans10aBody Mass Index10aCase-Control Studies10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aObesity10aPolymorphism, Single Nucleotide1 aMonda, Keri, L1 aChen, Gary, K1 aTaylor, Kira, C1 aPalmer, Cameron1 aEdwards, Todd, L1 aLange, Leslie, A1 aC Y Ng, Maggie1 aAdeyemo, Adebowale, A1 aAllison, Matthew, A1 aBielak, Lawrence, F1 aChen, Guanjie1 aGraff, Mariaelisa1 aIrvin, Marguerite, R1 aRhie, Suhn, K1 aLi, Guo1 aLiu, Yongmei1 aLiu, Youfang1 aLu, Yingchang1 aNalls, Michael, A1 aSun, Yan, V1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aAldrich, Melinda, C1 aAdemola, Adeyinka1 aAmos, Christopher, I1 aBandera, Elisa, V1 aBock, Cathryn, H1 aBritton, Angela1 aBroeckel, Ulrich1 aCai, Quiyin1 aCaporaso, Neil, E1 aCarlson, Chris, S1 aCarpten, John1 aCasey, Graham1 aChen, Wei-Min1 aChen, Fang1 aChen, Yii-der, I1 aChiang, Charleston, W K1 aCoetzee, Gerhard, A1 aDemerath, Ellen1 aDeming-Halverson, Sandra, L1 aDriver, Ryan, W1 aDubbert, Patricia1 aFeitosa, Mary, F1 aFeng, Ye1 aFreedman, Barry, I1 aGillanders, Elizabeth, M1 aGottesman, Omri1 aGuo, Xiuqing1 aHaritunians, Talin1 aHarris, Tamara1 aHarris, Curtis, C1 aHennis, Anselm, J M1 aHernandez, Dena, G1 aMcNeill, Lorna, H1 aHoward, Timothy, D1 aHoward, Barbara, V1 aHoward, Virginia, J1 aJohnson, Karen, C1 aKang, Sun, J1 aKeating, Brendan, J1 aKolb, Suzanne1 aKuller, Lewis, H1 aKutlar, Abdullah1 aLangefeld, Carl, D1 aLettre, Guillaume1 aLohman, Kurt1 aLotay, Vaneet1 aLyon, Helen1 aManson, JoAnn, E1 aMaixner, William1 aMeng, Yan, A1 aMonroe, Kristine, R1 aMorhason-Bello, Imran1 aMurphy, Adam, B1 aMychaleckyj, Josyf, C1 aNadukuru, Raj1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aWu, Suh-Yuh1 aLeske, Cristina1 aNeslund-Dudas, Christine1 aNeuhouser, Marian1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgunniyi, Adesola1 aOgundiran, Temidayo, O1 aOjengbede, Oladosu1 aOlopade, Olufunmilayo, I1 aPalmer, Julie, R1 aRuiz-Narvaez, Edward, A1 aPalmer, Nicholette, D1 aPress, Michael, F1 aRampersaud, Evandine1 aRasmussen-Torvik, Laura, J1 aRodriguez-Gil, Jorge, L1 aSalako, Babatunde1 aSchadt, Eric, E1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSiscovick, David1 aSmith, Shad, B1 aWassertheil-Smoller, Sylvia1 aSpeliotes, Elizabeth, K1 aSpitz, Margaret, R1 aSucheston, Lara1 aTaylor, Herman1 aTayo, Bamidele, O1 aTucker, Margaret, A1 aVan Den Berg, David, J1 aEdwards, Digna, R Velez1 aWang, Zhaoming1 aWiencke, John, K1 aWinkler, Thomas, W1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYang, James, J1 aLevin, Albert, M1 aYoung, Taylor, R1 aZakai, Neil, A1 aCushman, Mary1 aZanetti, Krista, A1 aZhao, Jing Hua1 aZhao, Wei1 aZheng, Yonglan1 aZhou, Jie1 aZiegler, Regina, G1 aZmuda, Joseph, M1 aFernandes, Jyotika, K1 aGilkeson, Gary, S1 aKamen, Diane, L1 aHunt, Kelly, J1 aSpruill, Ida, J1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aArnett, Donna, K1 aAtwood, Larry1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBorecki, Ingrid, B1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBurke, Gregory1 aChanock, Stephen, J1 aCooper, Richard, S1 aDing, Jingzhong1 aDuggan, David1 aEvans, Michele, K1 aFox, Caroline1 aGarvey, Timothy1 aBradfield, Jonathan, P1 aHakonarson, Hakon1 aGrant, Struan, F A1 aHsing, Ann1 aChu, Lisa1 aHu, Jennifer, J1 aHuo, Dezheng1 aIngles, Sue, A1 aJohn, Esther, M1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKardia, Sharon, L R1 aKittles, Rick, A1 aGoodman, Phyllis, J1 aKlein, Eric, A1 aKolonel, Laurence, N1 aLe Marchand, Loïc1 aLiu, Simin1 aMcKnight, Barbara1 aMillikan, Robert, C1 aMosley, Thomas, H1 aPadhukasahasram, Badri1 aWilliams, Keoki1 aPatel, Sanjay, R1 aPeters, Ulrike1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRotimi, Charles, N1 aRybicki, Benjamin, A1 aSale, Michèle, M1 aSchreiner, Pamela, J1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aStanford, Janet, L1 aStrom, Sara, S1 aThun, Michael, J1 aVitolins, Mara1 aZheng, Wei1 aMoore, Jason, H1 aWilliams, Scott, M1 aKetkar, Shamika1 aZhu, Xiaofeng1 aZonderman, Alan, B1 aKooperberg, Charles1 aPapanicolaou, George, J1 aHenderson, Brian, E1 aReiner, Alex, P1 aHirschhorn, Joel, N1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aNABEC Consortium1 aUKBEC Consortium1 aBioBank Japan Project1 aAGEN Consortium uhttps://chs-nhlbi.org/node/607803769nas a2200937 4500008004100000022001400041245009400055210006900149260001600218300001200234490000700246520111800253653002201371653001601393653002301409653004001432653001101472653001701483653002201500653003401522653001101556653001401567653001801581100002501599700001801624700001801642700002501660700002101685700001801706700002301724700002301747700002201770700001201792700002001804700002301824700002201847700002201869700002001891700002801911700002201939700002201961700002001983700002302003700001802026700002802044700001802072700002202090700002202112700001902134700002002153700001702173700002302190700002302213700002202236700002102258700001802279700002202297700002202319700002202341700002002363700002202383700001402405700001502419700002202434700002202456700002402478700002402502700002402526700001702550700002202567700001702589700002102606700002402627700002302651700002502674700002302699700002402722700002402746700002502770856003602795 2014 eng d a1460-208300aMeta-analysis of loci associated with age at natural menopause in African-American women.0 aMetaanalysis of loci associated with age at natural menopause in c2014 Jun 15 a3327-420 v233 aAge at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.
10aAfrican Americans10aAge Factors10aChromosomes, Human10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMenopause10aUnited States1 aChen, Christina, T L1 aLiu, Ching-Ti1 aChen, Gary, K1 aAndrews, Jeanette, S1 aArnold, Alice, M1 aDreyfus, Jill1 aFranceschini, Nora1 aGarcia, Melissa, E1 aKerr, Kathleen, F1 aLi, Guo1 aLohman, Kurt, K1 aMusani, Solomon, K1 aNalls, Michael, A1 aRaffel, Leslie, J1 aSmith, Jennifer1 aAmbrosone, Christine, B1 aBandera, Elisa, V1 aBernstein, Leslie1 aBritton, Angela1 aBrzyski, Robert, G1 aCappola, Anne1 aCarlson, Christopher, S1 aCouper, David1 aDeming, Sandra, L1 aGoodarzi, Mark, O1 aHeiss, Gerardo1 aJohn, Esther, M1 aLu, Xiaoning1 aLe Marchand, Loïc1 aMarciante, Kristin1 aMcKnight, Barbara1 aMillikan, Robert1 aNock, Nora, L1 aOlshan, Andrew, F1 aPress, Michael, F1 aVaiyda, Dhananjay1 aWoods, Nancy, F1 aTaylor, Herman, A1 aZhao, Wei1 aZheng, Wei1 aEvans, Michele, K1 aHarris, Tamara, B1 aHenderson, Brian, E1 aKardia, Sharon, L R1 aKooperberg, Charles1 aLiu, Yongmei1 aMosley, Thomas, H1 aPsaty, Bruce1 aWellons, Melissa1 aWindham, Beverly, G1 aZonderman, Alan, B1 aCupples, Adrienne, L1 aDemerath, Ellen, W1 aHaiman, Christopher1 aMurabito, Joanne, M1 aRajkovic, Aleksandar uhttps://chs-nhlbi.org/node/655207065nas a2201873 4500008004100000022001400041245015900055210006900214260001600283300001100299490000700310520180500317653000902122653002202131653001002153653002202163653001402185653001902199653001102218653003402229653001302263653001102276653000902287653002102296653001602317653003602333653001302369653001802382653002402400653002202424653002002446100002302466700003002489700001802519700001902537700001802556700001902574700001702593700002102610700002402631700002102655700001602676700002402692700003202716700002302748700001602771700001902787700002302806700001702829700001202846700002202858700002202880700002102902700002002923700002002943700002002963700002002983700001503003700001703018700001803035700001903053700002103072700002203093700001203115700001903127700001903146700002703165700001703192700002003209700002503229700001403254700001903268700001603287700001903303700002303322700002403345700001603369700001803385700002003403700001403423700002203437700001903459700002503478700002603503700002203529700002403551700001603575700001603591700001903607700002703626700002103653700002203674700002003696700001303716700002103729700002403750700002203774700001503796700002403811700002203835700002003857700001703877700001903894700001903913700002003932700001403952700002103966700002503987700002404012700002304036700002204059700002104081700001904102700001904121700002304140700002204163700002504185700002304210700001804233700001904251700002404270700002304294700002304317700002004340700001604360700002804376700002204404700003004426700002104456700002304477700002004500700002004520700001904540700002004559700002004579700002104599700002304620700002604643700002204669700002704691700002204718700002004740700001704760700002304777700002404800700002804824700002404852700003104876700002204907700002004929700001804949700002304967700001904990700002805009700002005037700002205057710007605079856003605155 2015 eng d a1873-240200aGenome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.0 aGenomewide studies of verbal declarative memory in nondemented o c2015 Apr 15 a749-630 v773 aBACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
10aAged10aAged, 80 and over10aAging10aApolipoproteins E10aClaudin-510aCohort Studies10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMemory Disorders10aMiddle Aged10aPolymorphism, Single Nucleotide10aProteins10aProteoglycans10aRegression Analysis10aSulfotransferases10aVerbal Learning1 aDebette, Stephanie1 aVerbaas, Carla, A Ibrahim1 aBressler, Jan1 aSchuur, Maaike1 aSmith, Albert1 aBis, Joshua, C1 aDavies, Gail1 aWolf, Christiane1 aGudnason, Vilmundur1 aChibnik, Lori, B1 aYang, Qiong1 aDeStefano, Anita, L1 ade Quervain, Dominique, J F1 aSrikanth, Velandai1 aLahti, Jari1 aGrabe, Hans, J1 aSmith, Jennifer, A1 aPriebe, Lutz1 aYu, Lei1 aKarbalai, Nazanin1 aHayward, Caroline1 aWilson, James, F1 aCampbell, Harry1 aPetrovic, Katja1 aFornage, Myriam1 aChauhan, Ganesh1 aYeo, Robin1 aBoxall, Ruth1 aBecker, James1 aStegle, Oliver1 aMather, Karen, A1 aChouraki, Vincent1 aSun, Qi1 aRose, Lynda, M1 aResnick, Susan1 aOldmeadow, Christopher1 aKirin, Mirna1 aWright, Alan, F1 aJonsdottir, Maria, K1 aAu, Rhoda1 aBecker, Albert1 aAmin, Najaf1 aNalls, Mike, A1 aTurner, Stephen, T1 aKardia, Sharon, L R1 aOostra, Ben1 aWindham, Gwen1 aCoker, Laura, H1 aZhao, Wei1 aKnopman, David, S1 aHeiss, Gerardo1 aGriswold, Michael, E1 aGottesman, Rebecca, F1 aVitart, Veronique1 aHastie, Nicholas, D1 aZgaga, Lina1 aRudan, Igor1 aPolasek, Ozren1 aHolliday, Elizabeth, G1 aSchofield, Peter1 aChoi, Seung, Hoan1 aTanaka, Toshiko1 aAn, Yang1 aPerry, Rodney, T1 aKennedy, Richard, E1 aSale, Michèle, M1 aWang, Jing1 aWadley, Virginia, G1 aLiewald, David, C1 aRidker, Paul, M1 aGow, Alan, J1 aPattie, Alison1 aStarr, John, M1 aPorteous, David1 aLiu, Xuan1 aThomson, Russell1 aArmstrong, Nicola, J1 aEiriksdottir, Gudny1 aAssareh, Arezoo, A1 aKochan, Nicole, A1 aWiden, Elisabeth1 aPalotie, Aarno1 aHsieh, Yi-Chen1 aEriksson, Johan, G1 aVogler, Christian1 avan Swieten, John, C1 aShulman, Joshua, M1 aBeiser, Alexa1 aRotter, Jerome1 aSchmidt, Carsten, O1 aHoffmann, Wolfgang1 aNöthen, Markus, M1 aFerrucci, Luigi1 aAttia, John1 aUitterlinden, André, G1 aAmouyel, Philippe1 aDartigues, Jean-François1 aAmieva, Hélène1 aRäikkönen, Katri1 aGarcia, Melissa1 aWolf, Philip, A1 aHofman, Albert1 aLongstreth, W T1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aDeJager, Philip, L1 aSachdev, Perminder, S1 aSchmidt, Reinhold1 aBreteler, Monique, M B1 aTeumer, Alexander1 aLopez, Oscar, L1 aCichon, Sven1 aChasman, Daniel, I1 aGrodstein, Francine1 aMüller-Myhsok, Bertram1 aTzourio, Christophe1 aPapassotiropoulos, Andreas1 aBennett, David, A1 aIkram, Arfan, M1 aDeary, Ian, J1 aDuijn, Cornelia, M1 aLauner, Lenore1 aFitzpatrick, Annette, L1 aSeshadri, Sudha1 aMosley, Thomas, H1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium uhttps://chs-nhlbi.org/node/668404127nas a2200877 4500008004100000022001400041245007800055210006900133260001300202300001000215490000700225520166400232653000901896653002201905653002201927653002801949653001901977653001101996653002802007653003502035653003402070653001102104653001402115653000902129653001602138653003602154653002702190100001702217700002102234700001802255700002102273700002102294700002402315700002202339700002302361700002102384700002002405700001202425700002102437700001902458700002402477700002402501700002402525700002002549700002302569700001902592700002202611700002402633700002102657700001902678700002002697700001802717700002002735700002602755700002202781700002002803700002202823700002202845700002802867700001402895700002502909700002202934700002002956700002402976700002203000700001903022700002203041700002103063700002003084700002303104700001903127700002003146700002303166700002403189856003603213 2015 eng d a1758-535X00aGWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.0 aGWAS of longevity in CHARGE consortium confirms APOE and FOXO3 c c2015 Jan a110-80 v703 aBACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.
METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.
RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).
CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.
10aAged10aAged, 80 and over10aApolipoproteins E10aCell Adhesion Molecules10aCohort Studies10aFemale10aForkhead Box Protein O310aForkhead Transcription Factors10aGenome-Wide Association Study10aHumans10aLongevity10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Kainic Acid1 aBroer, Linda1 aBuchman, Aron, S1 aDeelen, Joris1 aEvans, Daniel, S1 aFaul, Jessica, D1 aLunetta, Kathryn, L1 aSebastiani, Paola1 aSmith, Jennifer, A1 aSmith, Albert, V1 aTanaka, Toshiko1 aYu, Lei1 aArnold, Alice, M1 aAspelund, Thor1 aBenjamin, Emelia, J1 aDe Jager, Philip, L1 aEirkisdottir, Gudny1 aEvans, Denis, A1 aGarcia, Melissa, E1 aHofman, Albert1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKiel, Douglas, P1 aOostra, Ben, A1 aOrwoll, Eric, S1 aParimi, Neeta1 aPsaty, Bruce, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSeshadri, Sudha1 aSingleton, Andrew1 aTiemeier, Henning1 aUitterlinden, André, G1 aZhao, Wei1 aBandinelli, Stefania1 aBennett, David, A1 aFerrucci, Luigi1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aKarasik, David1 aLauner, Lenore, J1 aPerls, Thomas, T1 aSlagboom, Eline1 aTranah, Gregory, J1 aWeir, David, R1 aNewman, Anne, B1 aDuijn, Cornelia, M1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/655006153nas 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/668305220nas a2201201 4500008004100000022001400041245010300055210006900158260001600227300000800243490000700251520181700258100002002075700001802095700002302113700002602136700002302162700002002185700002002205700002202225700001902247700001702266700002302283700001602306700002202322700001702344700001802361700001802379700002802397700001902425700001902444700002002463700002202483700002202505700001702527700002302544700001302567700002302580700001902603700002302622700002202645700002102667700002102688700001802709700001602727700001402743700002402757700002902781700002102810700002502831700001802856700002002874700002002894700002102914700001902935700001902954700002202973700002102995700001403016700001603030700002003046700001903066700001903085700002003104700001903124700002503143700002203168700002403190700001903214700002303233700002403256700002403280700002103304700002503325700002503350700002503375700002003400700002603420700002203446700002203468700002303490700002803513700002603541700002103567700002203588700001703610700002303627700001803650700002203668700001903690700002003709700001603729700002903745700002103774700002103795700002103816700002603837700002403863700001903887710002703906710004903933856003603982 2016 eng d a1474-760X00aDNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.0 aDNA methylation signatures of chronic lowgrade inflammation are c2016 Dec 12 a2550 v173 aBACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
1 aLigthart, Symen1 aMarzi, Carola1 aAslibekyan, Stella1 aMendelson, Michael, M1 aConneely, Karen, N1 aTanaka, Toshiko1 aColicino, Elena1 aWaite, Lindsay, L1 aJoehanes, Roby1 aGuan, Weihua1 aBrody, Jennifer, A1 aElks, Cathy1 aMarioni, Riccardo1 aJhun, Min, A1 aAgha, Golareh1 aBressler, Jan1 aWard-Caviness, Cavin, K1 aChen, Brian, H1 aHuan, Tianxiao1 aBakulski, Kelly1 aSalfati, Elias, L1 aFiorito, Giovanni1 aWahl, Simone1 aSchramm, Katharina1 aSha, Jin1 aHernandez, Dena, G1 aJust, Allan, C1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aPilling, Luke, C1 aPankow, James, S1 aTsao, Phil, S1 aLiu, Chunyu1 aZhao, Wei1 aGuarrera, Simonetta1 aMichopoulos, Vasiliki, J1 aSmith, Alicia, K1 aPeters, Marjolein, J1 aMelzer, David1 aVokonas, Pantel1 aFornage, Myriam1 aProkisch, Holger1 aBis, Joshua, C1 aChu, Audrey, Y1 aHerder, Christian1 aGrallert, Harald1 aYao, Chen1 aShah, Sonia1 aMcRae, Allan, F1 aLin, Honghuang1 aHorvath, Steve1 aFallin, Daniele1 aHofman, Albert1 aWareham, Nicholas, J1 aWiggins, Kerri, L1 aFeinberg, Andrew, P1 aStarr, John, M1 aVisscher, Peter, M1 aMurabito, Joanne, M1 aKardia, Sharon, L R1 aAbsher, Devin, M1 aBinder, Elisabeth, B1 aSingleton, Andrew, B1 aBandinelli, Stefania1 aPeters, Annette1 aWaldenberger, Melanie1 aMatullo, Giuseppe1 aSchwartz, Joel, D1 aDemerath, Ellen, W1 aUitterlinden, André, G1 avan Meurs, Joyce, B J1 aFranco, Oscar, H1 aChen, Yii-Der Ida1 aLevy, Daniel1 aTurner, Stephen, T1 aDeary, Ian, J1 aRessler, Kerry, J1 aDupuis, Josée1 aFerrucci, Luigi1 aOng, Ken, K1 aAssimes, Themistocles, L1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aArnett, Donna, K1 aBaccarelli, Andrea, A1 aBenjamin, Emelia, J1 aDehghan, Abbas1 aWHI-EMPC Investigators1 aCHARGE epigenetics of Coronary Heart Disease uhttps://chs-nhlbi.org/node/734905010nas a2201129 4500008004100000022001400041245004800055210004700103260001300150300001200163490000600175520193900181100001902120700001902139700002502158700002102183700002502204700002402229700001702253700001202270700001902282700002302301700002902324700002302353700002302376700002102399700001802420700002102438700001702459700001902476700002002495700001702515700001302532700002102545700002002566700001402586700002302600700001802623700002002641700001902661700001602680700002602696700001402722700002102736700002002757700002202777700002302799700001902822700001902841700002002860700002502880700002502905700002502930700001502955700002002970700001802990700002403008700002803032700001903060700001903079700002003098700001603118700002303134700002303157700002503180700002503205700002303230700001803253700002103271700002103292700002503313700002003338700002003358700002003378700002403398700001803422700001903440700002403459700001903483700002203502700002303524700002203547700002403569700001803593700002603611700002603637700002103663700002103684700001603705700001703721700002603738700001803764700002003782700001703802700002503819856003603844 2016 eng d a1942-326800aEpigenetic Signatures of Cigarette Smoking.0 aEpigenetic Signatures of Cigarette Smoking c2016 Oct a436-4470 v93 aBACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.
METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.
CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
1 aJoehanes, Roby1 aJust, Allan, C1 aMarioni, Riccardo, E1 aPilling, Luke, C1 aReynolds, Lindsay, M1 aMandaviya, Pooja, R1 aGuan, Weihua1 aXu, Tao1 aElks, Cathy, E1 aAslibekyan, Stella1 aMoreno-Macias, Hortensia1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aDhingra, Radhika1 aYousefi, Paul1 aPankow, James, S1 aKunze, Sonja1 aShah, Sonia, H1 aMcRae, Allan, F1 aLohman, Kurt1 aSha, Jin1 aAbsher, Devin, M1 aFerrucci, Luigi1 aZhao, Wei1 aDemerath, Ellen, W1 aBressler, Jan1 aGrove, Megan, L1 aHuan, Tianxiao1 aLiu, Chunyu1 aMendelson, Michael, M1 aYao, Chen1 aKiel, Douglas, P1 aPeters, Annette1 aWang-Sattler, Rui1 aVisscher, Peter, M1 aWray, Naomi, R1 aStarr, John, M1 aDing, Jingzhong1 aRodriguez, Carlos, J1 aWareham, Nicholas, J1 aIrvin, Marguerite, R1 aZhi, Degui1 aBarrdahl, Myrto1 aVineis, Paolo1 aAmbatipudi, Srikant1 aUitterlinden, André, G1 aHofman, Albert1 aSchwartz, Joel1 aColicino, Elena1 aHou, Lifang1 aVokonas, Pantel, S1 aHernandez, Dena, G1 aSingleton, Andrew, B1 aBandinelli, Stefania1 aTurner, Stephen, T1 aWare, Erin, B1 aSmith, Alicia, K1 aKlengel, Torsten1 aBinder, Elisabeth, B1 aPsaty, Bruce, M1 aTaylor, Kent, D1 aGharib, Sina, A1 aSwenson, Brenton, R1 aLiang, Liming1 aDeMeo, Dawn, L1 aO'Connor, George, T1 aHerceg, Zdenko1 aRessler, Kerry, J1 aConneely, Karen, N1 aSotoodehnia, Nona1 aKardia, Sharon, L R1 aMelzer, David1 aBaccarelli, Andrea, A1 avan Meurs, Joyce, B J1 aRomieu, Isabelle1 aArnett, Donna, K1 aOng, Ken, K1 aLiu, Yongmei1 aWaldenberger, Melanie1 aDeary, Ian, J1 aFornage, Myriam1 aLevy, Daniel1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/726104458nas a2200937 4500008004100000022001400041245009600055210006900151260001300220300001200233490000700245520181500252100002102067700002002088700001902108700001602127700001802143700002002161700002302181700002102204700002602225700001702251700002102268700002202289700001702311700002402328700002102352700002102373700002302394700002202417700001202439700001902451700002102470700002202491700002402513700002002537700002102557700002302578700002702601700002402628700001902652700001902671700002002690700001902710700002202729700001702751700001702768700002602785700002202811700002802833700001902861700002102880700002302901700002802924700001702952700001902969700001902988700002003007700001403027700002403041700002103065700002203086700002403108700001803132700002003150700002203170700002403192700001903216700002803235700002003263700002003283700002403303700002603327700001803353700002503371700002003396700002303416700002103439700002403460856003603484 2016 eng d a1474-972600aGWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.0 aGWAS analysis of handgrip and lower body strength in older adult c2016 Oct a792-8000 v153 aDecline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
1 aMatteini, Amy, M1 aTanaka, Toshiko1 aKarasik, David1 aAtzmon, Gil1 aChou, Wen-Chi1 aEicher, John, D1 aJohnson, Andrew, D1 aArnold, Alice, M1 aCallisaya, Michele, L1 aDavies, Gail1 aEvans, Daniel, S1 aHoltfreter, Birte1 aLohman, Kurt1 aLunetta, Kathryn, L1 aMangino, Massimo1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTeumer, Alexander1 aYu, Lei1 aArking, Dan, E1 aBuchman, Aron, S1 aChibinik, Lori, B1 aDe Jager, Philip, L1 aEvans, Denis, A1 aFaul, Jessica, D1 aGarcia, Melissa, E1 aGillham-Nasenya, Irina1 aGudnason, Vilmundur1 aHofman, Albert1 aHsu, Yi-Hsiang1 aIttermann, Till1 aLahousse, Lies1 aLiewald, David, C1 aLiu, Yongmei1 aLopez, Lorna1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSiggeirsdottir, Kristin1 aStarr, John, M1 aThomson, Russell1 aTranah, Gregory, J1 aUitterlinden, André, G1 aVölker, Uwe1 aVölzke, Henry1 aWeir, David, R1 aYaffe, Kristine1 aZhao, Wei1 aZhuang, Wei, Vivian1 aZmuda, Joseph, M1 aBennett, David, A1 aCummings, Steven, R1 aDeary, Ian, J1 aFerrucci, Luigi1 aHarris, Tamara, B1 aKardia, Sharon, L R1 aKocher, Thomas1 aKritchevsky, Stephen, B1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aSpector, Timothy, D1 aSrikanth, Velandai, K1 aWindham, Gwen1 aZillikens, Carola, M1 aNewman, Anne, B1 aWalston, Jeremy, D1 aKiel, Douglas, P1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/714204937nas 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/726405818nas a2201705 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520107200254100002201326700002301348700002501371700002001396700002501416700002201441700001801463700002201481700002501503700002001528700002301548700002001571700003001591700001901621700002301640700002201663700001701685700001901702700001801721700001901739700001901758700002801777700001601805700002401821700002001845700002401865700002001889700002301909700001801932700001701950700001901967700002701986700001802013700001902031700001702050700001502067700001602082700002102098700002302119700001602142700002202158700002502180700002102205700001802226700002002244700002502264700001302289700002002302700002402322700001802346700002002364700002302384700002302407700002102430700002502451700002402476700001602500700003202516700002002548700002102568700002202589700002402611700002002635700002102655700002502676700001902701700002002720700002802740700001902768700001902787700001702806700002602823700001802849700002202867700001502889700002002904700002702924700001502951700002002966700002102986700001903007700002303026700001903049700002303068700001703091700002003108700002003128700002603148700002203174700002003196700001803216700002103234700002003255700002303275700001703298700001903315700002803334700002003362700001903382700002103401700001903422700001603441700002903457700002103486700002403507700002003531700002003551700002303571700001903594700001803613700002103631700002103652700001903673700002003692700002103712700002003733700002403753700002103777700001903798700002303817700002203840700002103862700001903883700001803902700002003920700002103940700002003961700003003981700002304011700002304034700001904057856003604076 2016 eng d a1460-208300aA meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.0 ametaanalysis of 120 246 individuals identifies 18 new loci for f c2016 Jan 15 a358-700 v253 aGenome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
1 ade Vries, Paul, S1 aChasman, Daniel, I1 aSabater-Lleal, Maria1 aChen, Ming-Huei1 aHuffman, Jennifer, E1 aSteri, Maristella1 aTang, Weihong1 aTeumer, Alexander1 aMarioni, Riccardo, E1 aGrossmann, Vera1 aHottenga, Jouke, J1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aZhao, Jing Hua1 aBrody, Jennifer, A1 aKleber, Marcus, E1 aGuo, Xiuqing1 aWang, Jie, Jin1 aAuer, Paul, L1 aAttia, John, R1 aYanek, Lisa, R1 aAhluwalia, Tarunveer, S1 aLahti, Jari1 aVenturini, Cristina1 aTanaka, Toshiko1 aBielak, Lawrence, F1 aJoshi, Peter, K1 aRocanin-Arjo, Ares1 aKolcic, Ivana1 aNavarro, Pau1 aRose, Lynda, M1 aOldmeadow, Christopher1 aRiess, Helene1 aMazur, Johanna1 aBasu, Saonli1 aGoel, Anuj1 aYang, Qiong1 aGhanbari, Mohsen1 aWillemsen, Gonneke1 aRumley, Ann1 aFiorillo, Edoardo1 ade Craen, Anton, J M1 aGrotevendt, Anne1 aScott, Robert1 aTaylor, Kent, D1 aDelgado, Graciela, E1 aYao, Jie1 aKifley, Annette1 aKooperberg, Charles1 aQayyum, Rehan1 aLopez, Lorna, M1 aBerentzen, Tina, L1 aRäikkönen, Katri1 aMangino, Massimo1 aBandinelli, Stefania1 aPeyser, Patricia, A1 aWild, Sarah1 aTrégouët, David-Alexandre1 aWright, Alan, F1 aMarten, Jonathan1 aZemunik, Tatijana1 aMorrison, Alanna, C1 aSennblad, Bengt1 aTofler, Geoffrey1 ade Maat, Moniek, P M1 aGeus, Eco, J C1 aLowe, Gordon, D1 aZoledziewska, Magdalena1 aSattar, Naveed1 aBinder, Harald1 aVölker, Uwe1 aWaldenberger, Melanie1 aKhaw, Kay-Tee1 aMcKnight, Barbara1 aHuang, Jie1 aJenny, Nancy, S1 aHolliday, Elizabeth, G1 aQi, Lihong1 aMcevoy, Mark, G1 aBecker, Diane, M1 aStarr, John, M1 aSarin, Antti-Pekka1 aHysi, Pirro, G1 aHernandez, Dena, G1 aJhun, Min, A1 aCampbell, Harry1 aHamsten, Anders1 aRivadeneira, Fernando1 aMcArdle, Wendy, L1 aSlagboom, Eline1 aZeller, Tanja1 aKoenig, Wolfgang1 aPsaty, Bruce, M1 aHaritunians, Talin1 aLiu, Jingmin1 aPalotie, Aarno1 aUitterlinden, André, G1 aStott, David, J1 aHofman, Albert1 aFranco, Oscar, H1 aPolasek, Ozren1 aRudan, Igor1 aMorange, Pierre-Emmanuel1 aWilson, James, F1 aKardia, Sharon, L R1 aFerrucci, Luigi1 aSpector, Tim, D1 aEriksson, Johan, G1 aHansen, Torben1 aDeary, Ian, J1 aBecker, Lewis, C1 aScott, Rodney, J1 aMitchell, Paul1 aMärz, Winfried1 aWareham, Nick, J1 aPeters, Annette1 aGreinacher, Andreas1 aWild, Philipp, S1 aJukema, Wouter1 aBoomsma, Dorret, I1 aHayward, Caroline1 aCucca, Francesco1 aTracy, Russell1 aWatkins, Hugh1 aReiner, Alex, P1 aFolsom, Aaron, R1 aRidker, Paul, M1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aStrachan, David, P1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/693605480nas 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/725706988nas 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/725505835nas a2201585 4500008004100000022001400041245012700055210006900182260001500251300001000266490000700276520141400283100001801697700002401715700001901739700002801758700001901786700001901805700002501824700001801849700001301867700002001880700002001900700002101920700001701941700002401958700002501982700001202007700002202019700002002041700002002061700002202081700002602103700001902129700001802148700001802166700002502184700002102209700002102230700002202251700002102273700001702294700001702311700001702328700001502345700002102360700002402381700003102405700002402436700002402460700002002484700001902504700001402523700002102537700002402558700001902582700002402601700002202625700001802647700001902665700002102684700002202705700001802727700002002745700002002765700002302785700001602808700002202824700002002846700001602866700002202882700002302904700002302927700001702950700002202967700002302989700001703012700002003029700002203049700002303071700001603094700002003110700001503130700002103145700002203166700001903188700002503207700002403232700002103256700002103277700002203298700001603320700002303336700002403359700002203383700001803405700001303423700001803436700002203454700002103476700002303497700002603520700002303546700002103569700002003590700002003610700002403630700001903654700002103673700002303694700002203717700002603739700002103765700002203786700002203808700002503830700002003855700002403875700002003899700002103919700002003940700001903960700002103979700002004000700002204020700002204042700002004064710002004084710002004104710002504124710002204149710002104171710002104192856003604213 2016 eng d a1537-660500aTrans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.0 aTransethnic Metaanalysis and Functional Annotation Illuminates t c2016 Jul 7 a56-750 v993 aKnowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
1 aLiu, Ching-Ti1 aRaghavan, Sridharan1 aMaruthur, Nisa1 aKabagambe, Edmond, Kato1 aHong, Jaeyoung1 aC Y Ng, Maggie1 aHivert, Marie-France1 aLu, Yingchang1 aAn, Ping1 aBentley, Amy, R1 aDrolet, Anne, M1 aGaulton, Kyle, J1 aGuo, Xiuqing1 aArmstrong, Loren, L1 aIrvin, Marguerite, R1 aLi, Man1 aLipovich, Leonard1 aRybin, Denis, V1 aTaylor, Kent, D1 aAgyemang, Charles1 aPalmer, Nicholette, D1 aCade, Brian, E1 aChen, Wei-Min1 aDauriz, Marco1 aDelaney, Joseph, A C1 aEdwards, Todd, L1 aEvans, Daniel, S1 aEvans, Michele, K1 aLange, Leslie, A1 aLeong, Aaron1 aLiu, Jingmin1 aLiu, Yongmei1 aNayak, Uma1 aPatel, Sanjay, R1 aPorneala, Bianca, C1 aRasmussen-Torvik, Laura, J1 aSnijder, Marieke, B1 aStallings, Sarah, C1 aTanaka, Toshiko1 aYanek, Lisa, R1 aZhao, Wei1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBiggs, Mary, L1 aBottinger, Erwin, P1 aBowden, Donald, W1 aChen, Guanjie1 aCorrea, Adolfo1 aCouper, David, J1 aCrawford, Dana, C1 aCushman, Mary1 aEicher, John, D1 aFornage, Myriam1 aFranceschini, Nora1 aFu, Yi-Ping1 aGoodarzi, Mark, O1 aGottesman, Omri1 aHara, Kazuo1 aHarris, Tamara, B1 aJensen, Richard, A1 aJohnson, Andrew, D1 aJhun, Min, A1 aKarter, Andrew, J1 aKeller, Margaux, F1 aKho, Abel, N1 aKizer, Jorge, R1 aKrauss, Ronald, M1 aLangefeld, Carl, D1 aLi, Xiaohui1 aLiang, Jingling1 aLiu, Simin1 aLowe, William, L1 aMosley, Thomas, H1 aNorth, Kari, E1 aPacheco, Jennifer, A1 aPeyser, Patricia, A1 aPatrick, Alan, L1 aRice, Kenneth, M1 aSelvin, Elizabeth1 aSims, Mario1 aSmith, Jennifer, A1 aTajuddin, Salman, M1 aVaidya, Dhananjay1 aWren, Mary, P1 aYao, Jie1 aZhu, Xiaofeng1 aZiegler, Julie, T1 aZmuda, Joseph, M1 aZonderman, Alan, B1 aZwinderman, Aeilko, H1 aAdeyemo, Adebowale1 aBoerwinkle, Eric1 aFerrucci, Luigi1 aHayes, Geoffrey1 aKardia, Sharon, L R1 aMiljkovic, Iva1 aPankow, James, S1 aRotimi, Charles, N1 aSale, Michèle, M1 aWagenknecht, Lynne, E1 aArnett, Donna, K1 aChen, Yii-Der Ida1 aNalls, Michael, A1 aProvince, Michael, A1 aKao, Linda, W H1 aSiscovick, David, S1 aPsaty, Bruce, M1 aWilson, James, G1 aLoos, Ruth, J F1 aDupuis, Josée1 aRich, Stephen, S1 aFlorez, Jose, C1 aRotter, Jerome, I1 aMorris, Andrew, P1 aMeigs, James, B1 aAAAG Consortium1 aCARe Consortium1 aCOGENT-BP Consortium1 aeMERGE Consortium1 aMEDIA Consortium1 aMAGIC Consortium uhttps://chs-nhlbi.org/node/714103238nas a2200433 4500008004100000022001400041245012200055210006900177260001600246520194400262100001802206700002202224700002502246700001902271700001902290700001702309700002102326700002202347700002002369700002002389700002002409700002402429700002202453700002502475700001902500700002302519700002502542700002202567700001602589700002402605700001802629700002302647700002002670700002302690700001602713700002302729700001602752856003602768 2017 eng d a1534-779600aBivariate Genome-Wide Association Study of Depressive Symptoms with Type 2 Diabetes and Quantitative Glycemic Traits.0 aBivariate GenomeWide Association Study of Depressive Symptoms wi c2017 Dec 273 aOBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type-2-Diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits.
METHODS: We estimated SNP-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the LD Score Regression (LDSC) by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by Diagram consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, HOMA-β, and HOMA-IR by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate GWAS approach with summary statistics from GWAS meta-analyses and reported loci with genome-wide significant bivariate association p-value (p < 5x10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases.
RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the LDSC analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). Yet, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes).
CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D or glycemic traits suggesting major differences in underlying biology of these traits. Yet, several potential pleiotropic loci were identified between depressive symptoms, T2D and fasting glucose suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.
1 aHaljas, Kadri1 aAmare, Azmeraw, T1 aAlizadeh, Behrooz, Z1 aHsu, Yi-Hsiang1 aMosley, Thomas1 aNewman, Anne1 aMurabito, Joanne1 aTiemeier, Henning1 aTanaka, Toshiko1 aDuijn, Cornelia1 aDing, Jingzhong1 aLlewellyn, David, J1 aBennett, David, A1 aTerracciano, Antonio1 aLauner, Lenore1 aLadwig, Karl-Heinz1 aCornelis, Marylin, C1 aTeumer, Alexander1 aGrabe, Hans1 aKardia, Sharon, L R1 aWare, Erin, B1 aSmith, Jennifer, A1 aSnieder, Harold1 aEriksson, Johan, G1 aGroop, Leif1 aRäikkönen, Katri1 aLahti, Jari uhttps://chs-nhlbi.org/node/756504071nas 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/734006485nas a2201489 4500008004100000022001400041245020200055210006900257260001600326300001300342490000700355520221400362100001902576700002202595700001802617700002102635700001902656700001802675700001902693700001902712700002102731700002402752700001802776700002302794700001902817700002402836700001502860700001702875700002102892700002202913700002002935700002402955700002202979700002203001700002703023700001803050700001803068700002203086700002503108700002703133700002303160700001503183700002403198700002803222700002203250700002003272700002103292700002203313700002103335700002403356700001803380700002403398700002203422700002003444700002303464700002003487700002303507700002003530700002403550700001903574700001703593700001803610700001903628700002003647700001803667700001603685700001203701700002203713700001503735700002203750700002203772700001903794700002203813700001903835700002503854700002203879700002303901700001703924700002403941700002303965700002503988700001604013700001904029700002204048700001904070700001304089700001804102700002304120700002304143700002304166700001704189700001804206700002104224700002204245700002104267700002804288700001804316700001904334700001404353700001504367700002104382700002304403700002404426700002904450700001404479700002304493700002204516700002004538700002204558700002104580700002304601700002204624700002204646700002404668700001204692700002104704700002004725700002204745700002104767700002204788700002504810700002704835700002004862700001904882710005804901856003604959 2017 eng d a1553-740400aDiscovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium.0 aDiscovery and finemapping of adiposity loci using high density i c2017 Apr 21 ae10067190 v133 aGenome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
1 aC Y Ng, Maggie1 aGraff, Mariaelisa1 aLu, Yingchang1 aJustice, Anne, E1 aMudgal, Poorva1 aLiu, Ching-Ti1 aYoung, Kristin1 aYanek, Lisa, R1 aFeitosa, Mary, F1 aWojczynski, Mary, K1 aRand, Kristin1 aBrody, Jennifer, A1 aCade, Brian, E1 aDimitrov, Latchezar1 aDuan, Qing1 aGuo, Xiuqing1 aLange, Leslie, A1 aNalls, Michael, A1 aOkut, Hayrettin1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aVedantam, Sailaja1 aBradfield, Jonathan, P1 aChen, Guanjie1 aChen, Wei-Min1 aChesi, Alessandra1 aIrvin, Marguerite, R1 aPadhukasahasram, Badri1 aSmith, Jennifer, A1 aZheng, Wei1 aAllison, Matthew, A1 aAmbrosone, Christine, B1 aBandera, Elisa, V1 aBartz, Traci, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBottinger, Erwin, P1 aCarpten, John1 aChanock, Stephen, J1 aChen, Yii-Der Ida1 aConti, David, V1 aCooper, Richard, S1 aFornage, Myriam1 aFreedman, Barry, I1 aGarcia, Melissa1 aGoodman, Phyllis, J1 aHsu, Yu-Han, H1 aHu, Jennifer1 aHuff, Chad, D1 aIngles, Sue, A1 aJohn, Esther, M1 aKittles, Rick1 aKlein, Eric1 aLi, Jin1 aMcKnight, Barbara1 aNayak, Uma1 aNemesure, Barbara1 aOgunniyi, Adesola1 aOlshan, Andrew1 aPress, Michael, F1 aRohde, Rebecca1 aRybicki, Benjamin, A1 aSalako, Babatunde1 aSanderson, Maureen1 aShao, Yaming1 aSiscovick, David, S1 aStanford, Janet, L1 aStevens, Victoria, L1 aStram, Alex1 aStrom, Sara, S1 aVaidya, Dhananjay1 aWitte, John, S1 aYao, Jie1 aZhu, Xiaofeng1 aZiegler, Regina, G1 aZonderman, Alan, B1 aAdeyemo, Adebowale1 aAmbs, Stefan1 aCushman, Mary1 aFaul, Jessica, D1 aHakonarson, Hakon1 aLevin, Albert, M1 aNathanson, Katherine, L1 aWare, Erin, B1 aWeir, David, R1 aZhao, Wei1 aZhi, Degui1 aArnett, Donna, K1 aGrant, Struan, F A1 aKardia, Sharon, L R1 aOloapde, Olufunmilayo, I1 aRao, D, C1 aRotimi, Charles, N1 aSale, Michèle, M1 aWilliams, Keoki1 aZemel, Babette, S1 aBecker, Diane, M1 aBorecki, Ingrid, B1 aEvans, Michele, K1 aHarris, Tamara, B1 aHirschhorn, Joel, N1 aLi, Yun1 aPatel, Sanjay, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aWilson, James, G1 aBowden, Donald, W1 aCupples, Adrienne, L1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aNorth, Kari, E1 aBone Mineral Density in Childhood Study (BMDCS) Group uhttps://chs-nhlbi.org/node/735204860nas a2201081 4500008004100000022001400041245007600055210006900131260001600200300001200216490000800228520186200236653000902098653001902107653001602126653002802142653002002170653002402190653002202214653003402236653001102270653003702281653001602318653002602334653002802360653001702388100002402405700001902429700002002448700002002468700001702488700002302505700002502528700002202553700001902575700002002594700002202614700001702636700001902653700002202672700002102694700001702715700002202732700001802754700002402772700001602796700002602812700002802838700002402866700002102890700002002911700001202931700002202943700001902965700002002984700002203004700002403026700001403050700002303064700001803087700002303105700001903128700002003147700001603167700001903183700002203202700002303224700002003247700002003267700002003287700002303307700002203330700001903352700001703371700001803388700001903406700002603425700001703451700002003468700002903488700002203517700002303539700002103562700001803583700002603601700002103627700001803648700001903666700001703685700002003702710002003722856003603742 2017 eng d a1537-660500aDNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.0 aDNA Methylation Analysis Identifies Loci for Blood Pressure Regu c2017 Dec 07 a888-9020 v1013 aGenome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
10aAged10aBlood Pressure10aCpG Islands10aCross-Sectional Studies10aDNA Methylation10aEpigenesis, Genetic10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMendelian Randomization Analysis10aMiddle Aged10aNerve Tissue Proteins10aQuantitative Trait Loci10aTetraspanins1 aRichard, Melissa, A1 aHuan, Tianxiao1 aLigthart, Symen1 aGondalia, Rahul1 aJhun, Min, A1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aMarioni, Riccardo1 aShen, Jincheng1 aTsai, Pei-Chien1 aMontasser, May, E1 aJia, Yucheng1 aSyme, Catriona1 aSalfati, Elias, L1 aBoerwinkle, Eric1 aGuan, Weihua1 aMosley, Thomas, H1 aBressler, Jan1 aMorrison, Alanna, C1 aLiu, Chunyu1 aMendelson, Michael, M1 aUitterlinden, André, G1 avan Meurs, Joyce, B1 aFranco, Oscar, H1 aZhang, Guosheng1 aLi, Yun1 aStewart, James, D1 aBis, Joshua, C1 aPsaty, Bruce, M1 aChen, Yii-Der Ida1 aKardia, Sharon, L R1 aZhao, Wei1 aTurner, Stephen, T1 aAbsher, Devin1 aAslibekyan, Stella1 aStarr, John, M1 aMcRae, Allan, F1 aHou, Lifang1 aJust, Allan, C1 aSchwartz, Joel, D1 aVokonas, Pantel, S1 aMenni, Cristina1 aSpector, Tim, D1 aShuldiner, Alan1 aDamcott, Coleen, M1 aRotter, Jerome, I1 aPalmas, Walter1 aLiu, Yongmei1 aPaus, Tomáš1 aHorvath, Steve1 aO'Connell, Jeffrey, R1 aGuo, Xiuqing1 aPausova, Zdenka1 aAssimes, Themistocles, L1 aSotoodehnia, Nona1 aSmith, Jennifer, A1 aArnett, Donna, K1 aDeary, Ian, J1 aBaccarelli, Andrea, A1 aBell, Jordana, T1 aWhitsel, Eric1 aDehghan, Abbas1 aLevy, Daniel1 aFornage, Myriam1 aBIOS Consortium uhttps://chs-nhlbi.org/node/758305566nas a2201489 4500008004100000022001400041245010700055210006900162260001600231300000800247490000600255520135700261100002001618700002001638700002801658700002001686700001701706700002601723700002001749700001901769700002601788700002501814700001401839700001901853700002101872700002901893700002101922700002301943700002301966700002201989700001402011700002802025700002002053700002002073700002102093700002002114700002502134700002502159700002202184700001902206700002402225700001902249700002102268700002402289700001902313700002402332700002102356700001602377700002102393700002402414700002102438700002302459700001702482700002102499700001402520700002602534700002002560700002202580700002102602700002402623700002302647700002002670700002002690700001802710700001502728700002102743700002302764700002402787700001902811700001802830700002502848700002202873700001702895700001502912700002502927700002402952700002602976700002003002700002603022700002203048700001803070700002203088700002003110700002003130700002003150700002303170700002203193700003503215700002603250700002303276700002303299700002403322700001803346700001803364700002303382700002303405700002203428700002203450700001903472700002703491700001803518700002003536700002403556700001903580700002103599700001703620700002003637700002303657700002103680700001903701700002403720700002803744700002303772700001903795700001903814700002103833700002303854700002203877700002003899700002403919700001903943700002003962700001603982700002103998700002104019856003604040 2017 eng d a2041-172300aGenome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.0 aGenomewide metaanalysis associates HLADQA1DRB1 and LPA and lifes c2017 Oct 13 a9100 v83 aGenomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
1 aJoshi, Peter, K1 aPirastu, Nicola1 aKentistou, Katherine, A1 aFischer, Krista1 aHofer, Edith1 aSchraut, Katharina, E1 aClark, David, W1 aNutile, Teresa1 aBarnes, Catriona, L K1 aTimmers, Paul, R H J1 aShen, Xia1 aGandin, Ilaria1 aMcDaid, Aaron, F1 aHansen, Thomas, Folkmann1 aGordon, Scott, D1 aGiulianini, Franco1 aBoutin, Thibaud, S1 aAbdellaoui, Abdel1 aZhao, Wei1 aMedina-Gómez, Carolina1 aBartz, Traci, M1 aTrompet, Stella1 aLange, Leslie, A1 aRaffield, Laura1 avan der Spek, Ashley1 aGalesloot, Tessel, E1 aProitsi, Petroula1 aYanek, Lisa, R1 aBielak, Lawrence, F1 aPayton, Antony1 aMurgia, Federico1 aConcas, Maria, Pina1 aBiino, Ginevra1 aTajuddin, Salman, M1 aSeppälä, Ilkka1 aAmin, Najaf1 aBoerwinkle, Eric1 aBørglum, Anders, D1 aCampbell, Archie1 aDemerath, Ellen, W1 aDemuth, Ilja1 aFaul, Jessica, D1 aFord, Ian1 aGialluisi, Alessandro1 aGögele, Martin1 aGraff, Mariaelisa1 aHingorani, Aroon1 aHottenga, Jouke-Jan1 aHougaard, David, M1 aHurme, Mikko, A1 aIkram, Arfan, M1 aJylhä, Marja1 aKuh, Diana1 aLigthart, Lannie1 aLill, Christina, M1 aLindenberger, Ulman1 aLumley, Thomas1 aMägi, Reedik1 aMarques-Vidal, Pedro1 aMedland, Sarah, E1 aMilani, Lili1 aNagy, Reka1 aOllier, William, E R1 aPeyser, Patricia, A1 aPramstaller, Peter, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRuggiero, Daniela1 aSaba, Yasaman1 aSchmidt, Reinhold1 aSchmidt, Helena1 aSlagboom, Eline1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aSteinhagen-Thiessen, Elisabeth1 avan Rooij, Frank, J A1 aVerbeek, André, L1 aVermeulen, Sita, H1 aVollenweider, Peter1 aWang, Yunpeng1 aWerge, Thomas1 aWhitfield, John, B1 aZonderman, Alan, B1 aLehtimäki, Terho1 aEvans, Michele, K1 aPirastu, Mario1 aFuchsberger, Christian1 aBertram, Lars1 aPendleton, Neil1 aKardia, Sharon, L R1 aCiullo, Marina1 aBecker, Diane, M1 aWong, Andrew1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWilson, James, G1 aJukema, Wouter1 aKiemeney, Lambertus1 aUitterlinden, André, G1 aFranceschini, Nora1 aNorth, Kari, E1 aWeir, David, R1 aMetspalu, Andres1 aBoomsma, Dorret, I1 aHayward, Caroline1 aChasman, Daniel1 aMartin, Nicholas, G1 aSattar, Naveed1 aCampbell, Harry1 aEsko, Tõnu1 aKutalik, Zoltán1 aWilson, James, F uhttps://chs-nhlbi.org/node/756807019nas a2201849 4500008004100000022001400041245009300055210006900148260001300217490000700230520169900237100001901936700001901955700002101974700002301995700001602018700002502034700002202059700001802081700001902099700001702118700002602135700001602161700003002177700002302207700002102230700002502251700002002276700002102296700002302317700001602340700002302356700002002379700001702399700002102416700002302437700002202460700001402482700002502496700002902521700002402550700002102574700001802595700001702613700002502630700001802655700001802673700002002691700002202711700002502733700001302758700002002771700002402791700002502815700001902840700001902859700002102878700002702899700001902926700001402945700002402959700002302983700002203006700002503028700002603053700002303079700002203102700002103124700002003145700001803165700002603183700001703209700001803226700002303244700002403267700001203291700002103303700002103324700002203345700002103367700002703388700002303415700001803438700002203456700002003478700002403498700001803522700001903540700002103559700001603580700002003596700002303616700002003639700002203659700001603681700002103697700001903718700002203737700001703759700002003776700002303796700002703819700002403846700001903870700002203889700001903911700002403930700001503954700002003969700001903989700002204008700001904030700002104049700002204070700002304092700001904115700001904134700002104153700002504174700002004199700002004219700002204239700001604261700002004277700002204297700002004319700001604339700002604355700001904381700001504400700002404415700002304439700002604462700002404488700002504512700002104537700002304558700002104581700002404602700002104626700002504647700001704672700002704689700002004716700002004736700002304756700002304779700001804802700002504820700001704845700002904862700002404891700002404915710004304939710015104982856003605133 2017 eng d a1942-326800aNew Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.0 aNew Blood PressureAssociated Loci Identified in MetaAnalyses of c2017 Oct0 v103 aBACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.
METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.
CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
1 aKraja, Aldi, T1 aCook, James, P1 aWarren, Helen, R1 aSurendran, Praveen1 aLiu, Chunyu1 aEvangelou, Evangelos1 aManning, Alisa, K1 aGrarup, Niels1 aDrenos, Fotios1 aSim, Xueling1 aSmith, Albert, Vernon1 aAmin, Najaf1 aBlakemore, Alexandra, I F1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aFarmaki, Aliki-Eleni1 aFava, Cristiano1 aFerreira, Teresa1 aHerzig, Karl-Heinz1 aGiri, Ayush1 aGiulianini, Franco1 aGrove, Megan, L1 aGuo, Xiuqing1 aHarris, Sarah, E1 aHave, Christian, T1 aHavulinna, Aki, S1 aZhang, He1 aJørgensen, Marit, E1 aKäräjämäki, AnneMari1 aKooperberg, Charles1 aLinneberg, Allan1 aLittle, Louis1 aLiu, Yongmei1 aBonnycastle, Lori, L1 aLu, Yingchang1 aMägi, Reedik1 aMahajan, Anubha1 aMalerba, Giovanni1 aMarioni, Riccardo, E1 aMei, Hao1 aMenni, Cristina1 aMorrison, Alanna, C1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRayner, Nigel, William1 aRiaz, Muhammad1 aRice, Ken1 aRichard, Melissa, A1 aSmith, Jennifer, A1 aSoutham, Lorraine1 aStančáková, Alena1 aStirrups, Kathleen, E1 aTragante, Vinicius1 aTuomi, Tiinamaija1 aTzoulaki, Ioanna1 aVarga, Tibor, V1 aWeiss, Stefan1 aYiorkas, Andrianos, M1 aYoung, Robin1 aZhang, Weihua1 aBarnes, Michael, R1 aCabrera, Claudia, P1 aGao, He1 aBoehnke, Michael1 aBoerwinkle, Eric1 aChambers, John, C1 aConnell, John, M1 aChristensen, Cramer, K1 ade Boer, Rudolf, A1 aDeary, Ian, J1 aDedoussis, George1 aDeloukas, Panos1 aDominiczak, Anna, F1 aDörr, Marcus1 aJoehanes, Roby1 aEdwards, Todd, L1 aEsko, Tõnu1 aFornage, Myriam1 aFranceschini, Nora1 aFranks, Paul, W1 aGambaro, Giovanni1 aGroop, Leif1 aHallmans, Göran1 aHansen, Torben1 aHayward, Caroline1 aHeikki, Oksa1 aIngelsson, Erik1 aTuomilehto, Jaakko1 aJarvelin, Marjo-Riitta1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKooner, Jaspal, S1 aLakka, Timo, A1 aLangenberg, Claudia1 aLind, Lars1 aLoos, Ruth, J F1 aLaakso, Markku1 aMcCarthy, Mark, I1 aMelander, Olle1 aMohlke, Karen, L1 aMorris, Andrew, P1 aPalmer, Colin, N A1 aPedersen, Oluf1 aPolasek, Ozren1 aPoulter, Neil, R1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSever, Peter, J1 aSkaaby, Tea1 aStafford, Jeanette, M1 aStarr, John, M1 aHarst, Pim1 avan der Meer, Peter1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aGudnason, Vilmundur1 aWareham, Nicholas, J1 aWilson, James, G1 aWiller, Cristen, J1 aWitte, Daniel, R1 aZeggini, Eleftheria1 aSaleheen, Danish1 aButterworth, Adam, S1 aDanesh, John1 aAsselbergs, Folkert, W1 aWain, Louise, V1 aEhret, Georg, B1 aChasman, Daniel, I1 aCaulfield, Mark, J1 aElliott, Paul1 aLindgren, Cecilia, M1 aLevy, Daniel1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aHowson, Joanna, M M1 aUnderstanding Society Scientific Group1 aCHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group† uhttps://chs-nhlbi.org/node/756905167nas a2201273 4500008004100000022001400041245013800055210006900193260001300262300001300275490000700288520164300295653002201938653001201960653004901972653001902021653001402040653002502054653001102079653001702090653003402107653001102141653001702152653000902169653002202178653000902200653003102209653003602240100002002276700001502296700002802311700002202339700002102361700002302382700001802405700002302423700001802446700001902464700002102483700002402504700001702528700001502545700001802560700002302578700001502601700002202616700002102638700001602659700002402675700002002699700001402719700001402733700002002747700002302767700001702790700001702807700002302824700002502847700002402872700001702896700001802913700002202931700002402953700002002977700002202997700001303019700001403032700002403046700001803070700002103088700002003109700001803129700002103147700002203168700001903190700001703209700002803226700002003254700002103274700001803295700001903313700002103332700002403353700001503377700001603392700002003408700002403428700002303452700002103475700002103496700001703517700002003534700002003554700001903574700002403593700002103617700001603638700002103654700001903675700002303694700001403717700002203731700002003753700001703773700002603790700001803816700002303834856003603857 2017 eng d a1553-740400aSingle-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.0 aSingletrait and multitrait genomewide association analyses ident c2017 May ae10067280 v133 aHypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
10aAfrican Americans10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aBlood Pressure10aCadherins10aCase-Control Studies10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMembrane Proteins10aMice10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide1 aLiang, Jingjing1 aLe, Thu, H1 aEdwards, Digna, R Velez1 aTayo, Bamidele, O1 aGaulton, Kyle, J1 aSmith, Jennifer, A1 aLu, Yingchang1 aJensen, Richard, A1 aChen, Guanjie1 aYanek, Lisa, R1 aSchwander, Karen1 aTajuddin, Salman, M1 aSofer, Tamar1 aKim, Wonji1 aKayima, James1 aMcKenzie, Colin, A1 aFox, Ervin1 aNalls, Michael, A1 aYoung, Hunter, J1 aSun, Yan, V1 aLane, Jacqueline, M1 aCechova, Sylvia1 aZhou, Jie1 aTang, Hua1 aFornage, Myriam1 aMusani, Solomon, K1 aWang, Heming1 aLee, Juyoung1 aAdeyemo, Adebowale1 aDreisbach, Albert, W1 aForrester, Terrence1 aChu, Pei-Lun1 aCappola, Anne1 aEvans, Michele, K1 aMorrison, Alanna, C1 aMartin, Lisa, W1 aWiggins, Kerri, L1 aHui, Qin1 aZhao, Wei1 aJackson, Rebecca, D1 aWare, Erin, B1 aFaul, Jessica, D1 aReiner, Alex, P1 aBray, Michael1 aDenny, Joshua, C1 aMosley, Thomas, H1 aPalmas, Walter1 aGuo, Xiuqing1 aPapanicolaou, George, J1 aPenman, Alan, D1 aPolak, Joseph, F1 aRice, Kenneth1 aTaylor, Ken, D1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aLiu, Kiang1 aRisch, Neil1 aHunt, Steven, C1 aKooperberg, Charles1 aZonderman, Alan, B1 aLaurie, Cathy, C1 aBecker, Diane, M1 aCai, Jianwen1 aLoos, Ruth, J F1 aPsaty, Bruce, M1 aWeir, David, R1 aKardia, Sharon, L R1 aArnett, Donna, K1 aWon, Sungho1 aEdwards, Todd, L1 aRedline, Susan1 aCooper, Richard, S1 aRao, D, C1 aRotter, Jerome, I1 aRotimi, Charles1 aLevy, Daniel1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/757203942nas a2200757 4500008004100000022001400041245010600055210006900161260001600230520175200246100002801998700002502026700001702051700002002068700002202088700001602110700001702126700002302143700002102166700001202187700002502199700002202224700002602246700002202272700001602294700002102310700002102331700003002352700001702382700001602399700001702415700002102432700003202453700001802485700002402503700002102527700002202548700002202570700001702592700002002609700002102629700002202650700002302672700002102695700001802716700001402734700001802748700002402766700002602790700002802816700002102844700001802865700002802883700002102911700002302932700001902955700002902974700001903003700001903022700002303041700001903064700002203083700002303105700002003128856003603148 2018 eng d a1528-002000aDNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis.0 aDNA methylation age is associated with an altered hemostatic pro c2018 Jul 243 aMany hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.
1 aWard-Caviness, Cavin, K1 aHuffman, Jennifer, E1 aEvertt, Karl1 aGermain, Marine1 avan Dongen, Jenny1 aHill, David1 aJhun, Min, A1 aBrody, Jennifer, A1 aGhanbari, Mohsen1 aDu, Lei1 aRoetker, Nicholas, S1 ade Vries, Paul, S1 aWaldenberger, Melanie1 aGieger, Christian1 aWolf, Petra1 aProkisch, Holger1 aKoenig, Wolfgang1 aO'Donnell, Christopher, J1 aLevy, Daniel1 aLiu, Chunyu1 aTruong, Vinh1 aWells, Philip, S1 aTrégouët, David-Alexandre1 aTang, Weihong1 aMorrison, Alanna, C1 aBoerwinkle, Eric1 aWiggins, Kerri, L1 aMcKnight, Barbara1 aGuo, Xiuqing1 aPsaty, Bruce, M1 aSotoodenia, Nona1 aBoomsa, Dorret, I1 aWillemsen, Gonneke1 aLigthart, Lannie1 aDeary, Ian, J1 aZhao, Wei1 aWare, Erin, B1 aKardia, Sharon, L R1 avan Meurs, Joyce, B J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aEriksson, Per1 aFranco-Cereceda, Anders1 aPankow, James, S1 aJohnson, Andrew, D1 aGagnon, France1 aMorange, Pierre-Emmanuel1 aGeus, Eco, J C1 aStarr, John, M1 aSmith, Jennifer, A1 aDehghan, Abbas1 aBjörck, Hanna, M1 aSmith, Nicholas, L1 aPeters, Annette uhttps://chs-nhlbi.org/node/781605244nas 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/779612060nas a2203745 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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/768611027nas a2203421 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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/779209584nas a2203049 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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/766808823nas a2202773 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2018 eng d a2041-172300aStudy of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.0 aStudy of 300486 individuals identifies 148 independent genetic l c2018 May 29 a20980 v93 aGeneral cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
1 aDavies, Gail1 aLam, Max1 aHarris, Sarah, E1 aTrampush, Joey, W1 aLuciano, Michelle1 aHill, David1 aHagenaars, Saskia, P1 aRitchie, Stuart, J1 aMarioni, Riccardo, E1 aFawns-Ritchie, Chloe1 aLiewald, David, C M1 aOkely, Judith, A1 aAhola-Olli, Ari, V1 aBarnes, Catriona, L K1 aBertram, Lars1 aBis, Joshua, C1 aBurdick, Katherine, E1 aChristoforou, Andrea1 aDeRosse, Pamela1 aDjurovic, Srdjan1 aEspeseth, Thomas1 aGiakoumaki, Stella1 aGiddaluru, Sudheer1 aGustavson, Daniel, E1 aHayward, Caroline1 aHofer, Edith1 aIkram, Arfan, M1 aKarlsson, Robert1 aKnowles, Emma1 aLahti, Jari1 aLeber, Markus1 aLi, Shuo1 aMather, Karen, A1 aMelle, Ingrid1 aMorris, Derek1 aOldmeadow, Christopher1 aPalviainen, Teemu1 aPayton, Antony1 aPazoki, Raha1 aPetrovic, Katja1 aReynolds, Chandra, A1 aSargurupremraj, Muralidharan1 aScholz, Markus1 aSmith, Jennifer, A1 aSmith, Albert, V1 aTerzikhan, Natalie1 aThalamuthu, Anbupalam1 aTrompet, Stella1 avan der Lee, Sven, J1 aWare, Erin, B1 aWindham, Gwen1 aWright, Margaret, J1 aYang, Jingyun1 aYu, Jin1 aAmes, David1 aAmin, Najaf1 aAmouyel, Philippe1 aAndreassen, Ole, A1 aArmstrong, Nicola, J1 aAssareh, Amelia, A1 aAttia, John, R1 aAttix, Deborah1 aAvramopoulos, Dimitrios1 aBennett, David, A1 aBöhmer, Anne, C1 aBoyle, Patricia, A1 aBrodaty, Henry1 aCampbell, Harry1 aCannon, Tyrone, D1 aCirulli, Elizabeth, T1 aCongdon, Eliza1 aConley, Emily, Drabant1 aCorley, Janie1 aCox, Simon, R1 aDale, Anders, M1 aDehghan, Abbas1 aDick, Danielle1 aDickinson, Dwight1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFord, Ian1 aFreimer, Nelson, A1 aGao, He1 aGiegling, Ina1 aGillespie, Nathan, A1 aGordon, Scott, D1 aGottesman, Rebecca, F1 aGriswold, Michael, E1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartmann, Annette, M1 aHatzimanolis, Alex1 aHeiss, Gerardo1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKähönen, Mika1 aKardia, Sharon, L R1 aKarlsson, Ida1 aKleineidam, Luca1 aKnopman, David, S1 aKochan, Nicole, A1 aKonte, Bettina1 aKwok, John, B1 aLe Hellard, Stephanie1 aLee, Teresa1 aLehtimäki, Terho1 aLi, Shu-Chen1 aLiu, Tian1 aKoini, Marisa1 aLondon, Edythe1 aLongstreth, Will, T1 aLopez, Oscar, L1 aLoukola, Anu1 aLuck, Tobias1 aLundervold, Astri, J1 aLundquist, Anders1 aLyytikäinen, Leo-Pekka1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aMurray, Alison, D1 aNeed, Anna, C1 aNoordam, Raymond1 aNyberg, Lars1 aOllier, William1 aPapenberg, Goran1 aPattie, Alison1 aPolasek, Ozren1 aPoldrack, Russell, A1 aPsaty, Bruce, M1 aReppermund, Simone1 aRiedel-Heller, Steffi, G1 aRose, Richard, J1 aRotter, Jerome, I1 aRoussos, Panos1 aRovio, Suvi, P1 aSaba, Yasaman1 aSabb, Fred, W1 aSachdev, Perminder, S1 aSatizabal, Claudia, L1 aSchmid, Matthias1 aScott, Rodney, J1 aScult, Matthew, A1 aSimino, Jeannette1 aSlagboom, Eline1 aSmyrnis, Nikolaos1 aSoumaré, Aïcha1 aStefanis, Nikos, C1 aStott, David, J1 aStraub, Richard, E1 aSundet, Kjetil1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, Andre1 aVitart, Veronique1 aVoineskos, Aristotle, N1 aKaprio, Jaakko1 aWagner, Michael1 aWagner, Holger1 aWeinhold, Leonie1 aWen, Hoyan1 aWiden, Elisabeth1 aYang, Qiong1 aZhao, Wei1 aAdams, Hieab, H H1 aArking, Dan, E1 aBilder, Robert, M1 aBitsios, Panos1 aBoerwinkle, Eric1 aChiba-Falek, Ornit1 aCorvin, Aiden1 aDe Jager, Philip, L1 aDebette, Stephanie1 aDonohoe, Gary1 aElliott, Paul1 aFitzpatrick, Annette, L1 aGill, Michael1 aGlahn, David, C1 aHägg, Sara1 aHansell, Narelle, K1 aHariri, Ahmad, R1 aIkram, Kamran1 aJukema, Wouter1 aVuoksimaa, Eero1 aKeller, Matthew, C1 aKremen, William, S1 aLauner, Lenore1 aLindenberger, Ulman1 aPalotie, Aarno1 aPedersen, Nancy, L1 aPendleton, Neil1 aPorteous, David, J1 aRäikkönen, Katri1 aRaitakari, Olli, T1 aRamirez, Alfredo1 aReinvang, Ivar1 aRudan, Igor1 aSchmidt, Reinhold1 aSchmidt, Helena1 aSchofield, Peter, W1 aSchofield, Peter, R1 aStarr, John, M1 aSteen, Vidar, M1 aTrollor, Julian, N1 aTurner, Steven, T1 aDuijn, Cornelia, M1 aVillringer, Arno1 aWeinberger, Daniel, R1 aWeir, David, R1 aWilson, James, F1 aMalhotra, Anil1 aMcIntosh, Andrew, M1 aGale, Catharine, R1 aSeshadri, Sudha1 aMosley, Thomas, H1 aBressler, Jan1 aLencz, Todd1 aDeary, Ian, J uhttps://chs-nhlbi.org/node/778815950nas a2205365 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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/819803604nas a2200553 4500008004100000022001400041245013100055210006900186260001200255300001100267490000600278520187600284653002202160653004502182653002802227653002902255653001102284653003502295653002902330653003602359653004102395653003402436100001502470700001402485700002602499700002302525700002202548700002002570700002302590700002202613700001602635700001502651700002402666700002002690700002002710700002202730700002302752700003102775700002402806700002102830700002102851700002302872700002402895700002202919700002702941700002102968700002502989856003603014 2019 eng d a2324-926900aGenome-wide meta-analysis of SNP and antihypertensive medication interactions on left ventricular traits in African Americans.0 aGenomewide metaanalysis of SNP and antihypertensive medication i c2019 10 ae007880 v73 aBACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography.
METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates.
RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population.
CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.
10aAfrican Americans10aAngiotensin-Converting Enzyme Inhibitors10aAntihypertensive Agents10aCalcium Channel Blockers10aHumans10aObservational Studies as Topic10aPharmacogenomic Variants10aPolymorphism, Single Nucleotide10aSodium Chloride Symporter Inhibitors10aVentricular Dysfunction, Left1 aDo, Anh, N1 aZhao, Wei1 aBaldridge, Abigail, S1 aRaffield, Laura, M1 aWiggins, Kerri, L1 aShah, Sanjiv, J1 aAslibekyan, Stella1 aTiwari, Hemant, K1 aLimdi, Nita1 aZhi, Degui1 aSitlani, Colleen, M1 aTaylor, Kent, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aBrody, Jennifer, A1 aRasmussen-Torvik, Laura, J1 aLloyd-Jones, Donald1 aLange, Leslie, A1 aWilson, James, G1 aSmith, Jennifer, A1 aKardia, Sharon, L R1 aMosley, Thomas, H1 aVasan, Ramachandran, S1 aArnett, Donna, K1 aIrvin, Marguerite, R uhttps://chs-nhlbi.org/node/851104639nas a2200829 4500008004100000022001400041245010700055210006900162260000900231300001300240490000700253520225600260100002802516700002202544700002202566700002502588700001902613700002402632700002302656700001702679700002202696700002002718700001802738700002202756700002502778700002502803700001702828700001902845700003002864700002402894700002102918700002602939700002202965700002102987700002103008700001803029700001603047700002303063700001303086700002503099700002803124700002103152700002303173700002203196700002203218700002003240700002303260700002103283700002403304700002303328700002603351700002003377700002003397700001303417700001903430700002203449700002003471700001903491700001903510700002103529700002403550700002203574700002003596700001803616700002303634700001903657700003003676700002303706700002003729700002403749856003603773 2019 eng d a1932-620300aMendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.0 aMendelian randomization evaluation of causal effects of fibrinog c2019 ae02162220 v143 aBACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.
METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.
CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
1 aWard-Caviness, Cavin, K1 ade Vries, Paul, S1 aWiggins, Kerri, L1 aHuffman, Jennifer, E1 aYanek, Lisa, R1 aBielak, Lawrence, F1 aGiulianini, Franco1 aGuo, Xiuqing1 aKleber, Marcus, E1 aKacprowski, Tim1 aGroß, Stefan1 aPetersman, Astrid1 aSmith, George, Davey1 aHartwig, Fernando, P1 aBowden, Jack1 aHemani, Gibran1 aMüller-Nuraysid, Martina1 aStrauch, Konstantin1 aKoenig, Wolfgang1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aPankratz, Nathan1 aBoerwinkle, Eric1 aTang, Weihong1 aFu, Yi-Ping1 aJohnson, Andrew, D1 aSong, Ci1 ade Maat, Moniek, P M1 aUitterlinden, André, G1 aFranco, Oscar, H1 aBrody, Jennifer, A1 aMcKnight, Barbara1 aChen, Yii-Der Ida1 aPsaty, Bruce, M1 aMathias, Rasika, A1 aBecker, Diane, M1 aPeyser, Patricia, A1 aSmith, Jennifer, A1 aBielinski, Suzette, J1 aRidker, Paul, M1 aTaylor, Kent, D1 aYao, Jie1 aTracy, Russell1 aDelgado, Graciela1 aTrompet, Stella1 aSattar, Naveed1 aJukema, Wouter1 aBecker, Lewis, C1 aKardia, Sharon, L R1 aRotter, Jerome, I1 aMärz, Winfried1 aDörr, Marcus1 aChasman, Daniel, I1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aPeters, Annette1 aMorrison, Alanna, C uhttps://chs-nhlbi.org/node/805010550nas 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 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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 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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 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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/797609368nas a2202785 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2020 eng d a1476-557800aGene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.0 aGeneeducational attainment interactions in a multiancestry genom c2020 May 053 aEducational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
1 aFuentes, Lisa, de Las1 aSung, Yun, Ju1 aNoordam, Raymond1 aWinkler, Thomas1 aFeitosa, Mary, F1 aSchwander, Karen1 aBentley, Amy, R1 aBrown, Michael, R1 aGuo, Xiuqing1 aManning, Alisa1 aChasman, Daniel, I1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aCampbell, Archie1 aCheng, Ching-Yu1 aDorajoo, Rajkumar1 aHartwig, Fernando, P1 aHorimoto, A, R V R1 aLi, Changwei1 aLi-Gao, Ruifang1 aLiu, Yongmei1 aMarten, Jonathan1 aMusani, Solomon, K1 aNtalla, Ioanna1 aRankinen, Tuomo1 aRichard, Melissa1 aSim, Xueling1 aSmith, Albert, V1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aVojinovic, Dina1 aWarren, Helen, R1 aXuan, Deng1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin-Fang1 aChen, Xu1 aChristensen, Kaare1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGirotto, Giorgia1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLi, Xiaoyin1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRueedi, Rico1 aShu, Xiao-Ou1 aSnieder, Harold1 aSofer, Tamar1 aTakeuchi, Fumihiko1 aVerweij, Niek1 aWare, Erin, B1 aWeiss, Stefan1 aYanek, Lisa, R1 aAmin, Najaf1 aArking, Dan, E1 aArnett, Donna, K1 aBergmann, Sven1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aBrumat, Marco1 aBurke, Gregory1 aCabrera, Claudia, P1 aCanouil, Mickaël1 aChee, Miao, Li1 aChen, Yii-Der Ida1 aCocca, Massimiliano1 aConnell, John1 ade Silva, Janaka1 ade Vries, Paul, S1 aEiriksdottir, Gudny1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFox, Ervin, F1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGiulianini, Franco1 aGu, Chi, Charles1 aGu, Dongfeng1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHunt, Steven1 aIkram, Arfan, M1 aIrvin, Marguerite, R1 aKähönen, Mika1 aKavousi, Maryam1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aKraja, Aldi, T1 aKrieger, J, E1 aLangefeld, Carl, D1 aLi, Yize1 aLiang, Jingjing1 aLiewald, David, C M1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLohman, Kurt, K1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMook-Kanamori, Dennis, O1 aNalls, Mike, A1 aNelson, Christopher, P1 aNorris, Jill, M1 aO'Connell, Jeff1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmer, Nicholette, D1 aPedersen, Nancy, L1 aPerls, Thomas1 aPeters, Annette1 aPetersmann, Astrid1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPorteous, David, J1 aRaffel, Leslie, J1 aRice, Treva, K1 aRotter, Jerome, I1 aRudan, Igor1 aRueda-Ochoa, Oscar-Leonel1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSchreiner, Pamela, J1 aShikany, James, M1 aSidney, Stephen, S1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aStarr, John, M1 aStrauch, Konstantin1 aSwertz, Morris, A1 aTeumer, Alexander1 aTham, Yih, Chung1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Ende, Yldau1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya-Xing1 aBin Wei, Wen-1 aWeir, David, R1 aWen, Wanqing1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBowden, Donald, W1 aDeary, Ian, J1 aDörr, Marcus1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKato, Norihiro1 aLakka, Timo, A1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aMarques-Vidal, Pedro1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aBouchard, Claude1 aCooper, Richard, S1 aCorrea, Adolfo1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aPalmas, Walter, R1 aPereira, A, C1 aProvince, Michael, M1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRotimi, Charles, N1 aTai, Shyong, E1 avan Dam, Rob, M1 aDuijn, Cornelia, M1 aWong, Tien, Yin1 aRice, Kenneth1 aGauderman, James1 aMorrison, Alanna, C1 aNorth, Kari, E1 aKardia, Sharon, L R1 aCaulfield, Mark, J1 aElliott, Paul1 aMunroe, Patricia, B1 aFranks, Paul, W1 aRao, Dabeeru, C1 aFornage, Myriam1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/838106570nas a2201753 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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/862103741nas a2200625 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520194400253100001402197700001402211700002002225700002402245700002302269700002102292700002302313700001702336700001502353700002102368700002402389700001702413700001602430700002502446700002202471700002202493700001502515700002402530700002002554700002002574700002102594700002502615700002002640700002402660700002302684700002602707700001302733700001402746700002002760700002402780700002402804700001802828700002902846700002502875700002002900700001902920700002002939700002202959700002102981700002403002710005303026856003603079 2020 eng d a2574-830000aRole of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.0 aRole of Rare and LowFrequency Variants in GeneAlcohol Interactio c2020 Aug ae0027720 v133 aBACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.
METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.
RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .
CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
1 aWang, Zhe1 aChen, Han1 aBartz, Traci, M1 aBielak, Lawrence, F1 aChasman, Daniel, I1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aLim, Elise1 aNoordam, Raymond1 aRichard, Melissa, A1 aWang, Heming1 aCade, Brian1 aCupples, Adrienne, L1 ade Vries, Paul, S1 aGiulanini, Franco1 aLee, Jiwon1 aLemaitre, Rozenn, N1 aMartin, Lisa, W1 aReiner, Alex, P1 aRich, Stephen, S1 aSchreiner, Pamela, J1 aSidney, Stephen1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 avan Dijk, Ko, Willems1 aYao, Jie1 aZhao, Wei1 aFornage, Myriam1 aKardia, Sharon, L R1 aKooperberg, Charles1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRidker, Paul, M1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aMorrison, Alanna, C1 aCHARGE Gene-Lifestyle Interactions Working Group uhttps://chs-nhlbi.org/node/840704156nas 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/898805153nas a2201369 4500008004100000022001400041245011700055210006900172260001500241300000900256490000700265520124400272100002301516700001901539700002101558700002701579700002001606700002201626700001901648700002601667700002601693700002001719700002001739700002301759700003001782700001901812700002301831700002901854700002801883700002401911700001901935700001901954700001201973700002401985700002102009700001702030700002502047700001902072700001802091700001502109700002402124700002002148700002002168700002202188700002002210700001702230700002602247700002602273700002102299700002402320700002302344700001802367700001902385700002102404700001902425700002102444700002202465700002102487700002102508700001902529700002102548700002202569700002002591700002102611700002002632700001902652700002202671700001802693700002202711700002402733700002002757700002302777700002002800700001802820700002202838700001402860700002002874700002002894700002202914700002402936700001802960700001702978700002402995700002103019700001803040700002403058700002003082700002203102700002303124700003003147700002503177700002503202700002603227700001903253700001903272700002103291700002003312700001403332700001903346700002503365700001703390700001903407700002103426700002203447700002703469700002203496700002503518700002203543700002403565700002103589700002003610700002003630700002003650710006503670710001203735856003603747 2021 eng d a2041-172300aChromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.0 aChromosome Xq23 is associated with lower atherogenic lipid conce c2021 04 12 a21820 v123 aAutosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
1 aNatarajan, Pradeep1 aPampana, Akhil1 aGraham, Sarah, E1 aRuotsalainen, Sanni, E1 aPerry, James, A1 ade Vries, Paul, S1 aBroome, Jai, G1 aPirruccello, James, P1 aHonigberg, Michael, C1 aAragam, Krishna1 aWolford, Brooke1 aBrody, Jennifer, A1 aAntonacci-Fulton, Lucinda1 aArden, Moscati1 aAslibekyan, Stella1 aAssimes, Themistocles, L1 aBallantyne, Christie, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aCade, Brian, E1 aDo, Ron1 aDoddapaneni, Harsha1 aEmery, Leslie, S1 aHung, Yi-Jen1 aIrvin, Marguerite, R1 aKhan, Alyna, T1 aLange, Leslie1 aLee, Jiwon1 aLemaitre, Rozenn, N1 aMartin, Lisa, W1 aMetcalf, Ginger1 aMontasser, May, E1 aMoon, Jee-Young1 aMuzny, Donna1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aStilp, Adrienne, M1 aTsai, Michael1 aWang, Fei, Fei1 aWeeks, Daniel, E1 aYanek, Lisa, R1 aWilson, James, G1 aAbecasis, Goncalo1 aArnett, Donna, K1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aChoi, Won, Jung1 aCorrea, Adolfo1 aCurran, Joanne, E1 aDaly, Mark, J1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aFornage, Myriam1 aFreedman, Barry, I1 aGabriel, Stacey1 aGermer, Soren1 aGibbs, Richard, A1 aHe, Jiang1 aHveem, Kristian1 aJarvik, Gail, P1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKenny, Eimear1 aKim, Ryan, W1 aKooperberg, Charles1 aLaurie, Cathy, C1 aLee, Seonwook1 aLloyd-Jones, Don, M1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aMathias, Rasika, A1 aMartinez, Karine, A Viaud1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aNickerson, Deborah, A1 aNorth, Kari, E1 aPalotie, Aarno1 aPark, Cheol, Joo1 aPsaty, Bruce, M1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSmith, Albert, V1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aKathiresan, Sekar1 aCupples, Adrienne, L1 aRotter, Jerome, I1 aMorrison, Alanna, C1 aRich, Stephen, S1 aRipatti, Samuli1 aWiller, Cristen1 aPeloso, Gina, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aFinnGen uhttps://chs-nhlbi.org/node/871105600nas a2201549 4500008004100000022001400041245011600055210006900171260001500240300000900255490000700264520122500271653003501496653001901531653001601550653002001566653001401586653001101600653003801611653003401649653004501683653000901728653001101737653000901748653001401757100001801771700002201789700002901811700002101840700001901861700001601880700001201896700001901908700002101927700003301948700001901981700003202000700002602032700002202058700001902080700001902099700002302118700002102141700002102162700001802183700002702201700002202228700001802250700001802268700001802286700001902304700001802323700002502341700002102366700001902387700002202406700002002428700002102448700001202469700001502481700002102496700002102517700001902538700002202557700002202579700002002601700002102621700001902642700002002661700002202681700001902703700001602722700002002738700002002758700002402778700001802802700002202820700002102842700002202863700002402885700002102909700002702930700002202957700001502979700001302994700002703007700002203034700001503056700002503071700002003096700002503116700002403141700001703165700002503182700002003207700002103227700002003248700002103268700002003289700002303309700002203332700002003354700002003374700001903394700002003413700002303433700002203456700002303478700002303501700002203524700002403546700002603570700003503596700001903631700001703650700002403667700003003691700001403721700001703735700001503752700002003767700002603787700001703813700002203830700002203852700002103874700002203895700001903917710003503936710004303971856003604014 2021 eng d a2041-172300aEpigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.0 aEpigenomewide association study of serum urate reveals insights c2021 12 09 a71730 v123 aElevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
10aAmino Acid Transport System y+10aCohort Studies10aCpG Islands10aDNA Methylation10aEpigenome10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlucose Transport Proteins, Facilitative10aGout10aHumans10aMale10aUric Acid1 aTin, Adrienne1 aSchlosser, Pascal1 aMatias-Garcia, Pamela, R1 aThio, Chris, H L1 aJoehanes, Roby1 aLiu, Hongbo1 aYu, Zhi1 aWeihs, Antoine1 aHoppmann, Anselm1 aGrundner-Culemann, Franziska1 aMin, Josine, L1 aKuhns, Victoria, L Halperin1 aAdeyemo, Adebowale, A1 aAgyemang, Charles1 aArnlöv, Johan1 aAziz, Nasir, A1 aBaccarelli, Andrea1 aBochud, Murielle1 aBrenner, Hermann1 aBressler, Jan1 aBreteler, Monique, M B1 aCarmeli, Cristian1 aChaker, Layal1 aCoresh, Josef1 aCorre, Tanguy1 aCorrea, Adolfo1 aCox, Simon, R1 aDelgado, Graciela, E1 aEckardt, Kai-Uwe1 aEkici, Arif, B1 aEndlich, Karlhans1 aFloyd, James, S1 aFraszczyk, Eliza1 aGao, Xu1 aGào, Xīn1 aGelber, Allan, C1 aGhanbari, Mohsen1 aGhasemi, Sahar1 aGieger, Christian1 aGreenland, Philip1 aGrove, Megan, L1 aHarris, Sarah, E1 aHemani, Gibran1 aHenneman, Peter1 aHerder, Christian1 aHorvath, Steve1 aHou, Lifang1 aHurme, Mikko, A1 aHwang, Shih-Jen1 aKardia, Sharon, L R1 aKasela, Silva1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKronenberg, Florian1 aKuhnel, Brigitte1 aLadd-Acosta, Christine1 aLehtimäki, Terho1 aLind, Lars1 aLiu, Dan1 aLloyd-Jones, Donald, M1 aLorkowski, Stefan1 aLu, Ake, T1 aMarioni, Riccardo, E1 aMärz, Winfried1 aMcCartney, Daniel, L1 aMeeks, Karlijn, A C1 aMilani, Lili1 aMishra, Pashupati, P1 aNauck, Matthias1 aNowak, Christoph1 aPeters, Annette1 aProkisch, Holger1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRatliff, Scott, M1 aReiner, Alex, P1 aSchöttker, Ben1 aSchwartz, Joel1 aSedaghat, Sanaz1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStocker, Hannah, R1 aStringhini, Silvia1 aSundström, Johan1 aSwenson, Brenton, R1 avan Meurs, Joyce, B J1 avan Vliet-Ostaptchouk, Jana, V1 aVenema, Andrea1 aVölker, Uwe1 aWinkelmann, Juliane1 aWolffenbuttel, Bruce, H R1 aZhao, Wei1 aZheng, Yinan1 aLoh, Marie1 aSnieder, Harold1 aWaldenberger, Melanie1 aLevy, Daniel1 aAkilesh, Shreeram1 aWoodward, Owen, M1 aSusztak, Katalin1 aTeumer, Alexander1 aKöttgen, Anna1 aEstonian Biobank Research Team1 aGenetics of DNA Methylation Consortium uhttps://chs-nhlbi.org/node/900611212nas a2203445 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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/883505906nas a2201705 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2021 eng d a2041-172300aMeta-analyses identify DNA methylation associated with kidney function and damage.0 aMetaanalyses identify DNA methylation associated with kidney fun c2021 12 09 a71740 v123 aChronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
10aAdult10aAged10aCpG Islands10aDNA Methylation10aFemale10aGlomerular Filtration Rate10aHumans10aInterferon Regulatory Factors10aKidney10aKidney Function Tests10aLIM Domain Proteins10aMale10aMembrane Proteins10aMiddle Aged10aRenal Insufficiency, Chronic10aTranscription Factors1 aSchlosser, Pascal1 aTin, Adrienne1 aMatias-Garcia, Pamela, R1 aThio, Chris, H L1 aJoehanes, Roby1 aLiu, Hongbo1 aWeihs, Antoine1 aYu, Zhi1 aHoppmann, Anselm1 aGrundner-Culemann, Franziska1 aMin, Josine, L1 aAdeyemo, Adebowale, A1 aAgyemang, Charles1 aArnlöv, Johan1 aAziz, Nasir, A1 aBaccarelli, Andrea1 aBochud, Murielle1 aBrenner, Hermann1 aBreteler, Monique, M B1 aCarmeli, Cristian1 aChaker, Layal1 aChambers, John, C1 aCole, Shelley, A1 aCoresh, Josef1 aCorre, Tanguy1 aCorrea, Adolfo1 aCox, Simon, R1 ade Klein, Niek1 aDelgado, Graciela, E1 aDomingo-Relloso, Arce1 aEckardt, Kai-Uwe1 aEkici, Arif, B1 aEndlich, Karlhans1 aEvans, Kathryn, L1 aFloyd, James, S1 aFornage, Myriam1 aFranke, Lude1 aFraszczyk, Eliza1 aGao, Xu1 aGào, Xīn1 aGhanbari, Mohsen1 aGhasemi, Sahar1 aGieger, Christian1 aGreenland, Philip1 aGrove, Megan, L1 aHarris, Sarah, E1 aHemani, Gibran1 aHenneman, Peter1 aHerder, Christian1 aHorvath, Steve1 aHou, Lifang1 aHurme, Mikko, A1 aHwang, Shih-Jen1 aJarvelin, Marjo-Riitta1 aKardia, Sharon, L R1 aKasela, Silva1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKramer, Holly1 aKronenberg, Florian1 aKuhnel, Brigitte1 aLehtimäki, Terho1 aLind, Lars1 aLiu, Dan1 aLiu, Yongmei1 aLloyd-Jones, Donald, M1 aLohman, Kurt1 aLorkowski, Stefan1 aLu, Ake, T1 aMarioni, Riccardo, E1 aMärz, Winfried1 aMcCartney, Daniel, L1 aMeeks, Karlijn, A C1 aMilani, Lili1 aMishra, Pashupati, P1 aNauck, Matthias1 aNavas-Acien, Ana1 aNowak, Christoph1 aPeters, Annette1 aProkisch, Holger1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRatliff, Scott, M1 aReiner, Alex, P1 aRosas, Sylvia, E1 aSchöttker, Ben1 aSchwartz, Joel1 aSedaghat, Sanaz1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStocker, Hannah, R1 aStringhini, Silvia1 aSundström, Johan1 aSwenson, Brenton, R1 aTellez-Plaza, Maria1 avan Meurs, Joyce, B J1 avan Vliet-Ostaptchouk, Jana, V1 aVenema, Andrea1 aVerweij, Niek1 aWalker, Rosie, M1 aWielscher, Matthias1 aWinkelmann, Juliane1 aWolffenbuttel, Bruce, H R1 aZhao, Wei1 aZheng, Yinan1 aLoh, Marie1 aSnieder, Harold1 aLevy, Daniel1 aWaldenberger, Melanie1 aSusztak, Katalin1 aKöttgen, Anna1 aTeumer, Alexander1 aEstonian Biobank Research Team1 aGenetics of DNA Methylation Consortium uhttps://chs-nhlbi.org/node/900206260nas a2201741 4500008004100000022001400041245015100055210006900206260001600275490000600291520132000297100001601617700002101633700002301654700001801677700002301695700002101718700002001739700001701759700002801776700002001804700002001824700002001844700002401864700002201888700002601910700002501936700002801961700001701989700002202006700002102028700002102049700002102070700002102091700002802112700001902140700002102159700002702180700001602207700001802223700001802241700001702259700001902276700001902295700002102314700001502335700002102350700002102371700002602392700002202418700002502440700002502465700002602490700002302516700002202539700002502561700002202586700001802608700002102626700002202647700002002669700002502689700001602714700002202730700002802752700002002780700002002800700001802820700001902838700002302857700002202880700002202902700002102924700001702945700001702962700001702979700002302996700002003019700002203039700002103061700002303082700002203105700002003127700002403147700002603171700002203197700002003219700001803239700002603257700002403283700002903307700002503336700002203361700002203383700001703405700002003422700001603442700002303458700002203481700002403503700001903527700001703546700002803563700002303591700002603614700001803640700001803658700002003676700001503696700001303711700001803724700001403742700001803756700002303774700002103797700001803818700002203836700001903858700002203877700001903899700002903918700002703947700002003974700001803994700001904012700001504031700002204046700002104068700002404089700002304113700001804136700002904154700002404183700002604207700002004233700001604253700001804269700002404287700001704311700001804328700002204346700002404368700002304392700002004415700002004435710002704455856003604482 2021 eng d a2666-247700aMulti-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.0 aMultiAncestry Genomewide Association Study Accounting for GenePs c2021 Jan 140 v23 aPsychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.
1 aSun, Daokun1 aRichard, Melissa1 aMusani, Solomon, K1 aSung, Yun, Ju1 aWinkler, Thomas, W1 aSchwander, Karen1 aChai, Jin, Fang1 aGuo, Xiuqing1 aKilpeläinen, Tuomas, O1 aVojinovic, Dina1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aBrown, Michael, R1 aChitrala, Kumaraswamy1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLiu, Yongmei1 aManning, Alisa, K1 aNoordam, Raymond1 aSmith, Albert, V1 aHarris, Sarah, E1 aKuhnel, Brigitte1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aRauramaa, Rainer1 avan der Most, Peter, J1 aWang, Rujia1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aArking, Dan, E1 aArnett, Donna, K1 aBarac, Ana1 aBoerwinkle, Eric1 aBroeckel, Ulrich1 aChakravarti, Aravinda1 aChen, Yii-Der Ida1 aCupples, Adrienne, L1 aDavigulus, Martha, L1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Vries, Paul, S1 aDelaney, Joseph, A C1 aRoux, Ana, V Diez1 aDörr, Marcus1 aFaul, Jessica, D1 aFretts, Amanda, M1 aGallo, Linda, C1 aGrabe, Hans, Jörgen1 aGu, Charles1 aHarris, Tamara, B1 aHartman, Catharina, C A1 aHeikkinen, Sami1 aIkram, Arfan, M1 aIsasi, Carmen1 aJohnson, Craig1 aJonas, Jost, Bruno1 aKaplan, Robert, C1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aLevy, Daniel1 aLiu, Jianjun1 aLohman, Kurt1 aLuik, Annemarie, I1 aMartin, Lisa, W1 aMeitinger, Thomas1 aMilaneschi, Yuri1 aO'Connell, Jeff, R1 aPalmas, Walter, R1 aPeters, Annette1 aPeyser, Patricia, A1 aPulkki-Råback, Laura1 aRaffel, Leslie, J1 aReiner, Alex, P1 aRice, Kenneth1 aRobinson, Jennifer, G1 aRosendaal, Frits, R1 aSchmidt, Carsten, Oliver1 aSchreiner, Pamela, J1 aSchwettmann, Lars1 aShikany, James, M1 aShu, Xiao-Ou1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStrauch, Konstantin1 aTai, Shyong, E1 aTaylor, Kent1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aWaldenberger, Melanie1 aWee, Hwee-Lin1 aBin Wei, Wen-1 aWilson, Gregory1 aXuan, Deng1 aYao, Jie1 aZeng, Donglin1 aZhao, Wei1 aZhu, Xiaofeng1 aZonderman, Alan, B1 aBecker, Diane, M1 aDeary, Ian, J1 aGieger, Christian1 aLakka, Timo, A1 aLehtimäki, Terho1 aNorth, Kari, E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aSnieder, Harold1 aWang, Ya-Xing1 aWeir, David, R1 aZheng, Wei1 aEvans, Michele, K1 aGauderman, James1 aGudnason, Vilmundur1 aHorta, Bernardo, L1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aMorrison, Alanna, C1 aPereira, Alexandre, C1 aPsaty, Bruce, M1 aAmin, Najaf1 aFox, Ervin, R1 aKooperberg, Charles1 aSim, Xueling1 aBierut, Laura1 aRotter, Jerome, I1 aKardia, Sharon, L R1 aFranceschini, Nora1 aRao, Dabeeru, C1 aFornage, Myriam1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/900503781nas a2200637 4500008004100000022001400041245011400055210006900169260001300238300001200251490000700263520196300270100001802233700002402251700002002275700002402295700001902319700002102338700001502359700002002374700002302394700002102417700001602438700001802454700001302472700001502485700002602500700002802526700001602554700002102570700002002591700002002611700002002631700002302651700002302674700003002697700001302727700002302740700002302763700001602786700001702802700001902819700002402838700002102862700002302883700001802906700002802924700002102952700002402973700002702997700002003024700002203044700002203066700001903088856003603107 2021 eng d a2574-830000aMultiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.0 aMultiethnic GenomeWide Association Study of Subclinical Atherosc c2021 Aug ae0032580 v143 aBACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.
METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.
RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).
CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
1 aLu, Yingchang1 aDimitrov, Latchezar1 aChen, Shyh-Huei1 aBielak, Lawrence, F1 aBis, Joshua, C1 aFeitosa, Mary, F1 aLu, Lingyi1 aKavousi, Maryam1 aRaffield, Laura, M1 aSmith, Albert, V1 aWang, Lihua1 aWeiss, Stefan1 aYao, Jie1 aZhu, Jiaxi1 aGudmundsson, Elias, F1 aGudmundsdottir, Valborg1 aBos, Daniel1 aGhanbari, Mohsen1 aIkram, Arfan, M1 aHwang, Shih-Jen1 aTaylor, Kent, D1 aBudoff, Matthew, J1 aGislason, Gauti, K1 aO'Donnell, Christopher, J1 aAn, Ping1 aFranceschini, Nora1 aFreedman, Barry, I1 aFu, Yi-Ping1 aGuo, Xiuqing1 aHeiss, Gerardo1 aKardia, Sharon, L R1 aWilson, James, G1 aLangefeld, Carl, D1 aSchminke, Ulf1 aUitterlinden, André, G1 aLange, Leslie, A1 aPeyser, Patricia, A1 aGudnason, Vilmundur, G1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aBowden, Donald, W1 aC Y Ng, Maggie uhttps://chs-nhlbi.org/node/883208483nas a2202413 4500008004100000022001400041245007200055210006900127260001200196300001200208490000800220520169100228100001901919700002201938700002401960700002201984700002402006700001702030700003002047700002002077700002702097700002002124700003002144700002202174700002002196700001802216700002302234700001802257700002202275700002102297700002302318700002002341700002502361700002102386700001702407700001802424700002402442700001802466700002002484700002202504700001902526700002302545700001902568700002302587700001802610700001802628700001702646700001902663700002102682700002102703700002402724700002402748700001902772700002102791700002202812700002302834700002502857700001902882700002202901700002202923700002302945700002202968700002002990700002203010700001903032700002003051700001903071700002203090700001803112700001903130700001903149700002303168700001903191700002203210700002403232700002103256700001703277700001803294700002103312700001703333700002003350700002303370700002703393700002803420700001803448700002103466700002403487700001703511700002103528700001403549700002603563700002303589700002503612700002103637700002303658700001903681700002403700700001803724700001903742700002103761700002103782700002003803700002303823700002403846700001903870700002103889700002203910700001703932700001603949700001803965700001603983700002003999700001704019700002104036700002204057700002404079700001904103700002104122700002204143700002304165700002204188700002504210700002004235700002304255700002204278700002204300700002504322700002504347700002204372700002504394700002404419700002404443700001904467700002304486700002104509700001904530700002604549700002604575700002104601700002004622700002404642700002004666700001904686700002004705700001404725700001904739700002504758700001504783700002204798700002004820700002104840700002604861700002304887700001904910700002004929700002304949700001904972700002404991700002305015700002305038700002205061700002305083700001805106700002005124700001905144700002505163700002205188700002705210700002705237700003005264700001805294700002105312700001905333700002005352700001805372700002305390700001805413700001705431700002105448700002805469700002405497700002105521700002005542700001905562700002105581700002105602700002405623700001805647700001605665700002805681700002605709700002405735700002105759700002405780700002105804700002505825700002105850700002405871700002305895700002505918700002505943710006505968856003606033 2021 eng d a1476-468700aSequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.0 aSequencing of 53831 diverse genomes from the NHLBI TOPMed Progra c2021 02 a290-2990 v5903 aThe Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
1 aTaliun, Daniel1 aHarris, Daniel, N1 aKessler, Michael, D1 aCarlson, Jedidiah1 aSzpiech, Zachary, A1 aTorres, Raul1 aTaliun, Sarah, A Gagliano1 aCorvelo, André1 aGogarten, Stephanie, M1 aKang, Hyun, Min1 aPitsillides, Achilleas, N1 aLeFaive, Jonathon1 aLee, Seung-Been1 aTian, Xiaowen1 aBrowning, Brian, L1 aDas, Sayantan1 aEmde, Anne-Katrin1 aClarke, Wayne, E1 aLoesch, Douglas, P1 aShetty, Amol, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aWong, Quenna1 aLiu, Xiaoming1 aConomos, Matthew, P1 aBobo, Dean, M1 aAguet, Francois1 aAlbert, Christine1 aAlonso, Alvaro1 aArdlie, Kristin, G1 aArking, Dan, E1 aAslibekyan, Stella1 aAuer, Paul, L1 aBarnard, John1 aBarr, Graham1 aBarwick, Lucas1 aBecker, Lewis, C1 aBeer, Rebecca, L1 aBenjamin, Emelia, J1 aBielak, Lawrence, F1 aBlangero, John1 aBoehnke, Michael1 aBowden, Donald, W1 aBrody, Jennifer, A1 aBurchard, Esteban, G1 aCade, Brian, E1 aCasella, James, F1 aChalazan, Brandon1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aCho, Michael, H1 aChoi, Seung, Hoan1 aChung, Mina, K1 aClish, Clary, B1 aCorrea, Adolfo1 aCurran, Joanne, E1 aCuster, Brian1 aDarbar, Dawood1 aDaya, Michelle1 ade Andrade, Mariza1 aDeMeo, Dawn, L1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aEng, Celeste1 aFatkin, Diane1 aFingerlin, Tasha1 aForer, Lukas1 aFornage, Myriam1 aFranceschini, Nora1 aFuchsberger, Christian1 aFullerton, Stephanie, M1 aGermer, Soren1 aGladwin, Mark, T1 aGottlieb, Daniel, J1 aGuo, Xiuqing1 aHall, Michael, E1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHeckbert, Susan, R1 aIrvin, Marguerite, R1 aJohnsen, Jill, M1 aJohnson, Andrew, D1 aKaplan, Robert1 aKardia, Sharon, L R1 aKelly, Tanika1 aKelly, Shannon1 aKenny, Eimear, E1 aKiel, Douglas, P1 aKlemmer, Robert1 aKonkle, Barbara, A1 aKooperberg, Charles1 aKöttgen, Anna1 aLange, Leslie, A1 aLasky-Su, Jessica1 aLevy, Daniel1 aLin, Xihong1 aLin, Keng-Han1 aLiu, Chunyu1 aLoos, Ruth, J F1 aGarman, Lori1 aGerszten, Robert1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aC Y Mak, Angel1 aManichaikul, Ani1 aManning, Alisa, K1 aMathias, Rasika, A1 aMcManus, David, D1 aMcGarvey, Stephen, T1 aMeigs, James, B1 aMeyers, Deborah, A1 aMikulla, Julie, L1 aMinear, Mollie, A1 aMitchell, Braxton, D1 aMohanty, Sanghamitra1 aMontasser, May, E1 aMontgomery, Courtney1 aMorrison, Alanna, C1 aMurabito, Joanne, M1 aNatale, Andrea1 aNatarajan, Pradeep1 aNelson, Sarah, C1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPankratz, Nathan1 aPeloso, Gina, M1 aPeyser, Patricia, A1 aPleiness, Jacob1 aPost, Wendy, S1 aPsaty, Bruce, M1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRoden, Dan1 aRotter, Jerome, I1 aRuczinski, Ingo1 aSarnowski, Chloe1 aSchoenherr, Sebastian1 aSchwartz, David, A1 aSeo, Jeong-Sun1 aSeshadri, Sudha1 aSheehan, Vivien, A1 aSheu, Wayne, H1 aShoemaker, Benjamin1 aSmith, Nicholas, L1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStilp, Adrienne, M1 aTang, Weihong1 aTaylor, Kent, D1 aTelen, Marilyn1 aThornton, Timothy, A1 aTracy, Russell, P1 aVan Den Berg, David, J1 aVasan, Ramachandran, S1 aViaud-Martinez, Karine, A1 aVrieze, Scott1 aWeeks, Daniel, E1 aWeir, Bruce, S1 aWeiss, Scott, T1 aWeng, Lu-Chen1 aWiller, Cristen, J1 aZhang, Yingze1 aZhao, Xutong1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBoerwinkle, Eric1 aGabriel, Stacey1 aGibbs, Richard1 aRice, Kenneth, M1 aRich, Stephen, S1 aSilverman, Edwin, K1 aQasba, Pankaj1 aGan, Weiniu1 aPapanicolaou, George, J1 aNickerson, Deborah, A1 aBrowning, Sharon, R1 aZody, Michael, C1 aZöllner, Sebastian1 aWilson, James, G1 aCupples, Adrienne, L1 aLaurie, Cathy, C1 aJaquish, Cashell, E1 aHernandez, Ryan, D1 aO'Connor, Timothy, D1 aAbecasis, Goncalo, R1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/866604296nas a2200973 4500008004100000022001400041245010700055210006900162260001600231520147300247100002301720700002101743700001901764700001801783700001901801700002301820700001901843700001701862700001901879700003001898700002601928700002801954700002801982700002102010700001702031700002202048700002302070700002202093700002202115700002102137700002402158700002302182700002002205700002402225700002002249700002102269700002302290700002402313700002402337700001902361700001902380700002002399700001902419700002502438700002302463700002402486700002002510700002302530700001602553700002202569700002002591700002002611700001702631700002202648700001802670700002402688700002402712700002302736700002402759700001902783700001502802700002302817700002502840700002502865700002202890700002402912700001902936700002602955700002602981700002103007700002103028700002203049700002303071700002003094700002703114700002103141700002003162700002103182700001903203700002003222700002303242700002103265856003603286 2021 eng d a1476-625600aA System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.0 aSystem for Phenotype Harmonization in the NHLBI TransOmics for P c2021 Apr 163 aGenotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
1 aStilp, Adrienne, M1 aEmery, Leslie, S1 aBroome, Jai, G1 aButh, Erin, J1 aKhan, Alyna, T1 aLaurie, Cecelia, A1 aWang, Fei, Fei1 aWong, Quenna1 aChen, Dongquan1 aD'Augustine, Catherine, M1 aHeard-Costa, Nancy, L1 aHohensee, Chancellor, R1 aJohnson, William, Craig1 aJuarez, Lucia, D1 aLiu, Jingmin1 aMutalik, Karen, M1 aRaffield, Laura, M1 aWiggins, Kerri, L1 ade Vries, Paul, S1 aKelly, Tanika, N1 aKooperberg, Charles1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aPeyser, Patricia, A1 aReiner, Alex, P1 aArnett, Donna, K1 aAslibekyan, Stella1 aBarnes, Kathleen, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aCade, Brian, E1 aChen, Ming-Huei1 aCorrea, Adolfo1 aCupples, Adrienne, L1 ade Andrade, Mariza1 aEllinor, Patrick, T1 aFornage, Myriam1 aFranceschini, Nora1 aGan, Weiniu1 aGanesh, Santhi, K1 aGraffelman, Jan1 aGrove, Megan, L1 aGuo, Xiuqing1 aHawley, Nicola, L1 aHsu, Wan-Ling1 aJackson, Rebecca, D1 aJaquish, Cashell, E1 aJohnson, Andrew, D1 aKardia, Sharon, L R1 aKelly, Shannon1 aLee, Jiwon1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNorth, Kari, E1 aNouraie, Seyed, Mehdi1 aOelsner, Elizabeth, C1 aPankratz, Nathan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aWeeks, Daniel, E1 aWeiss, Scott, T1 aWilson, Carla, G1 aYanek, Lisa, R1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aLaurie, Cathy, C uhttps://chs-nhlbi.org/node/871304975nas 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/916905976nas a2201393 4500008004100000022001400041245013400055210006900189260001600258300003400274520189200308100002102200700001402221700001702235700002202252700003002274700002502304700002502329700001502354700002302369700002302392700001702415700002002432700002202452700001302474700001902487700002402506700001902530700001802549700002302567700001902590700002602609700001602635700002302651700002402674700002102698700002902719700002202748700001602770700001902786700001802805700002102823700001802844700002602862700002202888700002102910700001802931700001602949700002002965700001902985700001803004700002403022700002503046700002203071700002103093700002203114700001703136700001703153700002003170700002103190700003303211700002403244700001703268700002203285700003403307700002503341700002203366700002103388700002103409700001903430700002203449700002003471700001903491700001403510700002503524700002103549700002503570700001703595700001403612700002303626700001803649700001703667700002203684700002103706700002203727700002403749700002103773700001903794700002203813700002103835700001903856700002603875700002103901700002003922700001903942700001903961700002503980700002004005700002304025700002404048700002204072700002304094700001404117700002004131700002004151700002004171700001904191700002104210700002204231700002404253700002104277700002504298700001804323700001704341700002104358700002404379710014304403856003604546 2022 eng d a1524-456300aInsights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.0 aInsights From a LargeScale WholeGenome Sequencing Study of Systo c2022 Jun 02 a101161HYPERTENSIONAHA122193243 aBACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.
METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.
RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively).
DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.
1 aKelly, Tanika, N1 aSun, Xiao1 aHe, Karen, Y1 aBrown, Michael, R1 aTaliun, Sarah, A Gagliano1 aHellwege, Jacklyn, N1 aIrvin, Marguerite, R1 aMi, Xuenan1 aBrody, Jennifer, A1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 ade Vries, Paul, S1 aGao, Yan1 aMoscati, Arden1 aNadkarni, Girish, N1 aYanek, Lisa, R1 aElfassy, Tali1 aSmith, Jennifer, A1 aChung, Ren-Hua1 aBeitelshees, Amber, L1 aPatki, Amit1 aAslibekyan, Stella1 aBlobner, Brandon, M1 aPeralta, Juan, M1 aAssimes, Themistocles, L1 aPalmas, Walter, R1 aLiu, Chunyu1 aBress, Adam, P1 aHuang, Zhijie1 aBecker, Lewis, C1 aHwa, Chii-Min1 aO'Connell, Jeffrey, R1 aCarlson, Jenna, C1 aWarren, Helen, R1 aDas, Sayantan1 aGiri, Ayush1 aMartin, Lisa, W1 aJohnson, Craig1 aFox, Ervin, R1 aBottinger, Erwin, P1 aRazavi, Alexander, C1 aVaidya, Dhananjay1 aChuang, Lee-Ming1 aChang, Yen-Pei, C1 aNaseri, Take1 aJain, Deepti1 aKang, Hyun, Min1 aHung, Adriana, M1 aSrinivasasainagendra, Vinodh1 aSnively, Beverly, M1 aGu, Dongfeng1 aMontasser, May, E1 aReupena, Muagututi'a, Sefuiva1 aHeavner, Benjamin, D1 aLeFaive, Jonathon1 aHixson, James, E1 aRice, Kenneth, M1 aWang, Fei, Fei1 aNielsen, Jonas, B1 aHuang, Jianfeng1 aKhan, Alyna, T1 aZhou, Wei1 aNierenberg, Jovia, L1 aLaurie, Cathy, C1 aArmstrong, Nicole, D1 aShi, Mengyao1 aPan, Yang1 aStilp, Adrienne, M1 aEmery, Leslie1 aWong, Quenna1 aHawley, Nicola, L1 aMinster, Ryan, L1 aCurran, Joanne, E1 aMunroe, Patricia, B1 aWeeks, Daniel, E1 aNorth, Kari, E1 aTracy, Russell, P1 aKenny, Eimear, E1 aShimbo, Daichi1 aChakravarti, Aravinda1 aRich, Stephen, S1 aReiner, Alex, P1 aBlangero, John1 aRedline, Susan1 aMitchell, Braxton, D1 aRao, Dabeeru, C1 aChen, Yii-Der, Ida1 aKardia, Sharon, L R1 aKaplan, Robert, C1 aMathias, Rasika, A1 aHe, Jiang1 aPsaty, Bruce, M1 aFornage, Myriam1 aLoos, Ruth, J F1 aCorrea, Adolfo1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aKooperberg, Charles1 aEdwards, Todd, L1 aAbecasis, Goncalo, R1 aZhu, Xiaofeng1 aLevy, Daniel1 aArnett, Donna, K1 aMorrison, Alanna, C1 aNHLBI Trans-Omics for Precision Medicine TOPMed) Consortium, The Samoan Obesity, Lifestyle, and Genetic Adaptations Study (OLaGA) Group† uhttps://chs-nhlbi.org/node/909913363nas a2204429 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2022 eng d a1546-171800aMulti-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.0 aMultiancestry genetic study of type 2 diabetes highlights the po c2022 May a560-5720 v543 aWe assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
10aDiabetes Mellitus, Type 210aEthnicity10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aZhang, Weihua1 aC Y Ng, Maggie1 aPetty, Lauren, E1 aKitajima, Hidetoshi1 aYu, Grace, Z1 aRüeger, Sina1 aSpeidel, Leo1 aKim, Young, Jin1 aHorikoshi, Momoko1 aMercader, Josep, M1 aTaliun, Daniel1 aMoon, Sanghoon1 aKwak, Soo-Heon1 aRobertson, Neil, R1 aRayner, Nigel, W1 aLoh, Marie1 aKim, Bong-Jo1 aChiou, Joshua1 aMiguel-Escalada, Irene1 aParolo, Pietro, Della Brio1 aLin, Kuang1 aBragg, Fiona1 aPreuss, Michael, H1 aTakeuchi, Fumihiko1 aNano, Jana1 aGuo, Xiuqing1 aLamri, Amel1 aNakatochi, Masahiro1 aScott, Robert, A1 aLee, Jung-Jin1 aHuerta-Chagoya, Alicia1 aGraff, Mariaelisa1 aChai, Jin-Fang1 aParra, Esteban, J1 aYao, Jie1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aSteinthorsdottir, Valgerdur1 aCook, James, P1 aKals, Mart1 aGrarup, Niels1 aSchmidt, Ellen, M1 aPan, Ian1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aAhmad, Meraj1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aLecoeur, Cécile1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aJensen, Richard, A1 aTajuddin, Salman1 aKabagambe, Edmond, K1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aFlanagan, Jack1 aAbaitua, Fernando1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAkiyama, Masato1 aAnand, Sonia, S1 aBertoni, Alain1 aBian, Zheng1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBrummett, Chad, M1 aBuchanan, Thomas, A1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFornage, Myriam1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aFuchsberger, Christian1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGoodarzi, Mark, O1 aGordon-Larsen, Penny1 aGorkin, David1 aGross, Myron1 aGuo, Yu1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKamatani, Yoichiro1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKohara, Katsuhiko1 aKriebel, Jennifer1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLigthart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLyssenko, Valeriya1 aMamakou, Vasiliki1 aMani, Radha, K1 aMeitinger, Thomas1 aMetspalu, Andres1 aMorris, Andrew, D1 aNadkarni, Girish, N1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNongmaithem, Suraj, S1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPorneala, Bianca1 aPrasad, Gauri1 aPreissl, Sebastian1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Kathryn1 aSabanayagam, Charumathi1 aSander, Maike1 aSandow, Kevin1 aSattar, Naveed1 aSchönherr, Sebastian1 aSchurmann, Claudia1 aShahriar, Mohammad1 aShi, Jinxiu1 aShin, Dong, Mun1 aShriner, Daniel1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aSuzuki, Ken1 aTakahashi, Atsushi1 aTaylor, Kent, D1 aThorand, Barbara1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTorres, Jason, M1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aVujkovic, Marijana1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWhitsel, Eric, A1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamauchi, Toshimasa1 aYengo, Loic1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZhang, Liang1 aZheng, Wei1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aHanis, Craig, L1 aPeyser, Patricia, A1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aZeggini, Eleftheria1 aYokota, Mitsuhiro1 aRich, Stephen, S1 aKooperberg, Charles1 aPankow, James, S1 aEngert, James, C1 aChen, Yii-Der Ida1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aKardia, Sharon, L R1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aGroop, Leif1 aMook-Kanamori, Dennis, O1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aBottinger, Erwin, P1 aDehghan, Abbas1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aPalmer, Colin, N A1 aLiu, Simin1 aAbecasis, Goncalo1 aKooner, Jaspal, S1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aFlorez, Jose, C1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aMägi, Reedik1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aMaeda, Shiro1 aKadowaki, Takashi1 aLee, Juyoung1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aMyers, Simon, R1 aFerrer, Jorge1 aGaulton, Kyle, J1 aMeigs, James, B1 aMohlke, Karen, L1 aGloyn, Anna, L1 aBowden, Donald, W1 aBelow, Jennifer, E1 aChambers, John, C1 aSim, Xueling1 aBoehnke, Michael1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aMorris, Andrew, P1 aFinnGen1 aeMERGE Consortium uhttps://chs-nhlbi.org/node/910408881nas a2202605 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2022 eng d a1537-660500aRare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.0 aRare coding variants in 35 genes associate with circulating lipi c2022 01 06 a81-960 v1093 aLarge-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
10aAlleles10aBlood Glucose10aCase-Control Studies10aComputational Biology10aDatabases, Genetic10aDiabetes Mellitus, Type 210aExome10aGenetic Predisposition to Disease10aGenetic Variation10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aLipids10aLiver10aMolecular Sequence Annotation10aMultifactorial Inheritance10aOpen Reading Frames10aPhenotype10aPolymorphism, Single Nucleotide1 aHindy, George1 aDornbos, Peter1 aChaffin, Mark, D1 aLiu, Dajiang, J1 aWang, Minxian1 aSelvaraj, Margaret, Sunitha1 aZhang, David1 aPark, Joseph1 aAguilar-Salinas, Carlos, A1 aAntonacci-Fulton, Lucinda1 aArdissino, Diego1 aArnett, Donna, K1 aAslibekyan, Stella1 aAtzmon, Gil1 aBallantyne, Christie, M1 aBarajas-Olmos, Francisco1 aBarzilai, Nir1 aBecker, Lewis, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBottinger, Erwin1 aBowden, Donald, W1 aBown, Matthew, J1 aBrody, Jennifer, A1 aBroome, Jai, G1 aBurtt, Noel, P1 aCade, Brian, E1 aCenteno-Cruz, Federico1 aChan, Edmund1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aCheng, Ching-Yu1 aChoi, Won, Jung1 aChowdhury, Raj1 aContreras-Cubas, Cecilia1 aCórdova, Emilio, J1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDanesh, John1 ade Vries, Paul, S1 aDeFronzo, Ralph, A1 aDoddapaneni, Harsha1 aDuggirala, Ravindranath1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aFlorez, Jose, C1 aFornage, Myriam1 aFreedman, Barry, I1 aFuster, Valentin1 aGaray-Sevilla, Ma, Eugenia1 aGarcía-Ortiz, Humberto1 aGermer, Soren1 aGibbs, Richard, A1 aGieger, Christian1 aGlaser, Benjamin1 aGonzalez, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGraff, Mariaelisa1 aGraham, Sarah, E1 aGrarup, Niels1 aGroop, Leif, C1 aGuo, Xiuqing1 aGupta, Namrata1 aHan, Sohee1 aHanis, Craig, L1 aHansen, Torben1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aIrvin, Marguerite, R1 aIslas-Andrade, Sergio1 aJarvik, Gail, P1 aKang, Hyun, Min1 aKardia, Sharon, L R1 aKelly, Tanika1 aKenny, Eimear, E1 aKhan, Alyna, T1 aKim, Bong-Jo1 aKim, Ryan, W1 aKim, Young, Jin1 aKoistinen, Heikki, A1 aKooperberg, Charles1 aKuusisto, Johanna1 aKwak, Soo, Heon1 aLaakso, Markku1 aLange, Leslie, A1 aLee, Jiwon1 aLee, Juyoung1 aLee, Seonwook1 aLehman, Donna, M1 aLemaitre, Rozenn, N1 aLinneberg, Allan1 aLiu, Jianjun1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aLyssenko, Valeriya1 aMa, Ronald, C W1 aMartin, Lisa, Warsinger1 aMartínez-Hernández, Angélica1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMcPherson, Ruth1 aMeigs, James, B1 aMeitinger, Thomas1 aMelander, Olle1 aMendoza-Caamal, Elvia1 aMetcalf, Ginger, A1 aMi, Xuenan1 aMohlke, Karen, L1 aMontasser, May, E1 aMoon, Jee-Young1 aMoreno-Macias, Hortensia1 aMorrison, Alanna, C1 aMuzny, Donna, M1 aNelson, Sarah, C1 aNilsson, Peter, M1 aO'Connell, Jeffrey, R1 aOrho-Melander, Marju1 aOrozco, Lorena1 aPalmer, Colin, N A1 aPalmer, Nicholette, D1 aPark, Cheol, Joo1 aPark, Kyong, Soo1 aPedersen, Oluf1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPost, Wendy, S1 aPreuss, Michael1 aPsaty, Bruce, M1 aQi, Qibin1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRevilla-Monsalve, Cristina1 aRich, Stephen, S1 aSamani, Nilesh1 aSchunkert, Heribert1 aSchurmann, Claudia1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSim, Xueling1 aSladek, Rob1 aSmall, Kerrin, S1 aSo, Wing, Yee1 aStilp, Adrienne, M1 aTai, Shyong, E1 aTam, Claudia, H T1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aThameem, Farook1 aTomlinson, Brian1 aTsai, Michael, Y1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 avan Dam, Rob, M1 aVasan, Ramachandran, S1 aMartinez, Karine, A Viaud1 aWang, Fei, Fei1 aWang, Xuzhi1 aWatkins, Hugh1 aWeeks, Daniel, E1 aWilson, James, G1 aWitte, Daniel, R1 aWong, Tien-Yin1 aYanek, Lisa, R1 aKathiresan, Sekar1 aRader, Daniel, J1 aRotter, Jerome, I1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aFlannick, Jason, A1 aKhera, Amit, V1 aPeloso, Gina, M1 aAMP-T2D-GENES, Myocardial Infarction Genetics Consortium1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aNHLBI TOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/897504507nas a2201189 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2022 eng d a2397-337400aRare genetic variants explain missing heritability in smoking.0 aRare genetic variants explain missing heritability in smoking c2022 Aug 043 aCommon genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
1 aJang, Seon-Kyeong1 aEvans, Luke1 aFialkowski, Allison1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBecker, Diane, M1 aBis, Joshua, C1 aBlangero, John1 aBleecker, Eugene, R1 aBoorgula, Meher, Preethi1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aJenkins, Brenda, W Campbell1 aCarson, April, P1 aChavan, Sameer1 aCupples, Adrienne, L1 aCuster, Brian1 aDamrauer, Scott, M1 aDavid, Sean, P1 ade Andrade, Mariza1 aDinardo, Carla, L1 aFingerlin, Tasha, E1 aFornage, Myriam1 aFreedman, Barry, I1 aGarrett, Melanie, E1 aGharib, Sina, A1 aGlahn, David, C1 aHaessler, Jeffrey1 aHeckbert, Susan, R1 aHokanson, John, E1 aHou, Lifang1 aHwang, Shih-Jen1 aHyman, Matthew, C1 aJudy, Renae1 aJustice, Anne, E1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKelly, Shannon1 aKim, Wonji1 aKooperberg, Charles1 aLevy, Daniel1 aLloyd-Jones, Donald, M1 aLoos, Ruth, J F1 aManichaikul, Ani, W1 aGladwin, Mark, T1 aMartin, Lisa, Warsinger1 aNouraie, Mehdi1 aMelander, Olle1 aMeyers, Deborah, A1 aMontgomery, Courtney, G1 aNorth, Kari, E1 aOelsner, Elizabeth, C1 aPalmer, Nicholette, D1 aPayton, Marinelle1 aPeljto, Anna, L1 aPeyser, Patricia, A1 aPreuss, Michael1 aPsaty, Bruce, M1 aQiao, Dandi1 aRader, Daniel, J1 aRafaels, Nicholas1 aRedline, Susan1 aReed, Robert, M1 aReiner, Alexander, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aSchwartz, David, A1 aShadyab, Aladdin, H1 aSilverman, Edwin, K1 aSmith, Nicholas, L1 aSmith, Gustav1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTang, Weihong1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aVasan, Ramachandran, S1 aGordeuk, Victor, R1 aWang, Zhe1 aWiggins, Kerri, L1 aYanek, Lisa, R1 aYang, Ivana, V1 aYoung, Kendra, A1 aYoung, Kristin, L1 aZhang, Yingze1 aLiu, Dajiang, J1 aKeller, Matthew, C1 aVrieze, Scott uhttps://chs-nhlbi.org/node/916805141nas a2201381 4500008004100000022001400041245014300055210006900198260001500267300000800282490000600290520117000296653003001466653001201496653001201508653001101520653001201531653005301543653002601596653003601622653002301658653002701681653001801708100002001726700002201746700002201768700002601790700002301816700002501839700001501864700002101879700002501900700001801925700002401943700002201967700002301989700002002012700001702032700002002049700002602069700001902095700002202114700001902136700001702155700001702172700003302189700002102222700001902243700001802262700002602280700002002306700002102326700002302347700002602370700002202396700002402418700002302442700002202465700002002487700002202507700002002529700002502549700002102574700002102595700001802616700001802634700002002652700002102672700002102693700001702714700002102731700003102752700002502783700003402808700002202842700002302864700002102887700001602908700001302924700001402937700002002951700001902971700002102990700001903011700002103030700001903051700002503070700002203095700002803117700001403145700002303159700002403182700001703206700002403223700001503247700002303262700002503285700002503310700002403335700002403359700002003383700001903403700002303422700002003445700002703465700003003492700002003522700002103542700001903563700002103582700002203603700001603625700001903641700002003660700002103680700002203701856003603723 2022 eng d a2399-364200aWhole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.0 aWhole genome sequence association analysis of fasting glucose an c2022 07 28 a7560 v53 aThe genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.
10aDiabetes Mellitus, Type 210aFasting10aGlucose10aHumans10aInsulin10aNational Heart, Lung, and Blood Institute (U.S.)10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPrecision Medicine10aReceptors, Immunologic10aUnited States1 aDiCorpo, Daniel1 aGaynor, Sheila, M1 aRussell, Emily, M1 aWesterman, Kenneth, E1 aRaffield, Laura, M1 aMajarian, Timothy, D1 aWu, Peitao1 aSarnowski, Chloe1 aHighland, Heather, M1 aJackson, Anne1 aHasbani, Natalie, R1 ade Vries, Paul, S1 aBrody, Jennifer, A1 aHidalgo, Bertha1 aGuo, Xiuqing1 aPerry, James, A1 aO'Connell, Jeffrey, R1 aLent, Samantha1 aMontasser, May, E1 aCade, Brian, E1 aJain, Deepti1 aWang, Heming1 aAlbanus, Ricardo, D'Oliveira1 aVarshney, Arushi1 aYanek, Lisa, R1 aLange, Leslie1 aPalmer, Nicholette, D1 aAlmeida, Marcio1 aPeralta, Juan, M1 aAslibekyan, Stella1 aBaldridge, Abigail, S1 aBertoni, Alain, G1 aBielak, Lawrence, F1 aChen, Chung-Shiuan1 aChen, Yii-Der Ida1 aChoi, Won, Jung1 aGoodarzi, Mark, O1 aFloyd, James, S1 aIrvin, Marguerite, R1 aKalyani, Rita, R1 aKelly, Tanika, N1 aLee, Seonwook1 aLiu, Ching-Ti1 aLoesch, Douglas1 aManson, JoAnn, E1 aMinster, Ryan, L1 aNaseri, Take1 aPankow, James, S1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aSelvin, Elizabeth1 aSmith, Jennifer, A1 aWeeks, Daniel, E1 aXu, Huichun1 aYao, Jie1 aZhao, Wei1 aParker, Stephen1 aAlonso, Alvaro1 aArnett, Donna, K1 aBlangero, John1 aBoerwinkle, Eric1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDuggirala, Ravindranath1 aHe, Jiang1 aHeckbert, Susan, R1 aKardia, Sharon, L R1 aKim, Ryan, W1 aKooperberg, Charles1 aLiu, Simin1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aShuldiner, Alan, R1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aViaud-Martinez, Karine, A1 aFlorez, Jose, C1 aWilson, James, G1 aSladek, Robert1 aRich, Stephen, S1 aRotter, Jerome, I1 aLin, Xihong1 aDupuis, Josée1 aMeigs, James, B1 aWessel, Jennifer1 aManning, Alisa, K uhttps://chs-nhlbi.org/node/915804169nas a2200757 4500008004100000022001400041245010600055210006900161260001600230520193200246100001402178700001402192700001502206700001802221700001702239700002102256700001702277700002002294700002302314700001802337700001902355700002102374700002302395700002202418700002402440700002602464700001802490700002102508700001702529700002002546700002502566700002302591700001902614700002202633700002202655700002002677700002702697700001602724700002302740700002502763700002402788700002402812700002102836700001902857700002302876700002702899700002102926700001702947700002202964700001902986700002203005700002403027700002503051700002003076700002203096700002203118700002403140700002003164700002103184700001403205700002103219710006503240710004103305710002903346856003603375 2022 eng d a1460-208300aWhole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease.0 aWholeExome Sequencing Study Identifies Four Novel Gene Loci Asso c2022 Nov 293 aDiabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.
1 aPan, Yang1 aSun, Xiao1 aMi, Xuenan1 aHuang, Zhijie1 aHsu, Yenchih1 aHixson, James, E1 aMunzy, Donna1 aMetcalf, Ginger1 aFranceschini, Nora1 aTin, Adrienne1 aKöttgen, Anna1 aFrancis, Michael1 aBrody, Jennifer, A1 aKestenbaum, Bryan1 aSitlani, Colleen, M1 aMychaleckyj, Josyf, C1 aKramer, Holly1 aLange, Leslie, A1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aIrvin, Marguerite, R1 aSmith, Jennifer, A1 aYanek, Lisa, R1 aVaidya, Dhananjay1 aChen, Yii-Der Ida1 aFornage, Myriam1 aLloyd-Jones, Donald, M1 aHou, Lifang1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aPeyser, Patricia, A1 aKardia, Sharon, L R1 aArnett, Donna, K1 aCorrea, Adolfo1 aRaffield, Laura, M1 aVasan, Ramachandran, S1 aCupple, Adrienne1 aLevy, Daniel1 aKaplan, Robert, C1 aNorth, Kari, E1 aRotter, Jerome, I1 aKooperberg, Charles1 aReiner, Alexander, P1 aPsaty, Bruce, M1 aTracy, Russell, P1 aGibbs, Richard, A1 aMorrison, Alanna, C1 aFeldman, Harold1 aBoerwinkle, Eric1 aHe, Jiang1 aKelly, Tanika, N1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Kidney Function Working Group1 aCRIC Study Investigators uhttps://chs-nhlbi.org/node/925806073nas a2201597 4500008004100000022001400041245008800055210006900143260001300212300001200225490000800237520158400245653001201829653001201841653002501853653003401878653001801912653002901930653001101959653000901970653001301979653003001992100002502022700002802047700002902075700002202104700001902126700001902145700001702164700001802181700001702199700001302216700002202229700001902251700002602270700002602296700002302322700001902345700002002364700001702384700002202401700003102423700001902454700002302473700002602496700002102522700002102543700002402564700002002588700002102608700002002629700002002649700001602669700002702685700001902712700001902731700002002750700001902770700002302789700002402812700001802836700001602854700002602870700002302896700002202919700002002941700001902961700002702980700001903007700002103026700002403047700002403071700001403095700002203109700001503131700001903146700002303165700002303188700002203211700002103233700002503254700001903279700002303298700001903321700002203340700001903362700002303381700001303404700002303417700002203440700002103462700002203483700002303505700002103528700002303549700001803572700001903590700002203609700002103631700002803652700002203680700001903702700002203721700002003743700001703763700001403780700001603794700002203810700001803832700002303850700001803873700002403891700002403915700001903939700001803958700002203976700002403998700001504022700002104037700001804058700002304076700002304099700002504122700002504147700002104172700001804193700002504211700002304236700002204259700002104281700002504302700002304327700002404350710006504374856003604439 2023 eng d a1476-468700aAberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.0 aAberrant activation of TCL1A promotes stem cell expansion in clo c2023 Apr a755-7630 v6163 aMutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
10aAlleles10aAnimals10aClonal Hematopoiesis10aGenome-Wide Association Study10aHematopoiesis10aHematopoietic Stem Cells10aHumans10aMice10aMutation10aPromoter Regions, Genetic1 aWeinstock, Joshua, S1 aGopakumar, Jayakrishnan1 aBurugula, Bala, Bharathi1 aUddin, Md, Mesbah1 aJahn, Nikolaus1 aBelk, Julia, A1 aBouzid, Hind1 aDaniel, Bence1 aMiao, Zhuang1 aLy, Nghi1 aMack, Taralynn, M1 aLuna, Sofia, E1 aProthro, Katherine, P1 aMitchell, Shaneice, R1 aLaurie, Cecelia, A1 aBroome, Jai, G1 aTaylor, Kent, D1 aGuo, Xiuqing1 aSinner, Moritz, F1 avon Falkenhausen, Aenne, S1 aKääb, Stefan1 aShuldiner, Alan, R1 aO'Connell, Jeffrey, R1 aLewis, Joshua, P1 aBoerwinkle, Eric1 aBarnes, Kathleen, C1 aChami, Nathalie1 aKenny, Eimear, E1 aLoos, Ruth, J F1 aFornage, Myriam1 aHou, Lifang1 aLloyd-Jones, Donald, M1 aRedline, Susan1 aCade, Brian, E1 aPsaty, Bruce, M1 aBis, Joshua, C1 aBrody, Jennifer, A1 aSilverman, Edwin, K1 aYun, Jeong, H1 aQiao, Dandi1 aPalmer, Nicholette, D1 aFreedman, Barry, I1 aBowden, Donald, W1 aCho, Michael, H1 aDeMeo, Dawn, L1 aVasan, Ramachandran, S1 aYanek, Lisa, R1 aBecker, Lewis, C1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aHe, Jiang1 aRienstra, Michiel1 aHarst, Pim1 aKaplan, Robert1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aArnett, Donna, K1 aIrvin, Marguerite, R1 aTiwari, Hemant1 aCutler, Michael, J1 aKnight, Stacey1 aMuhlestein, Brent1 aCorrea, Adolfo1 aRaffield, Laura, M1 aGao, Yan1 ade Andrade, Mariza1 aRotter, Jerome, I1 aRich, Stephen, S1 aTracy, Russell, P1 aKonkle, Barbara, A1 aJohnsen, Jill, M1 aWheeler, Marsha, M1 aSmith, Gustav1 aMelander, Olle1 aNilsson, Peter, M1 aCuster, Brian, S1 aDuggirala, Ravindranath1 aCurran, Joanne, E1 aBlangero, John1 aMcGarvey, Stephen1 aWilliams, Keoki1 aXiao, Shujie1 aYang, Mao1 aGu, Charles1 aChen, Yii-Der Ida1 aLee, Wen-Jane1 aMarcus, Gregory, M1 aKane, John, P1 aPullinger, Clive, R1 aShoemaker, Benjamin1 aDarbar, Dawood1 aRoden, Dan, M1 aAlbert, Christine1 aKooperberg, Charles1 aZhou, Ying1 aManson, JoAnn, E1 aDesai, Pinkal1 aJohnson, Andrew, D1 aMathias, Rasika, A1 aBlackwell, Thomas, W1 aAbecasis, Goncalo, R1 aSmith, Albert, V1 aKang, Hyun, M1 aSatpathy, Ansuman, T1 aNatarajan, Pradeep1 aKitzman, Jacob, O1 aWhitsel, Eric, A1 aReiner, Alexander, P1 aBick, Alexander, G1 aJaiswal, Siddhartha1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/938708759nas a2202509 4500008004100000022001400041245012000055210006900175260000900244300001200253490000700265520183300272100002602105700002402131700002202155700002002177700002302197700001802220700002402238700002102262700001802283700002302301700002002324700002402344700002002368700002002388700002202408700002102430700001702451700002502468700002102493700001802514700001502532700001702547700002202564700002102586700002302607700002102630700002502651700002002676700002402696700002002720700002102740700002002761700002302781700001702804700002202821700002302843700002302866700001502889700002302904700002102927700001402948700001802962700002102980700002203001700001603023700002803039700001903067700001903086700002103105700001903126700002303145700001703168700002303185700002203208700002703230700001803257700001803275700001803293700001703311700001903328700001803347700001603365700001903381700002503400700002103425700002303446700002103469700002103490700002203511700001803533700002203551700001303573700003303586700002403619700001803643700002303661700002103684700002203705700001203727700002103739700002103760700002003781700002403801700002503825700002103850700001603871700002103887700002003908700002003928700001803948700001703966700002003983700002104003700002004024700002304044700002804067700001904095700002204114700002304136700002004159700001504179700001704194700001704211700001804228700002404246700002304270700002204293700002104315700002004336700002704356700002604383700002604409700002604435700001804461700002004479700001904499700002304518700001804541700001904559700002104578700002804599700002504627700001704652700002004669700001604689700002304705700001904728700002404747700001904771700002004790700002104810700002804831700002204859700002604881700001804907700001804925700002004943700001504963700001304978700001704991700001905008700001405027700002105041700002305062700002205085700002305107700001805130700001905148700001605167700002005183700002205203700002205225700001905247700001905266700001905285700001905304700002205323700002705345700001905372700001905391700002005410700002205430700002005452700002405472700001505496700001905511700002605530700001905556700002405575700001705599700001505616700001805631700002105649700002305670700002205693700001805715700002405733700002205757700002305779700002405802700002705826700002905853700002405882700002505906700002005931700001605951700001705967700002005984700002006004700002306024700002006047700002106067700002006088700002106108700001806129700002406147700002206171700002006193856003606213 2023 eng d a1664-802100aGene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.0 aGeneeducational attainment interactions in a multipopulation gen c2023 a12353370 v143 aEducational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.
1 aFuentes, Lisa, de Las1 aSchwander, Karen, L1 aBrown, Michael, R1 aBentley, Amy, R1 aWinkler, Thomas, W1 aSung, Yun, Ju1 aMunroe, Patricia, B1 aMiller, Clint, L1 aAschard, Hugo1 aAslibekyan, Stella1 aBartz, Traci, M1 aBielak, Lawrence, F1 aChai, Jin, Fang1 aCheng, Ching-Yu1 aDorajoo, Rajkumar1 aFeitosa, Mary, F1 aGuo, Xiuqing1 aHartwig, Fernando, P1 aHorimoto, Andrea1 aKolcic, Ivana1 aLim, Elise1 aLiu, Yongmei1 aManning, Alisa, K1 aMarten, Jonathan1 aMusani, Solomon, K1 aNoordam, Raymond1 aPadmanabhan, Sandosh1 aRankinen, Tuomo1 aRichard, Melissa, A1 aRidker, Paul, M1 aSmith, Albert, V1 aVojinovic, Dina1 aZonderman, Alan, B1 aAlver, Maris1 aBoissel, Mathilde1 aChristensen, Kaare1 aFreedman, Barry, I1 aGao, Chuan1 aGiulianini, Franco1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLi, Xiaoyin1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aPoveda, Alaitz1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRobino, Antonietta1 aSofer, Tamar1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVerweij, Niek1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhan, Yiqiang1 aAmin, Najaf1 aArking, Dan, E1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aChai, Xiaoran1 aChen, Yii-Der Ida1 aChen, Xu1 aChitrala, Kumaraswamy, Naidu1 aConcas, Maria, Pina1 ade Faire, Ulf1 ade Mutsert, Renée1 ade Silva, Janaka1 ade Vries, Paul, S1 aDo, Ahn1 aFaul, Jessica, D1 aFisher, Virginia1 aFloyd, James, S1 aForrester, Terrence1 aFriedlander, Yechiel1 aGirotto, Giorgia1 aGu, Charles1 aHallmans, Göran1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHomuth, Georg1 aHunt, Steven1 aIkram, Arfan, M1 aJacobs, David, R1 aKavousi, Maryam1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aLangefeld, Carl, D1 aLiang, Jingjing1 aLiu, Kiang1 aLiu, Jianjun1 aLohman, Kurt1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMilaneschi, Yuri1 aNauck, Matthias1 aNelson, Christopher, P1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPereira, Alexandre, C1 aPerls, Thomas1 aPeters, Annette1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRice, Kenneth1 aRice, Treva, K1 aRich, Stephen, S1 aSabanayagam, Charumathi1 aSchreiner, Pamela, J1 aShu, Xiao-Ou1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aStarr, John, M1 aStrauch, Konstantin1 aTai, Shyong, E1 aTaylor, Kent, D1 aTsai, Michael, Y1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Ya-Xing1 aBin Wei, Wen-1 aWilson, Gregory1 aXuan, Deng1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aBecker, Diane, M1 aBonnefond, Amélie1 aBowden, Donald, W1 aCooper, Richard, S1 aDeary, Ian, J1 aDivers, Jasmin1 aEsko, Tõnu1 aFranks, Paul, W1 aFroguel, Philippe1 aGieger, Christian1 aJonas, Jost, B1 aKato, Norihiro1 aLakka, Timo, A1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aNorth, Kari, E1 aNtalla, Ioanna1 aPenninx, Brenda1 aSamani, Nilesh, J1 aSnieder, Harold1 aSpedicati, Beatrice1 aHarst, Pim1 aVölzke, Henry1 aWagenknecht, Lynne, E1 aWeir, David, R1 aWojczynski, Mary, K1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aBouchard, Claude1 aChasman, Daniel, I1 aEvans, Michele, K1 aFox, Ervin, R1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aKrieger, Jose, Eduardo1 aMook-Kanamori, Dennis, O1 aPeyser, Patricia, A1 aProvince, Michael, M1 aPsaty, Bruce, M1 aRudan, Igor1 aSim, Xueling1 aSmith, Blair, H1 avan Dam, Rob, M1 aDuijn, Cornelia, M1 aWong, Tien, Yin1 aArnett, Donna, K1 aRao, Dabeeru, C1 aGauderman, James1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aRotter, Jerome, I1 aFornage, Myriam uhttps://chs-nhlbi.org/node/953502914nas a2200553 4500008004100000245010000041210006900141260001600210520130500226100002001531700001901551700002001570700002501590700002101615700002401636700002101660700002101681700002401702700002001726700002101746700001601767700002401783700001701807700002401824700001701848700002301865700002301888700002201911700001801933700002001951700001601971700002001987700002002007700001902027700001902046700002002065700002402085700002102109700001902130700001802149700002202167700001402189700001502203700001702218700002302235700001702258710004902275856003602324 2023 eng d00aMachine learning models for blood pressure phenotypes combining multiple polygenic risk scores.0 aMachine learning models for blood pressure phenotypes combining c2023 Dec 143 aWe construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1% to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8% to 5.1% (SBP) and 4.7% to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs.
1 aHrytsenko, Yana1 aShea, Benjamin1 aElgart, Michael1 aKurniansyah, Nuzulul1 aLyons, Genevieve1 aMorrison, Alanna, C1 aCarson, April, P1 aHaring, Bernhard1 aMitchel, Braxton, D1 aPsaty, Bruce, M1 aJaeger, Byron, C1 aGu, Charles1 aKooperberg, Charles1 aLevy, Daniel1 aLloyd-Jones, Donald1 aChoi, Eunhee1 aBrody, Jennifer, A1 aSmith, Jennifer, A1 aRotter, Jerome, I1 aMoll, Matthew1 aFornage, Myriam1 aSimon, Noah1 aCastaldi, Peter1 aCasanova, Ramon1 aChung, Ren-Hua1 aKaplan, Robert1 aLoos, Ruth, J F1 aKardia, Sharon, L R1 aRich, Stephen, S1 aRedline, Susan1 aKelly, Tanika1 aO'Connor, Timothy1 aZhao, Wei1 aKim, Wonji1 aGuo, Xiuqing1 aChen, Yii, Der Ida1 aSofer, Tamar1 aTrans-Omics in Precision Medicine Consortium uhttps://chs-nhlbi.org/node/958603311nas a2200829 4500008004100000022001400041245009300055210006900148260001300217300001400230490000700244520101000251653001701261653001801278653003401296653002301330653001101353653001401364653002301378100002501401700001501426700002001441700001701461700002001478700001701498700001801515700002101533700001901554700002101573700002301594700002101617700002301638700001701661700001701678700002401695700001501719700002301734700002001757700001701777700002401794700002101818700002001839700001701859700002601876700002201902700002301924700002501947700002601972700001601998700002102014700002402035700002302059700001702082700002302099700002702122700001902149700002102168700002202189700002402211700002302235700002002258700001902278700002002297700001502317700001202332700001802344700002302362700002502385700001702410700001802427856003602445 2023 eng d a1546-171800aMosaic chromosomal alterations in blood across ancestries using whole-genome sequencing.0 aMosaic chromosomal alterations in blood across ancestries using c2023 Nov a1912-19190 v553 aMegabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.
10aBlack People10aGenome, Human10aGenome-Wide Association Study10aHispanic or Latino10aHumans10aMosaicism10aPrecision Medicine1 aJakubek, Yasminka, A1 aZhou, Ying1 aStilp, Adrienne1 aBacon, Jason1 aWong, Justin, W1 aOzcan, Zuhal1 aArnett, Donna1 aBarnes, Kathleen1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aCarson, April, P1 aChasman, Daniel, I1 aChen, Jiawen1 aCho, Michael1 aConomos, Matthew, P1 aCox, Nancy1 aDoyle, Margaret, F1 aFornage, Myriam1 aGuo, Xiuqing1 aKardia, Sharon, L R1 aLewis, Joshua, P1 aLoos, Ruth, J F1 aMa, Xiaolong1 aMachiela, Mitchell, J1 aMack, Taralynn, M1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aMychaleckyj, Josyf, C1 aNorth, Kari1 aPankratz, Nathan1 aPeyser, Patricia, A1 aPreuss, Michael, H1 aPsaty, Bruce1 aRaffield, Laura, M1 aVasan, Ramachandran, S1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSilverman, Edwin, K1 aSmith, Jennifer, A1 aSmith, Aaron, P1 aTaub, Margaret1 aTaylor, Kent, D1 aYun, Jeong1 aLi, Yun1 aDesai, Pinkal1 aBick, Alexander, G1 aReiner, Alexander, P1 aScheet, Paul1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/953804607nas 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/950113865nas a2204393 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2023 eng d00aMulti-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.0 aMultiancestry genomewide study in 25 million individuals reveals c2023 Mar 313 aType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.
1 aSuzuki, Ken1 aHatzikotoulas, Konstantinos1 aSoutham, Lorraine1 aTaylor, Henry, J1 aYin, Xianyong1 aLorenz, Kim, M1 aMandla, Ravi1 aHuerta-Chagoya, Alicia1 aRayner, Nigel, W1 aBocher, Ozvan1 ade, S, V Arruda A1 aSonehara, Kyuto1 aNamba, Shinichi1 aLee, Simon, S K1 aPreuss, Michael, H1 aPetty, Lauren, E1 aSchroeder, Philip1 aVanderwerff, Brett1 aKals, Mart1 aBragg, Fiona1 aLin, Kuang1 aGuo, Xiuqing1 aZhang, Weihua1 aYao, Jie1 aKim, Young, Jin1 aGraff, Mariaelisa1 aTakeuchi, Fumihiko1 aNano, Jana1 aLamri, Amel1 aNakatochi, Masahiro1 aMoon, Sanghoon1 aScott, Robert, A1 aCook, James, P1 aLee, Jung-Jin1 aPan, Ian1 aTaliun, Daniel1 aParra, Esteban, J1 aChai, Jin-Fang1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aThorleifsson, Gudmar1 aGrarup, Niels1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aKwak, Soo-Heon1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aNongmaithem, Suraj, S1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aBrody, Jennifer, A1 aKabagambe, Edmond1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aBroadaway, Alaine1 aWilliamson, Alice1 aKamali, Zoha1 aCui, Jinrui1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAhluwalia, Tarunveer, S1 aAnand, Sonia, S1 aBertoni, Alain1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBuchanan, Thomas, A1 aBurant, Charles, F1 aButterworth, Adam, S1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDanesh, John1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGordon-Larsen, Penny1 aGross, Myron1 aGuare, Lindsay, A1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHorikoshi, Momoko1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Torben1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Kyung, Min1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLithgart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLynch, Julie, A1 aLyssenko, Valeriya1 aMaeda, Shiro1 aMamakou, Vasiliki1 aMansuri, Sohail, Rafik1 aMatsuda, Koichi1 aMeitinger, Thomas1 aMetspalu, Andres1 aMo, Huan1 aMorris, Andrew, D1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPatil, Snehal1 aPei, Pei1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPolikowsky, Hannah, G1 aPorneala, Bianca1 aPrasad, Gauri1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Katheryn1 aSabanayagam, Charumathi1 aSandow, Kevin1 aSankareswaran, Alagu1 aSattar, Naveed1 aSchönherr, Sebastian1 aShahriar, Mohammad1 aShen, Botong1 aShi, Jinxiu1 aShin, Dong, Mun1 aShojima, Nobuhiro1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aSteinthorsdottir, Valgerdur1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aTaylor, Kent, D1 aThorand, Barbara1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTran, Tam, C1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamamoto, Kenichi1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZawistowski, Matthew1 aZhang, Liang1 aZheng, Wei1 aProject, Biobank, Japan1 aBioBank, Penn, Medicine1 aCenter, Regeneron, Genetics1 aConsortium, eMERGE1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aFornage, Myriam1 aHanis, Craig, L1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aYokota, Mitsuhiro1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aPankow, James, S1 aEngert, James, C1 aBonnefond, Amélie1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aMook-Kanamori, Dennis, O1 aTuomi, Tiinamaija1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aChen, Yii-Der Ida1 aRich, Stephen, S1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aGhanbari, Mohsen1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aBowden, Donald, W1 aPalmer, Colin, N A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aLiu, Simin1 aNorth, Kari, E1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aWareham, Nicholas, J1 aLee, Juyoung1 aKim, Bong-Jo1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aGoodarzi, Mark, O1 aMohlke, Karen, L1 aLangenberg, Claudia1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aFlorez, Jose, C1 aRader, Daniel, J1 aRitchie, Marylyn, D1 aZöllner, Sebastian1 aMägi, Reedik1 aDenny, Joshua, C1 aYamauchi, Toshimasa1 aKadowaki, Takashi1 aChambers, John, C1 aC Y Ng, Maggie1 aSim, Xueling1 aBelow, Jennifer, E1 aTsao, Philip, S1 aChang, Kyong-Mi1 aMcCarthy, Mark, I1 aMeigs, James, B1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aMercader, Josep, M1 aBoehnke, Michael1 aRotter, Jerome, I1 aVujkovic, Marijana1 aVoight, Benjamin, F1 aMorris, Andrew, P1 aZeggini, Eleftheria1 aVA Million Veteran Program, AMED GRIFIN Diabetes Initiative Japan1 aInternational Consortium for Blood Pressure (ICBP)1 aMeta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) uhttps://chs-nhlbi.org/node/938504817nas a2201309 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2023 eng d a1546-171800aMulti-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.0 aMultiancestry transcriptomewide association analyses yield insig c2023 Feb a291-3000 v553 aMost transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.
10aBiology10aDrug Repositioning10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aTobacco Use10aTranscriptome1 aChen, Fang1 aWang, Xingyan1 aJang, Seon-Kyeong1 aQuach, Bryan, C1 aWeissenkampen, Dylan1 aKhunsriraksakul, Chachrit1 aYang, Lina1 aSauteraud, Renan1 aAlbert, Christine, M1 aAllred, Nicholette, D D1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBarr, Graham1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoorgula, Meher, Preethi1 aChasman, Daniel, I1 aChavan, Sameer1 aChen, Yii-der, I1 aChuang, Lee-Ming1 aCorrea, Adolfo1 aCurran, Joanne, E1 aDavid, Sean, P1 aFuentes, Lisa, de Las1 aDeka, Ranjan1 aDuggirala, Ravindranath1 aFaul, Jessica, D1 aGarrett, Melanie, E1 aGharib, Sina, A1 aGuo, Xiuqing1 aHall, Michael, E1 aHawley, Nicola, L1 aHe, Jiang1 aHobbs, Brian, D1 aHokanson, John, E1 aHsiung, Chao, A1 aHwang, Shih-Jen1 aHyde, Thomas, M1 aIrvin, Marguerite, R1 aJaffe, Andrew, E1 aJohnson, Eric, O1 aKaplan, Robert1 aKardia, Sharon, L R1 aKaufman, Joel, D1 aKelly, Tanika, N1 aKleinman, Joel, E1 aKooperberg, Charles1 aLee, I-Te1 aLevy, Daniel1 aLutz, Sharon, M1 aManichaikul, Ani, W1 aMartin, Lisa, W1 aMarx, Olivia1 aMcGarvey, Stephen, T1 aMinster, Ryan, L1 aMoll, Matthew1 aMoussa, Karine, A1 aNaseri, Take1 aNorth, Kari, E1 aOelsner, Elizabeth, C1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRafaels, Nicholas1 aRaffield, Laura, M1 aReupena, Muagututi'a, Sefuiva1 aRich, Stephen, S1 aRotter, Jerome, I1 aSchwartz, David, A1 aShadyab, Aladdin, H1 aSheu, Wayne, H-H1 aSims, Mario1 aSmith, Jennifer, A1 aSun, Xiao1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aWatson, Harold1 aWeeks, Daniel, E1 aWeir, David, R1 aYanek, Lisa, R1 aYoung, Kendra, A1 aYoung, Kristin, L1 aZhao, Wei1 aHancock, Dana, B1 aJiang, Bibo1 aVrieze, Scott1 aLiu, Dajiang, J uhttps://chs-nhlbi.org/node/941203992nas a2200925 4500008004100000245012300041210006900164260001600233520132600249100001401575700001401589700003201603700002001635700001701655700001701672700001401689700002201703700001201725700002101737700001901758700001901777700002101796700002201817700002301839700001901862700002101881700002201902700002001924700002201944700002201966700002201988700002002010700002302030700002302053700001602076700002602092700001402118700001602132700001702148700002502165700002202190700002402212700001802236700002102254700002402275700001902299700001702318700002002335700002402355700002002379700002302399700002102422700002502443700002202468700002402490700002602514700002402540700002002564700002302584700001902607700002502626700002102651700002402672700002302696700002002719700001902739700002702758700001402785700001902799700001302818700002102831700002202852700002002874700002302894700001402917700001802931700001602949710006502965856003603030 2023 eng d00aA statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.0 astatistical framework for powerful multitrait rare variant analy c2023 Nov 023 aLarge-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.
1 aLi, Xihao1 aChen, Han1 aSelvaraj, Margaret, Sunitha1 aVan Buren, Eric1 aZhou, Hufeng1 aWang, Yuxuan1 aSun, Ryan1 aMcCaw, Zachary, R1 aYu, Zhi1 aArnett, Donna, K1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aCarson, April, P1 aCarlson, Jenna, C1 aChami, Nathalie1 aChen, Yii-Der Ida1 aCurran, Joanne, E1 ade Vries, Paul, S1 aFornage, Myriam1 aFranceschini, Nora1 aFreedman, Barry, I1 aGu, Charles1 aHeard-Costa, Nancy, L1 aHe, Jiang1 aHou, Lifang1 aHung, Yi-Jen1 aIrvin, Marguerite, R1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKelly, Tanika1 aKonigsberg, Iain1 aKooperberg, Charles1 aKral, Brian, G1 aLi, Changwei1 aLoos, Ruth, J F1 aMahaney, Michael, C1 aMartin, Lisa, W1 aMathias, Rasika, A1 aMinster, Ryan, L1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aPalmer, Nicholette, D1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRedline, Susan1 aReiner, Alexander, P1 aRich, Stephen, S1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aTiwari, Hemant1 aVasan, Ramachandran, S1 aWang, Zhe1 aYanek, Lisa, R1 aYu, Bing1 aRice, Kenneth, M1 aRotter, Jerome, I1 aPeloso, Gina, M1 aNatarajan, Pradeep1 aLi, Zilin1 aLiu, Zhonghua1 aLin, Xihong1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/954304412nas a2200865 4500008004100000022001400041245010800055210006900163260001600232300001200248520183100260100002402091700002602115700002002141700001402161700001402175700002002189700002102209700001902230700002102249700001502270700002402285700001702309700002302326700002002349700002402369700002202393700002602415700002302441700002002464700001902484700001702503700002202520700002302542700002802565700002102593700002102614700002102635700002502656700002302681700002002704700001802724700002202742700002002764700002302784700002002807700002202827700001902849700002402868700001902892700001902911700002002930700001902950700003002969700002102999700002103020700001903041700001903060700001803079700002203097700002003119700002103139700001803160700002103178700002403199700002403223700002703247700001603274700002203290700002003312700002203332700002203354710013403376856003603510 2023 eng d a2574-830000aType 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.0 aType 2 Diabetes Modifies the Association of CAD Genomic Risk Var c2023 Nov 28 ae0041763 aBACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.
METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.
RESULTS: Using a Bonferroni-corrected significance threshold of <1.6×10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.
CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.
1 aHasbani, Natalie, R1 aWesterman, Kenneth, E1 aKwak, Soo, Heon1 aChen, Han1 aLi, Xihao1 aDiCorpo, Daniel1 aWessel, Jennifer1 aBis, Joshua, C1 aSarnowski, Chloe1 aWu, Peitao1 aBielak, Lawrence, F1 aGuo, Xiuqing1 aHeard-Costa, Nancy1 aKinney, Gregory1 aMahaney, Michael, C1 aMontasser, May, E1 aPalmer, Nicholette, D1 aRaffield, Laura, M1 aTerry, James, G1 aYanek, Lisa, R1 aBon, Jessica1 aBowden, Donald, W1 aBrody, Jennifer, A1 aDuggirala, Ravindranath1 aJacobs, David, R1 aKalyani, Rita, R1 aLange, Leslie, A1 aMitchell, Braxton, D1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aCarson, April1 aCurran, Joanne, E1 aFornage, Myriam1 aFreedman, Barry, I1 aGabriel, Stacey1 aGibbs, Richard, A1 aGupta, Namrata1 aKardia, Sharon, L R1 aKral, Brian, G1 aMomin, Zeineen1 aNewman, Anne, B1 aPost, Wendy, S1 aViaud-Martinez, Karine, A1 aYoung, Kendra, A1 aBecker, Lewis, C1 aBertoni, Alain1 aBlangero, John1 aCarr, John, J1 aPratte, Katherine1 aPsaty, Bruce, M1 aRich, Stephen, S1 aWu, Joseph, C1 aMalhotra, Rajeev1 aPeyser, Patricia, A1 aMorrison, Alanna, C1 aVasan, Ramachandran, S1 aLin, Xihong1 aRotter, Jerome, I1 aMeigs, James, B1 aManning, Alisa, K1 ade Vries, Paul, S1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Atherosclerosis Working Group; TOPMed Diabetes Working Group uhttps://chs-nhlbi.org/node/953703713nas a2200661 4500008004100000022001400041245015600055210006900211260000900280300001200289490000700301520176300308100002502071700003302096700001802129700002902147700002602176700002002202700001902222700002302241700001402264700002202278700002002300700002302320700001702343700002502360700001902385700001802404700002402422700002002446700002102466700002602487700002202513700002602535700002002561700001402581700002102595700001402616700001402630700002102644700002102665700002102686700002102707700002402728700002002752700002402772700002702796700002002823700002002843700001902863700002102882700002202903700002302925700002102948700002502969700002102994856003603015 2023 eng d a1664-802100aWhole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.0 aWhole genome sequence analysis of apparent treatment resistant h c2023 a12782150 v143 aApparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.
1 aArmstrong, Nicole, D1 aSrinivasasainagendra, Vinodh1 aAmmous, Farah1 aAssimes, Themistocles, L1 aBeitelshees, Amber, L1 aBrody, Jennifer1 aCade, Brian, E1 aChen, Yii-Der, Ida1 aChen, Han1 ade Vries, Paul, S1 aFloyd, James, S1 aFranceschini, Nora1 aGuo, Xiuqing1 aHellwege, Jacklyn, N1 aHouse, John, S1 aHwu, Chii-Min1 aKardia, Sharon, L R1 aLange, Ethan, M1 aLange, Leslie, A1 aMcDonough, Caitrin, W1 aMontasser, May, E1 aO'Connell, Jeffrey, R1 aShuey, Megan, M1 aSun, Xiao1 aTanner, Rikki, M1 aWang, Zhe1 aZhao, Wei1 aCarson, April, P1 aEdwards, Todd, L1 aKelly, Tanika, N1 aKenny, Eimear, E1 aKooperberg, Charles1 aLoos, Ruth, J F1 aMorrison, Alanna, C1 aMotsinger-Reif, Alison1 aPsaty, Bruce, M1 aRao, Dabeeru, C1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Jennifer, A1 aSmith, Albert, V1 aIrvin, Marguerite, R1 aArnett, Donna, K uhttps://chs-nhlbi.org/node/958105493nas a2201573 4500008004100000245011200041210006900153260001600222520100600238100001801244700002301262700002201285700002501307700002001332700001501352700001401367700002001381700002101401700002201422700001401444700001401458700002401472700002101496700002401517700001901541700002901560700002201589700001901611700001801630700002801648700002001676700001901696700001901715700002101734700002401755700001901779700001701798700002801815700001701843700002201860700002301882700002401905700001701929700001801946700002501964700002001989700002102009700001602030700002002046700001602066700001302082700001802095700002402113700001702137700002102154700002402175700002102199700002002220700002002240700001702260700002202277700002802299700002302327700002402350700001702374700002302391700003002414700002602444700002102470700002002491700001902511700002302530700001402553700002402567700002402591700001802615700002802633700002402661700002302685700002202708700002702730700001702757700002102774700002102795700002202816700002202838700002302860700001902883700002302902700001402925700002402939700002102963700002802984700002403012700001903036700002103055700002503076700002103101700002303122700002203145700002203167700002003189700002303209700001403232700002303246700001603269700002503285700002403310700002103334700002503355700001903380700002003399700002303419700002503442700002103467700002203488700002403510700002303534700002003557700002203577700002003599700001803619700002503637700001603662700001603678700002503694700002103719700001803740700002003758700001903778700002103797710006503818856003603883 2023 eng d00aWHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.0 aWHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES N c2023 Aug 223 aObesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.
1 aZhang, Xinruo1 aBrody, Jennifer, A1 aGraff, Mariaelisa1 aHighland, Heather, M1 aChami, Nathalie1 aXu, Hanfei1 aWang, Zhe1 aFerrier, Kendra1 aChittoor, Geetha1 aJosyula, Navya, S1 aLi, Xihao1 aLi, Zilin1 aAllison, Matthew, A1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBoorgula, Meher, Preethi1 aBowden, Donald, W1 aBroome, Jai, G1 aButh, Erin, J1 aCarlson, Christopher, S1 aChang, Kyong-Mi1 aChavan, Sameer1 aChiu, Yen-Feng1 aChuang, Lee-Ming1 aConomos, Matthew, P1 aDeMeo, Dawn, L1 aDu, Margaret1 aDuggirala, Ravindranath1 aEng, Celeste1 aFohner, Alison, E1 aFreedman, Barry, I1 aGarrett, Melanie, E1 aGuo, Xiuqing1 aHaiman, Chris1 aHeavner, Benjamin, D1 aHidalgo, Bertha1 aHixson, James, E1 aHo, Yuk-Lam1 aHobbs, Brian, D1 aHu, Donglei1 aHui, Qin1 aHwu, Chii-Min1 aJackson, Rebecca, D1 aJain, Deepti1 aKalyani, Rita, R1 aKardia, Sharon, L R1 aKelly, Tanika, N1 aLange, Ethan, M1 aLeNoir, Michael1 aLi, Changwei1 aLe Marchand, Loic1 aMcDonald, Merry-Lynn, N1 aMcHugh, Caitlin, P1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey1 aO'Donnell, Christopher, J1 aPalmer, Nicholette, D1 aPankow, James, S1 aPerry, James, A1 aPeters, Ulrike1 aPreuss, Michael, H1 aRao, D, C1 aRegan, Elizabeth, A1 aReupena, Sefuiva, M1 aRoden, Dan, M1 aRodriguez-Santana, Jose1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aTiwari, Hemant, K1 aVasan, Ramachandran, S1 aWang, Zeyuan1 aWeeks, Daniel, E1 aWessel, Jennifer1 aWiggins, Kerri, L1 aWilkens, Lynne, R1 aWilson, Peter, W F1 aYanek, Lisa, R1 aYoneda, Zachary, T1 aZhao, Wei1 aZöllner, Sebastian1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBlangero, John1 aBoerwinkle, Eric1 aBurchard, Esteban, G1 aCarson, April, P1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aCurran, Joanne, E1 aFornage, Myriam1 aGordeuk, Victor, R1 aHe, Jiang1 aHeckbert, Susan, R1 aHou, Lifang1 aIrvin, Marguerite, R1 aKooperberg, Charles1 aMinster, Ryan, L1 aMitchell, Braxton, D1 aNouraie, Mehdi1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aReiner, Alexander, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aShoemaker, Benjamin1 aSmith, Nicholas, L1 aTaylor, Kent, D1 aTelen, Marilyn, J1 aWeiss, Scott, T1 aZhang, Yingze1 aCosta, Nancy, Heard-1 aSun, Yan, V1 aLin, Xihong1 aCupples, Adrienne, L1 aLange, Leslie, A1 aLiu, Ching-Ti1 aLoos, Ruth, J F1 aNorth, Kari, E1 aJustice, Anne, E1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/948414002nas a2204477 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2024 eng d a1476-468700aGenetic drivers of heterogeneity in type 2 diabetes pathophysiology.0 aGenetic drivers of heterogeneity in type 2 diabetes pathophysiol c2024 Feb 193 aType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
1 aSuzuki, Ken1 aHatzikotoulas, Konstantinos1 aSoutham, Lorraine1 aTaylor, Henry, J1 aYin, Xianyong1 aLorenz, Kim, M1 aMandla, Ravi1 aHuerta-Chagoya, Alicia1 aMelloni, Giorgio, E M1 aKanoni, Stavroula1 aRayner, Nigel, W1 aBocher, Ozvan1 aArruda, Ana, Luiza1 aSonehara, Kyuto1 aNamba, Shinichi1 aLee, Simon, S K1 aPreuss, Michael, H1 aPetty, Lauren, E1 aSchroeder, Philip1 aVanderwerff, Brett1 aKals, Mart1 aBragg, Fiona1 aLin, Kuang1 aGuo, Xiuqing1 aZhang, Weihua1 aYao, Jie1 aKim, Young, Jin1 aGraff, Mariaelisa1 aTakeuchi, Fumihiko1 aNano, Jana1 aLamri, Amel1 aNakatochi, Masahiro1 aMoon, Sanghoon1 aScott, Robert, A1 aCook, James, P1 aLee, Jung-Jin1 aPan, Ian1 aTaliun, Daniel1 aParra, Esteban, J1 aChai, Jin-Fang1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aThorleifsson, Gudmar1 aGrarup, Niels1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aKwak, Soo-Heon1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aNongmaithem, Suraj, S1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aBrody, Jennifer, A1 aKabagambe, Edmond1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aBroadaway, Alaine1 aWilliamson, Alice1 aKamali, Zoha1 aCui, Jinrui1 aThangam, Manonanthini1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAhluwalia, Tarunveer, S1 aAnand, Sonia, S1 aBertoni, Alain1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBuchanan, Thomas, A1 aBurant, Charles, F1 aButterworth, Adam, S1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDanesh, John1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGordon-Larsen, Penny1 aGross, Myron1 aGuare, Lindsay, A1 aHackinger, Sophie1 aHakaste, Liisa1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHorikoshi, Momoko1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Torben1 aKamanu, Frederick, K1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Kyung, Min1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLigthart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLynch, Julie, A1 aLyssenko, Valeriya1 aMaeda, Shiro1 aMamakou, Vasiliki1 aMansuri, Sohail, Rafik1 aMatsuda, Koichi1 aMeitinger, Thomas1 aMelander, Olle1 aMetspalu, Andres1 aMo, Huan1 aMorris, Andrew, D1 aMoura, Filipe, A1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPatil, Snehal1 aPei, Pei1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPolikowsky, Hannah, G1 aPorneala, Bianca1 aPrasad, Gauri1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Katheryn1 aSabanayagam, Charumathi1 aSandow, Kevin1 aSankareswaran, Alagu1 aSattar, Naveed1 aSchönherr, Sebastian1 aShahriar, Mohammad1 aShen, Botong1 aShi, Jinxiu1 aShin, Dong, Mun1 aShojima, Nobuhiro1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aSteinthorsdottir, Valgerdur1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aTaylor, Kent, D1 aThorand, Barbara1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTran, Tam, C1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamamoto, Kenichi1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZawistowski, Matthew1 aZhang, Liang1 aZheng, Wei1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aFornage, Myriam1 aHanis, Craig, L1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aYokota, Mitsuhiro1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aPankow, James, S1 aEngert, James, C1 aBonnefond, Amélie1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aMook-Kanamori, Dennis, O1 aTuomi, Tiinamaija1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aChen, Yii-Der Ida1 aRich, Stephen, S1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aGhanbari, Mohsen1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aBowden, Donald, W1 aPalmer, Colin, N A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aLiu, Simin1 aNorth, Kari, E1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aWareham, Nicholas, J1 aLee, Juyoung1 aKim, Bong-Jo1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aAhlqvist, Emma1 aGoodarzi, Mark, O1 aMohlke, Karen, L1 aLangenberg, Claudia1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aFlorez, Jose, C1 aRader, Daniel, J1 aRitchie, Marylyn, D1 aZöllner, Sebastian1 aMägi, Reedik1 aMarston, Nicholas, A1 aRuff, Christian, T1 avan Heel, David, A1 aFiner, Sarah1 aDenny, Joshua, C1 aYamauchi, Toshimasa1 aKadowaki, Takashi1 aChambers, John, C1 aC Y Ng, Maggie1 aSim, Xueling1 aBelow, Jennifer, E1 aTsao, Philip, S1 aChang, Kyong-Mi1 aMcCarthy, Mark, I1 aMeigs, James, B1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aMercader, Josep, M1 aBoehnke, Michael1 aRotter, Jerome, I1 aVujkovic, Marijana1 aVoight, Benjamin, F1 aMorris, Andrew, P1 aZeggini, Eleftheria1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/961904874nas a2201033 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2024 eng d a1758-919300aMulti-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.0 aMultiomics and pathway analyses of genomewide associations impli c2024 Jan 20 a140 v163 aBACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.
METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.
RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.
CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.
10aAged10aCognition10aGenome-Wide Association Study10aHumans10aMemory10aMicroRNAs10aMultiomics10aPolymorphism, Single Nucleotide1 aMei, Hao1 aSimino, Jeannette1 aLi, Lianna1 aJiang, Fan1 aBis, Joshua, C1 aDavies, Gail1 aHill, David1 aXia, Charley1 aGudnason, Vilmundur1 aYang, Qiong1 aLahti, Jari1 aSmith, Jennifer, A1 aKirin, Mirna1 aDe Jager, Philip1 aArmstrong, Nicola, J1 aGhanbari, Mohsen1 aKolcic, Ivana1 aMoran, Christopher1 aTeumer, Alexander1 aSargurupremraj, Murali1 aMahmud, Shamsed1 aFornage, Myriam1 aZhao, Wei1 aSatizabal, Claudia, L1 aPolasek, Ozren1 aRäikkönen, Katri1 aLiewald, David, C1 aHomuth, Georg1 aCallisaya, Michele1 aMather, Karen, A1 aWindham, Gwen1 aZemunik, Tatijana1 aPalotie, Aarno1 aPattie, Alison1 avan der Auwera, Sandra1 aThalamuthu, Anbupalam1 aKnopman, David, S1 aRudan, Igor1 aStarr, John, M1 aWittfeld, Katharina1 aKochan, Nicole, A1 aGriswold, Michael, E1 aVitart, Veronique1 aBrodaty, Henry1 aGottesman, Rebecca1 aCox, Simon, R1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aChasman, Daniel, I1 aGrodstein, Francine1 aSachdev, Perminder, S1 aSrikanth, Velandai1 aHayward, Caroline1 aWilson, James, F1 aEriksson, Johan, G1 aKardia, Sharon, L R1 aGrabe, Hans, J1 aBennett, David, A1 aIkram, Arfan, M1 aDeary, Ian, J1 aDuijn, Cornelia, M1 aLauner, Lenore1 aFitzpatrick, Annette, L1 aSeshadri, Sudha1 aBressler, Jan1 aDebette, Stephanie1 aMosley, Thomas, H uhttps://chs-nhlbi.org/node/9578