02719nas a2200469 4500008004100000022001400041245010800055210006900163260001600232300001100248490000700259520132600266653000901592653001001601653002801611653001901639653002401658653002801682653003401710653003301744653002201777653001801799653003401817653001101851653002501862653002701887653002001914653002101934653002001955653001801975100002401993700002102017700001902038700002202057700002502079700002202104700002102126700002502147700002102172700002002193856003602213 2015 eng d a1097-025800aGeneralized estimating equations for genome-wide association studies using longitudinal phenotype data.0 aGeneralized estimating equations for genomewide association stud c2015 Jan 15 a118-300 v343 a
Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.
10aAged10aAging10aCardiovascular Diseases10aCohort Studies10aComputer Simulation10aCross-Sectional Studies10aEpidemiologic Research Design10aGene-Environment Interaction10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aMeta-Analysis as Topic10aModels, Genetic10aPharmacogenetics10aRisk Assessment10aUnited States1 aSitlani, Colleen, M1 aRice, Kenneth, M1 aLumley, Thomas1 aMcKnight, Barbara1 aCupples, Adrienne, L1 aAvery, Christy, L1 aNoordam, Raymond1 aStricker, Bruno, H C1 aWhitsel, Eric, A1 aPsaty, Bruce, M uhttps://chs-nhlbi.org/node/660204580nas a2200937 4500008004100000022001400041245022100055210006900276260001300345300001200358490000700370520179400377100002102171700002402192700002202216700002202238700002702260700002202287700002002309700002102329700001602350700002102366700001602387700001202403700002102415700001902436700002302455700001902478700002302497700002102520700002402541700002502565700001502590700002102605700002902626700002202655700002302677700002202700700001902722700002002741700001702761700002202778700001202800700002002812700002102832700001802853700002302871700002302894700002902917700001802946700002502964700002102989700001903010700002503029700002403054700001903078700001703097700002303114700002003137700002403157700002203181700002003203700001803223700002003241700002503261700002803286700002403314700002103338700002403359700001903383700002103402700001703423700002903440700002403469700002203493700002703515700002003542700002303562700002103585856003603606 2017 eng d a1468-624400aA genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.0 agenomewide interaction analysis of tricyclictetracyclic antidepr c2017 May a313-3230 v543 aBACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.
METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.
CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.
1 aNoordam, Raymond1 aSitlani, Colleen, M1 aAvery, Christy, L1 aStewart, James, D1 aGogarten, Stephanie, M1 aWiggins, Kerri, L1 aTrompet, Stella1 aWarren, Helen, R1 aSun, Fangui1 aEvans, Daniel, S1 aLi, Xiaohui1 aLi, Jin1 aSmith, Albert, V1 aBis, Joshua, C1 aBrody, Jennifer, A1 aBusch, Evan, L1 aCaulfield, Mark, J1 aChen, Yii-der, I1 aCummings, Steven, R1 aCupples, Adrienne, L1 aDuan, Qing1 aFranco, Oscar, H1 aMéndez-Giráldez, Rául1 aHarris, Tamara, B1 aHeckbert, Susan, R1 avan Heemst, Diana1 aHofman, Albert1 aFloyd, James, S1 aKors, Jan, A1 aLauner, Lenore, J1 aLi, Yun1 aLi-Gao, Ruifang1 aLange, Leslie, A1 aLin, Henry, J1 ade Mutsert, Renée1 aNapier, Melanie, D1 aNewton-Cheh, Christopher1 aPoulter, Neil1 aReiner, Alexander, P1 aRice, Kenneth, M1 aRoach, Jeffrey1 aRodriguez, Carlos, J1 aRosendaal, Frits, R1 aSattar, Naveed1 aSever, Peter1 aSeyerle, Amanda, A1 aSlagboom, Eline1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStott, David, J1 aStürmer, Til1 aTaylor, Kent, D1 aThornton, Timothy, A1 aUitterlinden, André, G1 aWilhelmsen, Kirk, C1 aWilson, James, G1 aGudnason, Vilmundur1 aJukema, Wouter1 aLaurie, Cathy, C1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aStricker, Bruno, H1 aWhitsel, Eric, A uhttps://chs-nhlbi.org/node/735304416nas a2200913 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520169200286653003701978653002902015653001902044653003802063653001802101653003402119653001102153653002302164653003602187653001702223653001402240653002502254100002402279700001702303700001902320700001902339700001802358700002802376700002002404700002802424700001902452700003002471700002402501700002102525700002402546700002102570700002302591700002602614700001902640700002002659700002202679700002202701700002602723700001802749700002302767700002102790700002502811700002202836700002702858700002102885700002602906700001702932700002702949700002102976700002002997700001903017700002303036700002403059700002403083700002003107700001503127700002003142700002903162700002303191700002203214700001903236700002003255700003103275700002303306700002103329700002503350700002603375700002003401700002503421700002003446856003603466 2017 eng d a1537-660500aLow-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.0 aLowFrequency Synonymous Coding Variation in CYP2R1 Has Large Eff c2017 Aug 03 a227-2380 v1013 aVitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
10aCholestanetriol 26-Monooxygenase10aCytochrome P450 Family 210aGene Frequency10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMultiple Sclerosis10aPolymorphism, Single Nucleotide10aRisk Factors10aVitamin D10aVitamin D Deficiency1 aManousaki, Despoina1 aDudding, Tom1 aHaworth, Simon1 aHsu, Yi-Hsiang1 aLiu, Ching-Ti1 aMedina-Gómez, Carolina1 aVoortman, Trudy1 avan der Velde, Nathalie1 aMelhus, Håkan1 aRobinson-Cohen, Cassianne1 aCousminer, Diana, L1 aNethander, Maria1 aVandenput, Liesbeth1 aNoordam, Raymond1 aForgetta, Vincenzo1 aGreenwood, Celia, M T1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aZemel, Babette, S1 aMitchell, Jonathan, A1 aTaylor, Bruce1 aLorentzon, Mattias1 aKarlsson, Magnus1 aJaddoe, Vincent, V W1 aTiemeier, Henning1 aCampos-Obando, Natalia1 aFranco, Oscar, H1 aUtterlinden, Andre, G1 aBroer, Linda1 avan Schoor, Natasja, M1 aHam, Annelies, C1 aIkram, Arfan, M1 aKarasik, David1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aHeijer, Martin, den1 aWang, Thomas, J1 aLind, Lars1 aOrwoll, Eric, S1 aMook-Kanamori, Dennis, O1 aMichaëlsson, Karl1 aKestenbaum, Bryan1 aOhlsson, Claes1 aMellström, Dan1 ade Groot, Lisette, C P G M1 aGrant, Struan, F A1 aKiel, Douglas, P1 aZillikens, Carola, M1 aRivadeneira, Fernando1 aSawcer, Stephen1 aTimpson, Nicholas, J1 aRichards, Brent uhttps://chs-nhlbi.org/node/748710328nas a2203505 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2018 eng d a1546-171800aGenetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.0 aGenetic analysis of over 1 million people identifies 535 new loc c2018 Oct a1412-14250 v503 aHigh blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
1 aEvangelou, Evangelos1 aWarren, Helen, R1 aMosen-Ansorena, David1 aMifsud, Borbala1 aPazoki, Raha1 aGao, He1 aNtritsos, Georgios1 aDimou, Niki1 aCabrera, Claudia, P1 aKaraman, Ibrahim1 aNg, Fu, Liang1 aEvangelou, Marina1 aWitkowska, Katarzyna1 aTzanis, Evan1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aEdwards, Digna, R Velez1 aSun, Yan, V1 aCho, Kelly1 aGaziano, Michael1 aWilson, Peter, W F1 aTsao, Philip, S1 aKovesdy, Csaba, P1 aEsko, Tõnu1 aMägi, Reedik1 aMilani, Lili1 aAlmgren, Peter1 aBoutin, Thibaud1 aDebette, Stephanie1 aDing, Jun1 aGiulianini, Franco1 aHolliday, Elizabeth, G1 aJackson, Anne, U1 aLi-Gao, Ruifang1 aLin, Wei-Yu1 aLuan, Jian'an1 aMangino, Massimo1 aOldmeadow, Christopher1 aPrins, Bram, Peter1 aQian, Yong1 aSargurupremraj, Muralidharan1 aShah, Nabi1 aSurendran, Praveen1 aThériault, Sébastien1 aVerweij, Niek1 aWillems, Sara, M1 aZhao, Jing-Hua1 aAmouyel, Philippe1 aConnell, John1 ade Mutsert, Renée1 aDoney, Alex, S F1 aFarrall, Martin1 aMenni, Cristina1 aMorris, Andrew, D1 aNoordam, Raymond1 aParé, Guillaume1 aPoulter, Neil, R1 aShields, Denis, C1 aStanton, Alice1 aThom, Simon1 aAbecasis, Goncalo1 aAmin, Najaf1 aArking, Dan, E1 aAyers, Kristin, L1 aBarbieri, Caterina, M1 aBatini, Chiara1 aBis, Joshua, C1 aBlake, Tineka1 aBochud, Murielle1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrumat, Marco1 aCampbell, Archie1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChauhan, Ganesh1 aCiullo, Marina1 aCocca, Massimiliano1 aCollins, Francis1 aCordell, Heather, J1 aDavies, Gail1 ade Borst, Martin, H1 ade Geus, Eco, J1 aDeary, Ian, J1 aDeelen, Joris1 aM, Fabiola, del Greco1 aDemirkale, Cumhur, Yusuf1 aDörr, Marcus1 aEhret, Georg, B1 aElosua, Roberto1 aEnroth, Stefan1 aErzurumluoglu, Mesut1 aFerreira, Teresa1 aFrånberg, Mattias1 aFranco, Oscar, H1 aGandin, Ilaria1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGoel, Anuj1 aGow, Alan, J1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHarris, Sarah, E1 aHartman, Catharina, A1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHofer, Edith1 aHofman, Albert1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aIngelsson, Erik1 aJames, Alan1 aJansen, Rick1 aJarvelin, Marjo-Riitta1 aJoehanes, Roby1 aJohansson, Asa1 aJohnson, Andrew, D1 aJoshi, Peter, K1 aJousilahti, Pekka1 aJukema, Wouter1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKeavney, Bernard, D1 aKhaw, Kay-Tee1 aKnekt, Paul1 aKnight, Joanne1 aKolcic, Ivana1 aKooner, Jaspal, S1 aKoskinen, Seppo1 aKristiansson, Kati1 aKutalik, Zoltán1 aLaan, Maris1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLopez, Lorna, M1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aMamasoula, Chrysovalanto1 aMarrugat, Jaume1 aMarten, Jonathan1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNalls, Mike, A1 aNandakumar, Priyanka1 aNelson, Christopher, P1 aNiiranen, Teemu1 aNolte, Ilja, M1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aO'Reilly, Paul, F1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPalotie, Aarno1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPramstaller, Peter, P1 aNguyen, Quang, Tri1 aRaitakari, Olli, T1 aRen, Meixia1 aRettig, Rainer1 aRice, Kenneth1 aRidker, Paul, M1 aRied, Janina, S1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRose, Lynda, M1 aRotter, Jerome, I1 aRudan, Igor1 aRuggiero, Daniela1 aSaba, Yasaman1 aSala, Cinzia, F1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aSchmidt, Helena1 aShrine, Nick1 aSiscovick, David1 aSmith, Albert, V1 aSnieder, Harold1 aSõber, Siim1 aSorice, Rossella1 aStarr, John, M1 aStott, David, J1 aStrachan, David, P1 aStrawbridge, Rona, J1 aSundström, Johan1 aSwertz, Morris, A1 aTaylor, Kent, D1 aTeumer, Alexander1 aTobin, Martin, D1 aTomaszewski, Maciej1 aToniolo, Daniela1 aTraglia, Michela1 aTrompet, Stella1 aTuomilehto, Jaakko1 aTzourio, Christophe1 aUitterlinden, André, G1 aVaez, Ahmad1 avan der Most, Peter, J1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aVerwoert, Germaine, C1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVuckovic, Dragana1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWright, Alan, F1 aYao, Jie1 aZemunik, Tatijana1 aZhang, Weihua1 aAttia, John, R1 aButterworth, Adam, S1 aChasman, Daniel, I1 aConen, David1 aCucca, Francesco1 aDanesh, John1 aHayward, Caroline1 aHowson, Joanna, M M1 aLaakso, Markku1 aLakatta, Edward, G1 aLangenberg, Claudia1 aMelander, Olle1 aMook-Kanamori, Dennis, O1 aPalmer, Colin, N A1 aRisch, Lorenz1 aScott, Robert, A1 aScott, Rodney, J1 aSever, Peter1 aSpector, Tim, D1 aHarst, Pim1 aWareham, Nicholas, J1 aZeggini, Eleftheria1 aLevy, Daniel1 aMunroe, Patricia, B1 aNewton-Cheh, Christopher1 aBrown, Morris, J1 aMetspalu, Andres1 aHung, Adriana, M1 aO'Donnell, Christopher, J1 aEdwards, Todd, L1 aPsaty, Bruce, M1 aTzoulaki, Ioanna1 aBarnes, Michael, R1 aWain, Louise, V1 aElliott, Paul1 aCaulfield, Mark, J1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/784502630nas a2200421 4500008004100000022001400041245015400055210006900209260001600278520131200294100002501606700002401631700002101655700002301676700001901699700002001718700001201738700001901750700003301769700001901802700002301821700002901844700002201873700002501895700001801920700002001938700002101958700002801979700002202007700002102029700001502050700002302065700002202088700002102110700002002131700002102151856003602172 2018 eng d a1473-115000aGenome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry.0 aGenomewide metaanalysis of SNPby9ACEIARB and SNPbythiazide diure c2018 Jun 013 aWe evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.
1 aIrvin, Marguerite, R1 aSitlani, Colleen, M1 aNoordam, Raymond1 aAvery, Christie, L1 aBis, Joshua, C1 aFloyd, James, S1 aLi, Jin1 aLimdi, Nita, A1 aSrinivasasainagendra, Vinodh1 aStewart, James1 ade Mutsert, Renée1 aMook-Kanamori, Dennis, O1 aLipovich, Leonard1 aKleinbrink, Erica, L1 aSmith, Albert1 aBartz, Traci, M1 aWhitsel, Eric, A1 aUitterlinden, André, G1 aWiggins, Kerri, L1 aWilson, James, G1 aZhi, Degui1 aStricker, Bruno, H1 aRotter, Jerome, I1 aArnett, Donna, K1 aPsaty, Bruce, M1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/779407247nas a2202185 4500008004100000022001400041245013000055210006900185260001500254300000900269490000600278520110800284653002001392653003101412653003501443653002101478653003801499653003401537653001101571653001401582653002801596653003601624653002801660653001701688100002301705700002801728700002201756700001701778700001901795700002401814700002201838700002401860700002301884700001601907700002001923700001901943700002101962700001701983700003002000700001902030700001502049700001902064700003302083700002102116700002002137700002002157700002102177700002502198700002002223700002302243700001802266700001902284700001802303700001902321700002302340700001902363700002202382700001902404700002802423700001702451700002102468700002002489700001902509700002002528700002002548700001602568700002102584700002302605700002302628700002502651700002402676700002002700700002502720700002302745700002002768700001502788700001902803700002002822700001702842700002102859700002002880700002002900700002102920700002602941700001902967700002002986700001903006700002003025700002003045700001903065700002003084700001803104700001903122700002503141700002203166700001603188700002303204700002003227700002003247700002003267700001703287700001803304700002003322700001903342700003103361700001503392700002303407700002203430700002003452700001803472700002103490700002103511700002103532700001803553700001903571700001903590700001903609700002003628700002103648700002603669700001903695700002203714700002203736700002003758700001803778700001703796700001803813700002103831700002103852700001903873700002203892700002303914700002303937700002503960700002203985700001604007700001604023700002104039700002004060700002004080700001704100700002304117700001604140700002204156700002204178700002504200700001504225700001804240700002104258700002304279700001604302700001804318700002004336700001704356700001804373700001904391700002204410700002404432700002004456700002004476700002304496700002304519700002904542700002204571700002004593700002104613700002104634700002204655700002304677700002004700700001904720700002804739700002104767700002204788700002304810700002404833700001704857700002404874700002404898700002804922700001904950700003004969710002604999856003605025 2018 eng d a2041-172300aGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.0 aGWAS and colocalization analyses implicate carotid intimamedia t c2018 12 03 a51410 v93 aCarotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
10aADAMTS9 Protein10aAmino Acid Oxidoreductases10aCarotid Intima-Media Thickness10aCoronary Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLod Score10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors1 aFranceschini, Nora1 aGiambartolomei, Claudia1 ade Vries, Paul, S1 aFinan, Chris1 aBis, Joshua, C1 aHuntley, Rachael, P1 aLovering, Ruth, C1 aTajuddin, Salman, M1 aWinkler, Thomas, W1 aGraff, Misa1 aKavousi, Maryam1 aDale, Caroline1 aSmith, Albert, V1 aHofer, Edith1 avan Leeuwen, Elisabeth, M1 aNolte, Ilja, M1 aLu, Lingyi1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aPitkänen, Niina1 aFranzén, Oscar1 aJoshi, Peter, K1 aNoordam, Raymond1 aMarioni, Riccardo, E1 aHwang, Shih-Jen1 aMusani, Solomon, K1 aSchminke, Ulf1 aPalmas, Walter1 aIsaacs, Aaron1 aCorrea, Adolfo1 aZonderman, Alan, B1 aHofman, Albert1 aTeumer, Alexander1 aCox, Amanda, J1 aUitterlinden, André, G1 aWong, Andrew1 aSmit, Andries, J1 aNewman, Anne, B1 aBritton, Annie1 aRuusalepp, Arno1 aSennblad, Bengt1 aHedblad, Bo1 aPasaniuc, Bogdan1 aPenninx, Brenda, W1 aLangefeld, Carl, D1 aWassel, Christina, L1 aTzourio, Christophe1 aFava, Cristiano1 aBaldassarre, Damiano1 aO'Leary, Daniel, H1 aTeupser, Daniel1 aKuh, Diana1 aTremoli, Elena1 aMannarino, Elmo1 aGrossi, Enzo1 aBoerwinkle, Eric1 aSchadt, Eric, E1 aIngelsson, Erik1 aVeglia, Fabrizio1 aRivadeneira, Fernando1 aBeutner, Frank1 aChauhan, Ganesh1 aHeiss, Gerardo1 aSnieder, Harold1 aCampbell, Harry1 aVölzke, Henry1 aMarkus, Hugh, S1 aDeary, Ian, J1 aJukema, Wouter1 ade Graaf, Jacqueline1 aPrice, Jacqueline1 aPott, Janne1 aHopewell, Jemma, C1 aLiang, Jingjing1 aThiery, Joachim1 aEngmann, Jorgen1 aGertow, Karl1 aRice, Kenneth1 aTaylor, Kent, D1 aDhana, Klodian1 aKiemeney, Lambertus, A L M1 aLind, Lars1 aRaffield, Laura, M1 aLauner, Lenore, J1 aHoldt, Lesca, M1 aDörr, Marcus1 aDichgans, Martin1 aTraylor, Matthew1 aSitzer, Matthias1 aKumari, Meena1 aKivimaki, Mika1 aNalls, Mike, A1 aMelander, Olle1 aRaitakari, Olli1 aFranco, Oscar, H1 aRueda-Ochoa, Oscar, L1 aRoussos, Panos1 aWhincup, Peter, H1 aAmouyel, Philippe1 aGiral, Philippe1 aAnugu, Pramod1 aWong, Quenna1 aMalik, Rainer1 aRauramaa, Rainer1 aBurkhardt, Ralph1 aHardy, Rebecca1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aMorris, Richard, W1 aStrawbridge, Rona, J1 aWannamethee, Goya1 aHägg, Sara1 aShah, Sonia1 aMcLachlan, Stela1 aTrompet, Stella1 aSeshadri, Sudha1 aKurl, Sudhir1 aHeckbert, Susan, R1 aRing, Susan1 aHarris, Tamara, B1 aLehtimäki, Terho1 aGalesloot, Tessel, E1 aShah, Tina1 ade Faire, Ulf1 aPlagnol, Vincent1 aRosamond, Wayne, D1 aPost, Wendy1 aZhu, Xiaofeng1 aZhang, Xiaoling1 aGuo, Xiuqing1 aSaba, Yasaman1 aDehghan, Abbas1 aSeldenrijk, Adrie1 aMorrison, Alanna, C1 aHamsten, Anders1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLawlor, Deborah, A1 aMook-Kanamori, Dennis, O1 aBowden, Donald, W1 aSchmidt, Helena1 aWilson, James, F1 aWilson, James, G1 aRotter, Jerome, I1 aWardlaw, Joanna, M1 aDeanfield, John1 aHalcox, Julian1 aLyytikäinen, Leo-Pekka1 aLoeffler, Markus1 aEvans, Michele, K1 aDebette, Stephanie1 aHumphries, Steve, E1 aVölker, Uwe1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aBjörkegren, Johan, L M1 aCasas, Juan, P1 aO'Donnell, Christopher, J1 aMEGASTROKE Consortium uhttps://chs-nhlbi.org/node/791312060nas a2203745 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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/768608664nas a2202749 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2018 eng d a1546-171800aMulti-ethnic genome-wide association study for atrial fibrillation.0 aMultiethnic genomewide association study for atrial fibrillation c2018 Sep a1225-12330 v503 aAtrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
1 aRoselli, Carolina1 aChaffin, Mark, D1 aWeng, Lu-Chen1 aAeschbacher, Stefanie1 aAhlberg, Gustav1 aAlbert, Christine, M1 aAlmgren, Peter1 aAlonso, Alvaro1 aAnderson, Christopher, D1 aAragam, Krishna, G1 aArking, Dan, E1 aBarnard, John1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aBihlmeyer, Nathan, A1 aBis, Joshua, C1 aBloom, Heather, L1 aBoerwinkle, Eric1 aBottinger, Erwin, B1 aBrody, Jennifer, A1 aCalkins, Hugh1 aCampbell, Archie1 aCappola, Thomas, P1 aCarlquist, John1 aChasman, Daniel, I1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aChoi, Eue-Keun1 aChoi, Seung, Hoan1 aChristophersen, Ingrid, E1 aChung, Mina, K1 aCole, John, W1 aConen, David1 aCook, James1 aCrijns, Harry, J1 aCutler, Michael, J1 aDamrauer, Scott, M1 aDaniels, Brian, R1 aDarbar, Dawood1 aDelgado, Graciela1 aDenny, Joshua, C1 aDichgans, Martin1 aDörr, Marcus1 aDudink, Elton, A1 aDudley, Samuel, C1 aEsa, Nada1 aEsko, Tõnu1 aEskola, Markku1 aFatkin, Diane1 aFelix, Stephan, B1 aFord, Ian1 aFranco, Oscar, H1 aGeelhoed, Bastiaan1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGupta, Namrata1 aGustafsson, Stefan1 aGutmann, Rebecca1 aHamsten, Anders1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHernesniemi, Jussi1 aHocking, Lynne, J1 aHofman, Albert1 aHorimoto, Andrea, R V R1 aHuang, Jie1 aHuang, Paul, L1 aHuffman, Jennifer1 aIngelsson, Erik1 aIpek, Esra, Gucuk1 aIto, Kaoru1 aJimenez-Conde, Jordi1 aJohnson, Renee1 aJukema, Wouter1 aKääb, Stefan1 aKähönen, Mika1 aKamatani, Yoichiro1 aKane, John, P1 aKastrati, Adnan1 aKathiresan, Sekar1 aKatschnig-Winter, Petra1 aKavousi, Maryam1 aKessler, Thorsten1 aKietselaer, Bas, L1 aKirchhof, Paulus1 aKleber, Marcus, E1 aKnight, Stacey1 aKrieger, Jose, E1 aKubo, Michiaki1 aLauner, Lenore, J1 aLaurikka, Jari1 aLehtimäki, Terho1 aLeineweber, Kirsten1 aLemaitre, Rozenn, N1 aLi, Man1 aLim, Hong, Euy1 aLin, Henry, J1 aLin, Honghuang1 aLind, Lars1 aLindgren, Cecilia, M1 aLokki, Marja-Liisa1 aLondon, Barry1 aLoos, Ruth, J F1 aLow, Siew-Kee1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMacfarlane, Peter, W1 aMagnusson, Patrik, K1 aMahajan, Anubha1 aMalik, Rainer1 aMansur, Alfredo, J1 aMarcus, Gregory, M1 aMargolin, Lauren1 aMargulies, Kenneth, B1 aMärz, Winfried1 aMcManus, David, D1 aMelander, Olle1 aMohanty, Sanghamitra1 aMontgomery, Jay, A1 aMorley, Michael, P1 aMorris, Andrew, P1 aMüller-Nurasyid, Martina1 aNatale, Andrea1 aNazarian, Saman1 aNeumann, Benjamin1 aNewton-Cheh, Christopher1 aNiemeijer, Maartje, N1 aNikus, Kjell1 aNilsson, Peter1 aNoordam, Raymond1 aOellers, Heidi1 aOlesen, Morten, S1 aOrho-Melander, Marju1 aPadmanabhan, Sandosh1 aPak, Hui-Nam1 aParé, Guillaume1 aPedersen, Nancy, L1 aPera, Joanna1 aPereira, Alexandre1 aPorteous, David1 aPsaty, Bruce, M1 aPulit, Sara, L1 aPullinger, Clive, R1 aRader, Daniel, J1 aRefsgaard, Lena1 aRibasés, Marta1 aRidker, Paul, M1 aRienstra, Michiel1 aRisch, Lorenz1 aRoden, Dan, M1 aRosand, Jonathan1 aRosenberg, Michael, A1 aRost, Natalia1 aRotter, Jerome, I1 aSaba, Samir1 aSandhu, Roopinder, K1 aSchnabel, Renate, B1 aSchramm, Katharina1 aSchunkert, Heribert1 aSchurman, Claudia1 aScott, Stuart, A1 aSeppälä, Ilkka1 aShaffer, Christian1 aShah, Svati1 aShalaby, Alaa, A1 aShim, Jaemin1 aShoemaker, Benjamin1 aSiland, Joylene, E1 aSinisalo, Juha1 aSinner, Moritz, F1 aSlowik, Agnieszka1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Gustav1 aSmith, Jonathan, D1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSun, Albert1 aSun, Han1 aSvendsen, Jesper, H1 aTanaka, Toshihiro1 aTanriverdi, Kahraman1 aTaylor, Kent, D1 aTeder-Laving, Maris1 aTeumer, Alexander1 aThériault, Sébastien1 aTrompet, Stella1 aTucker, Nathan, R1 aTveit, Arnljot1 aUitterlinden, André, G1 aHarst, Pim1 aVan Gelder, Isabelle, C1 aVan Wagoner, David, R1 aVerweij, Niek1 aVlachopoulou, Efthymia1 aVölker, Uwe1 aWang, Biqi1 aWeeke, Peter, E1 aWeijs, Bob1 aWeiss, Raul1 aWeiss, Stefan1 aWells, Quinn, S1 aWiggins, Kerri, L1 aWong, Jorge, A1 aWoo, Daniel1 aWorrall, Bradford, B1 aYang, Pil-Sung1 aYao, Jie1 aYoneda, Zachary, T1 aZeller, Tanja1 aZeng, Lingyao1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/781104963nas a2201357 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2018 eng d a2041-172300aMultiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.0 aMultiethnic metaanalysis identifies ancestryspecific and crossan c2018 Jul 30 a29760 v93 aNearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
1 aWyss, Annah, B1 aSofer, Tamar1 aLee, Mi, Kyeong1 aTerzikhan, Natalie1 aNguyen, Jennifer, N1 aLahousse, Lies1 aLatourelle, Jeanne, C1 aSmith, Albert, Vernon1 aBartz, Traci, M1 aFeitosa, Mary, F1 aGao, Wei1 aAhluwalia, Tarunveer, S1 aTang, Wenbo1 aOldmeadow, Christopher1 aDuan, Qing1 ade Jong, Kim1 aWojczynski, Mary, K1 aWang, Xin-Qun1 aNoordam, Raymond1 aHartwig, Fernando, Pires1 aJackson, Victoria, E1 aWang, Tianyuan1 aObeidat, Ma'en1 aHobbs, Brian, D1 aHuan, Tianxiao1 aGui, Hongsheng1 aParker, Margaret, M1 aHu, Donglei1 aMogil, Lauren, S1 aKichaev, Gleb1 aJin, Jianping1 aGraff, Mariaelisa1 aHarris, Tamara, B1 aKalhan, Ravi1 aHeckbert, Susan, R1 aPaternoster, Lavinia1 aBurkart, Kristin, M1 aLiu, Yongmei1 aHolliday, Elizabeth, G1 aWilson, James, G1 aVonk, Judith, M1 aSanders, Jason, L1 aBarr, Graham1 ade Mutsert, Renée1 aMenezes, Ana, Maria Bapt1 aAdams, Hieab, H H1 avan den Berge, Maarten1 aJoehanes, Roby1 aLevin, Albert, M1 aLiberto, Jennifer1 aLauner, Lenore, J1 aMorrison, Alanna, C1 aSitlani, Colleen, M1 aCeledón, Juan, C1 aKritchevsky, Stephen, B1 aScott, Rodney, J1 aChristensen, Kaare1 aRotter, Jerome, I1 aBonten, Tobias, N1 aWehrmeister, Fernando, César1 aBossé, Yohan1 aXiao, Shujie1 aOh, Sam1 aFranceschini, Nora1 aBrody, Jennifer, A1 aKaplan, Robert, C1 aLohman, Kurt1 aMcEvoy, Mark1 aProvince, Michael, A1 aRosendaal, Frits, R1 aTaylor, Kent, D1 aNickle, David, C1 aWilliams, Keoki1 aBurchard, Esteban, G1 aWheeler, Heather, E1 aSin, Don, D1 aGudnason, Vilmundur1 aNorth, Kari, E1 aFornage, Myriam1 aPsaty, Bruce, M1 aMyers, Richard, H1 aO'Connor, George1 aHansen, Torben1 aLaurie, Cathy, C1 aCassano, Patricia, A1 aSung, Joohon1 aKim, Woo, Jin1 aAttia, John, R1 aLange, Leslie1 aBoezen, Marike1 aThyagarajan, Bharat1 aRich, Stephen, S1 aMook-Kanamori, Dennis, O1 aHorta, Bernardo, Lessa1 aUitterlinden, André, G1 aIm, Hae, Kyung1 aCho, Michael, H1 aBrusselle, Guy, G1 aGharib, Sina, A1 aDupuis, Josée1 aManichaikul, Ani1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/781911027nas a2203421 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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 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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/779208823nas 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 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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/778813143nas a2204261 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2019 eng d a1546-171800aA catalog of genetic loci associated with kidney function from analyses of a million individuals.0 acatalog of genetic loci associated with kidney function from ana c2019 06 a957-9720 v513 aChronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aInheritance Patterns10aKidney Function Tests10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRenal Insufficiency, Chronic10aUromodulin1 aWuttke, Matthias1 aLi, Yong1 aLi, Man1 aSieber, Karsten, B1 aFeitosa, Mary, F1 aGorski, Mathias1 aTin, Adrienne1 aWang, Lihua1 aChu, Audrey, Y1 aHoppmann, Anselm1 aKirsten, Holger1 aGiri, Ayush1 aChai, Jin-Fang1 aSveinbjornsson, Gardar1 aTayo, Bamidele, O1 aNutile, Teresa1 aFuchsberger, Christian1 aMarten, Jonathan1 aCocca, Massimiliano1 aGhasemi, Sahar1 aXu, Yizhe1 aHorn, Katrin1 aNoce, Damia1 avan der Most, Peter, J1 aSedaghat, Sanaz1 aYu, Zhi1 aAkiyama, Masato1 aAfaq, Saima1 aAhluwalia, Tarunveer, S1 aAlmgren, Peter1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoissel, Mathilde1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrenner, Hermann1 aBrumat, Marco1 aBurkhardt, Ralph1 aButterworth, Adam, S1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCanouil, Mickaël1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aChee, Miao-Ling1 aChee, Miao-Li1 aChen, Xu1 aCheng, Ching-Yu1 aCheng, Yurong1 aChristensen, Kaare1 aCifkova, Renata1 aCiullo, Marina1 aConcas, Maria, Pina1 aCook, James, P1 aCoresh, Josef1 aCorre, Tanguy1 aSala, Cinzia, Felicita1 aCusi, Daniele1 aDanesh, John1 aDaw, Warwick1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDegenhardt, Frauke1 aDelgado, Graciela1 aDemirkan, Ayse1 aDi Angelantonio, Emanuele1 aDittrich, Katalin1 aDivers, Jasmin1 aDorajoo, Rajkumar1 aEckardt, Kai-Uwe1 aEhret, Georg1 aElliott, Paul1 aEndlich, Karlhans1 aEvans, Michele, K1 aFelix, Janine, F1 aFoo, Valencia, Hui Xian1 aFranco, Oscar, H1 aFranke, Andre1 aFreedman, Barry, I1 aFreitag-Wolf, Sandra1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGansevoort, Ron, T1 aGao, He1 aGasparini, Paolo1 aGaziano, Michael1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGiulianini, Franco1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHartman, Catharina, A1 aHayward, Caroline1 aHellwege, Jacklyn, N1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHofer, Edith1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aIndridason, Olafur, S1 aIngelsson, Erik1 aIsing, Marcus1 aJaddoe, Vincent, W V1 aJakobsdottir, Johanna1 aJonas, Jost, B1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKanai, Masahiro1 aKastarinen, Mika1 aKerr, Shona, M1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKörner, Antje1 aKovacs, Peter1 aKraja, Aldi, T1 aKrajcoviechova, Alena1 aKramer, Holly1 aKrämer, Bernhard, K1 aKronenberg, Florian1 aKubo, Michiaki1 aKuhnel, Brigitte1 aKuokkanen, Mikko1 aKuusisto, Johanna1 aLa Bianca, Martina1 aLaakso, Markku1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLee, Jeannette, Jen-Mai1 aLehne, Benjamin1 aLehtimäki, Terho1 aLieb, Wolfgang1 aLim, Su-Chi1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Jun1 aLiu, Jianjun1 aLoeffler, Markus1 aLoos, Ruth, J F1 aLucae, Susanne1 aLukas, Mary, Ann1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMahajan, Anubha1 aMartin, Nicholas, G1 aMartins, Jade1 aMärz, Winfried1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMeisinger, Christa1 aMeitinger, Thomas1 aMelander, Olle1 aMetspalu, Andres1 aMikaelsdottir, Evgenia, K1 aMilaneschi, Yuri1 aMiliku, Kozeta1 aMishra, Pashupati, P1 aMohlke, Karen, L1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMychaleckyj, Josyf, C1 aNadkarni, Girish, N1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey1 aO'Donoghue, Michelle, L1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aOrho-Melander, Marju1 aOuwehand, Willem, H1 aPadmanabhan, Sandosh1 aPalmer, Nicholette, D1 aPalsson, Runolfur1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPerola, Markus1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPodgornaia, Anna, I1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPramstaller, Peter, P1 aPreuss, Michael, H1 aPrins, Bram, P1 aProvince, Michael, A1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRizzi, Federica1 aRoberts, David, J1 aRobino, Antonietta1 aRossing, Peter1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSalvi, Erika1 aSaum, Kai-Uwe1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSchöttker, Ben1 aSchulz, Christina-Alexandra1 aSchupf, Nicole1 aShaffer, Christian, M1 aShi, Yuan1 aSmith, Albert, V1 aSmith, Blair, H1 aSoranzo, Nicole1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStringham, Heather, M1 aStumvoll, Michael1 aSvensson, Per, O1 aSzymczak, Silke1 aTai, E-Shyong1 aTajuddin, Salman, M1 aTan, Nicholas, Y Q1 aTaylor, Kent, D1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomsen, Hauke1 aThorleifsson, Gudmar1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aTzoulaki, Ioanna1 aUitterlinden, André, G1 aVaccargiu, Simona1 avan Dam, Rob, M1 aHarst, Pim1 aDuijn, Cornelia, M1 aEdward, Digna, R Velez1 aVerweij, Niek1 aVogelezang, Suzanne1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWallentin, Lars1 aWang, Ya, Xing1 aWang, Chaolong1 aWaterworth, Dawn, M1 aBin Wei, Wen1 aWhite, Harvey1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWojczynski, Mary, K1 aWong, Charlene1 aWong, Tien-Yin1 aXu, Liang1 aYang, Qiong1 aYasuda, Masayuki1 aYerges-Armstrong, Laura, M1 aZhang, Weihua1 aZonderman, Alan, B1 aRotter, Jerome, I1 aBochud, Murielle1 aPsaty, Bruce, M1 aVitart, Veronique1 aWilson, James, G1 aDehghan, Abbas1 aParsa, Afshin1 aChasman, Daniel, I1 aHo, Kevin1 aMorris, Andrew, P1 aDevuyst, Olivier1 aAkilesh, Shreeram1 aPendergrass, Sarah, A1 aSim, Xueling1 aBöger, Carsten, A1 aOkada, Yukinori1 aEdwards, Todd, L1 aSnieder, Harold1 aStefansson, Kari1 aHung, Adriana, M1 aHeid, Iris, M1 aScholz, Markus1 aTeumer, Alexander1 aKöttgen, Anna1 aPattaro, Cristian1 aLifeLines Cohort Study1 aV. A. Million Veteran Program uhttps://chs-nhlbi.org/node/810904831nas a2201009 4500008004100000022001400041245014800055210006900203260001600272300001400288490000700302520194700309653000902256653002802265653003002293653001902323653002502342653004102367653002902408653002502437653002002462653003502482653001102517653001102528653001702539653003402556653001102590653001702601653000902618653001602627653002402643653001802667653001802685653002102703653002902724653003602753653002002789653001702809653002602826653001802852653001702870100002502887700002402912700002002936700002002956700001902976700002202995700002103017700001803038700001903056700002003075700001603095700001803111700001503129700002503144700002103169700001903190700001803209700002103227700002203248700002103270700002203291700001303313700001603326700001703342700001603359700002603375700001803401700001903419700002003438700001403458700001903472700002403491700002903515700002003544700001903564700002103583700002503604700001603629700002703645700002103672700002103693700002803714700002103742700002203763856003603785 2019 eng d a1941-722500aGenome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.0 aGenomeWide Association Study of Apparent TreatmentResistant Hype c2019 Nov 15 a1146-11530 v323 aBACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.
METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.
RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.
CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
10aAged10aAntihypertensive Agents10aBlack or African American10aBlood Pressure10aCase-Control Studies10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methyltransferase 3A10aDNA-Binding Proteins10aDrug Resistance10aDystrophin-Associated Proteins10aEurope10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMiddle Aged10aMyosin Heavy Chains10aMyosin Type V10aNeuropeptides10aPharmacogenetics10aPharmacogenomic Variants10aPolymorphism, Single Nucleotide10aRisk Assessment10aRisk Factors10aTranscription Factors10aUnited States10aWhite People1 aIrvin, Marguerite, R1 aSitlani, Colleen, M1 aFloyd, James, S1 aPsaty, Bruce, M1 aBis, Joshua, C1 aWiggins, Kerri, L1 aWhitsel, Eric, A1 aStürmer, Til1 aStewart, James1 aRaffield, Laura1 aSun, Fangui1 aLiu, Ching-Ti1 aXu, Hanfei1 aCupples, Adrienne, L1 aTanner, Rikki, M1 aRossing, Peter1 aSmith, Albert1 aZilhão, Nuno, R1 aLauner, Lenore, J1 aNoordam, Raymond1 aRotter, Jerome, I1 aYao, Jie1 aLi, Xiaohui1 aGuo, Xiuqing1 aLimdi, Nita1 aSundaresan, Aishwarya1 aLange, Leslie1 aCorrea, Adolfo1 aStott, David, J1 aFord, Ian1 aJukema, Wouter1 aGudnason, Vilmundur1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aPalmas, Walter1 aWarren, Helen, R1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aO'donnell, Christopher1 aHung, Adriana, M1 aEdwards, Todd, L1 aAhluwalia, Tarunveer, S1 aArnett, Donna, K1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/937210550nas a2203325 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2019 eng d a1476-625600aMulti-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.0 aMultiAncestry GenomeWide Association Study of Lipid Levels Incor c2019 Jan 293 aAn individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
1 ade Vries, Paul, S1 aBrown, Michael, R1 aBentley, Amy, R1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aSchwander, Karen1 aKraja, Aldi, T1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDeng, Xuan1 aDorajoo, Rajkumar1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aEvangelou, Evangelos1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLee, Joseph, H1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aRiaz, Muhammad1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aConnell, John, M1 ade Faire, Ulf1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDing, Jingzhong1 aDominiczak, Anna, F1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGrabe, Hans, J1 aGrove, Megan, L1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJacobs, David, R1 aJohnson, Craig1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Steve, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLemaitre, Rozenn, N1 aLi, Yize1 aLiang, Jingjing1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMukamal, Kenneth, J1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRice, Treva, K1 aRich, Stephen, S1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTan, Nicholas1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 avan Heemst, Diana1 aVuckovic, Dragana1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Yujie1 aWang, Zhe1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aPenninx, Brenda1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aZheng, Wei1 aElliott, Paul1 aNorth, Kari, E1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aLiu, Ching-Ti1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aKardia, Sharon, L R1 aZhu, Xiaofeng1 aRotimi, Charles, N1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLiu, Jingmin1 aRotter, Jerome, I1 aGauderman, James1 aProvince, Michael, A1 aMunroe, Patricia, B1 aRice, Kenneth1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aMorrison, Alanna, C1 aInterAct Consortium1 aLifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study) uhttps://chs-nhlbi.org/node/797011178nas a2203793 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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, 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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/800506391nas a2201909 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2019 eng d a2041-172300aMulti-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.0 aMultiancestry sleepbySNP interaction analysis in 126926 individu c2019 Nov 12 a51210 v103 aBoth short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
1 aNoordam, Raymond1 aBos, Maxime, M1 aWang, Heming1 aWinkler, Thomas, W1 aBentley, Amy, R1 aKilpeläinen, Tuomas, O1 ade Vries, Paul, S1 aSung, Yun, Ju1 aSchwander, Karen1 aCade, Brian, E1 aManning, Alisa1 aAschard, Hugues1 aBrown, Michael, R1 aChen, Han1 aFranceschini, Nora1 aMusani, Solomon, K1 aRichard, Melissa1 aVojinovic, Dina1 aAslibekyan, Stella1 aBartz, Traci, M1 aFuentes, Lisa, de Las1 aFeitosa, Mary1 aHorimoto, Andrea, R1 aIlkov, Marjan1 aKho, Minjung1 aKraja, Aldi1 aLi, Changwei1 aLim, Elise1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aRankinen, Tuomo1 aTajuddin, Salman, M1 avan der Spek, Ashley1 aWang, Zhe1 aMarten, Jonathan1 aLaville, Vincent1 aAlver, Maris1 aEvangelou, Evangelos1 aGraff, Maria, E1 aHe, Meian1 aKuhnel, Brigitte1 aLyytikäinen, Leo-Pekka1 aMarques-Vidal, Pedro1 aNolte, Ilja, M1 aPalmer, Nicholette, D1 aRauramaa, Rainer1 aShu, Xiao-Ou1 aSnieder, Harold1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aAdolfo, Correa1 aBallantyne, Christie1 aBielak, Larry1 aBiermasz, Nienke, R1 aBoerwinkle, Eric1 aDimou, Niki1 aEiriksdottir, Gudny1 aGao, Chuan1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aHaba-Rubio, José1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeinzer, Raphael1 aHixson, James, E1 aHomuth, Georg1 aIkram, Arfan, M1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aLee, Jiwon1 aLiu, Jingmin1 aLohman, Kurt, K1 aLuik, Annemarie, I1 aMägi, Reedik1 aMartin, Lisa, W1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aNalls, Mike, A1 aO'Connell, Jeff1 aPeters, Annette1 aPeyser, Patricia1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRensen, Patrick, C N1 aRice, Treva, K1 aRich, Stephen, S1 aRoenneberg, Till1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aShikany, James1 aSidney, Stephen, S1 aSims, Mario1 aSitlani, Colleen, M1 aSofer, Tamar1 aStrauch, Konstantin1 aSwertz, Morris, A1 aTaylor, Kent, D1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aWaldenberger, Melanie1 aWallance, Robert, B1 aDijk, Ko Willems1 aYu, Caizheng1 aZonderman, Alan, B1 aBecker, Diane, M1 aElliott, Paul1 aEsko, Tõnu1 aGieger, Christian1 aGrabe, Hans, J1 aLakka, Timo, A1 aLehtimäki, Terho1 aNorth, Kari, E1 aPenninx, Brenda, W J H1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aXiang, Yong-Bing1 aZheng, Wei1 aArnett, Donna, K1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLoos, Ruth, J F1 aPereira, Alexandre, C1 aProvince, Mike1 aPsaty, Bruce, M1 aRotimi, Charles1 aZhu, Xiaofeng1 aAmin, Najaf1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, F1 aGuo, Xiuqing1 aGauderman, James1 aRice, Kenneth1 aKooperberg, Charles1 aMunroe, Patricia, B1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 avan Heemst, Diana1 aRedline, Susan uhttps://chs-nhlbi.org/node/820210097nas 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, 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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/797609183nas 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2019 eng d a1546-171800aTarget genes, variants, tissues and transcriptional pathways influencing human serum urate levels.0 aTarget genes variants tissues and transcriptional pathways influ c2019 Oct a1459-14740 v513 aElevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
1 aTin, Adrienne1 aMarten, Jonathan1 aKuhns, Victoria, L Halperin1 aLi, Yong1 aWuttke, Matthias1 aKirsten, Holger1 aSieber, Karsten, B1 aQiu, Chengxiang1 aGorski, Mathias1 aYu, Zhi1 aGiri, Ayush1 aSveinbjornsson, Gardar1 aLi, Man1 aChu, Audrey, Y1 aHoppmann, Anselm1 aO'Connor, Luke, J1 aPrins, Bram1 aNutile, Teresa1 aNoce, Damia1 aAkiyama, Masato1 aCocca, Massimiliano1 aGhasemi, Sahar1 avan der Most, Peter, J1 aHorn, Katrin1 aXu, Yizhe1 aFuchsberger, Christian1 aSedaghat, Sanaz1 aAfaq, Saima1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrumat, Marco1 aBurkhardt, Ralph1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aCiullo, Marina1 aConcas, Maria, Pina1 aCoresh, Josef1 aCorre, Tanguy1 aCusi, Daniele1 aFelicita, Sala, Cinzia1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDelgado, Graciela1 aDemirkan, Ayse1 aDevuyst, Olivier1 aDittrich, Katalin1 aEckardt, Kai-Uwe1 aEhret, Georg1 aEndlich, Karlhans1 aEvans, Michele, K1 aGansevoort, Ron, T1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHayward, Caroline1 aHicks, Andrew, A1 aHofer, Edith1 aHolm, Hilma1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aLewis, Raychel, M1 aIngelsson, Erik1 aJakobsdottir, Johanna1 aJonsdottir, Ingileif1 aJonsson, Helgi1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerr, Shona, M1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKörner, Antje1 aKovacs, Peter1 aKrämer, Bernhard, K1 aKronenberg, Florian1 aKubo, Michiaki1 aKuhnel, Brigitte1 aLa Bianca, Martina1 aLange, Leslie, A1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiu, Jun1 aLoeffler, Markus1 aLoos, Ruth, J F1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMahajan, Anubha1 aMartin, Nicholas, G1 aMärz, Winfried1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMeisinger, Christa1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aO'Donnell, Christopher, J1 aWilson, Otis, D1 aGaziano, Michael1 aMishra, Pashupati, P1 aMohlke, Karen, L1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMüller-Nurasyid, Martina1 aNadkarni, Girish, N1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey, R1 aOlafsson, Isleifur1 aPadmanabhan, Sandosh1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPeters, Annette1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPreuss, Michael, H1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRizzi, Federica1 aRobino, Antonietta1 aRudan, Igor1 aKrajcoviechova, Alena1 aCifkova, Renata1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSalvi, Erika1 aSchmidt, Helena1 aSchmidt, Reinhold1 aShaffer, Christian, M1 aSmith, Albert, V1 aSmith, Blair, H1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStumvoll, Michael1 aSulem, Patrick1 aTajuddin, Salman, M1 aTeren, Andrej1 aThiery, Joachim1 aThio, Chris, H L1 aThorsteinsdottir, Unnur1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aUitterlinden, André, G1 aVaccargiu, Simona1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aYang, Qiong1 aZhang, Weihua1 aZonderman, Alan, B1 aBochud, Murielle1 aWilson, James, G1 aPendergrass, Sarah, A1 aHo, Kevin1 aParsa, Afshin1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aBöger, Carsten, A1 aSnieder, Harold1 aButterworth, Adam, S1 aOkada, Yukinori1 aEdwards, Todd, L1 aStefansson, Kari1 aSusztak, Katalin1 aScholz, Markus1 aHeid, Iris, M1 aHung, Adriana, M1 aTeumer, Alexander1 aPattaro, Cristian1 aWoodward, Owen, M1 aVitart, Veronique1 aKöttgen, Anna1 aGerman Chronic Kidney Disease Study1 aLifeLines Cohort Study1 aV. A. Million Veteran Program uhttps://chs-nhlbi.org/node/820709368nas a2202785 4500008004100000022001400041245012700055210006900182260001600251520166300267100002601930700001801956700002101974700002001995700002102015700002102036700002002057700002202077700001702099700001902116700002302135700002002158700002002178700002402198700002102222700002002243700002202263700002502285700002302310700001702333700002002350700001702370700002102387700002302408700001902431700002002450700002102470700001702491700002102508700002402529700002202553700002002575700002102595700001502616700001702631700002202648700001902670700001302689700002302702700001902725700002502744700001502769700002102784700002102805700001402826700001802840700002102858700002202879700001602901700002802917700001902945700001902964700002102983700001903004700001703023700001703040700002003057700001703077700002303094700001803117700001803135700001803153700001903171700001603190700001903206700002103225700001903246700002103265700002303286700002103309700001803330700001903348700002403367700002203391700001903413700002203432700002403454700001803478700002103496700002203517700002403539700002103563700002103584700002403605700001803629700002503647700001203672700001903684700002303703700002103726700001703747700002203764700001403786700002003800700002003820700001703840700002003857700002503877700002003902700002003922700002303942700002803965700001903993700002204012700001904034700001804053700002304071700001304094700002004107700002404127700001804151700001704169700002004186700001804206700002304224700002204247700002104269700002104290700001704311700002904328700001904357700002704376700002004403700002004423700002204443700002504465700002604490700002304516700001804539700002004557700002304577700002404600700001904624700002304643700002204666700001904688700002204707700001604729700003004745700002804775700002504803700002504828700002204853700002304875700001604898700002404914700002304938700001904961700002404980700002205004700002205026700002105048700002805069700002205097700002405119700002605143700001605169700001805185700001805203700001905221700001705240700001305257700001305270700001705283700001905300700001405319700002305333700002105356700002205377700001805399700001805417700001605435700002305451700002205474700002105496700002205517700002305539700002505562700001905587700001905606700001905625700002205644700002705666700002505693700002705718700002205745700001505767700002605782700001705808700001505825700001805840700002105858700002305879700001905902700002205921700002405943700002205967700002305989700002106012700002806033700001706061700002206078700001806100700002506118700002006143700002006163700002306183700001906206700002006225700002306245700002006268700001806288700002106306700002406327700001906351700002406370700002306394700001806417700002406435700002006459700002006479700002006499710002706519856003606546 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/838106209nas a2201549 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2020 eng d a1573-728400aMendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.0 aMendelian randomization analysis does not support causal associa c2020 Jul a685-6970 v353 aEpidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.
1 aZheng, Yan1 aHuang, Tao1 aWang, Tiange1 aMei, Zhendong1 aSun, Zhonghan1 aZhang, Tao1 aEllervik, Christina1 aChai, Jin-Fang1 aSim, Xueling1 avan Dam, Rob, M1 aTai, E-Shyong1 aKoh, Woon-Puay1 aDorajoo, Rajkumar1 aSaw, Seang-Mei1 aSabanayagam, Charumathi1 aWong, Tien, Yin1 aGupta, Preeti1 aRossing, Peter1 aAhluwalia, Tarunveer, S1 aVinding, Rebecca, K1 aBisgaard, Hans1 aBønnelykke, Klaus1 aWang, Yujie1 aGraff, Mariaelisa1 aVoortman, Trudy1 avan Rooij, Frank, J A1 aHofman, Albert1 avan Heemst, Diana1 aNoordam, Raymond1 aEstampador, Angela, C1 aVarga, Tibor, V1 aEnzenbach, Cornelia1 aScholz, Markus1 aThiery, Joachim1 aBurkhardt, Ralph1 aOrho-Melander, Marju1 aSchulz, Christina-Alexandra1 aEricson, Ulrika1 aSonestedt, Emily1 aKubo, Michiaki1 aAkiyama, Masato1 aZhou, Ang1 aKilpeläinen, Tuomas, O1 aHansen, Torben1 aKleber, Marcus, E1 aDelgado, Graciela1 aMcCarthy, Mark1 aLemaitre, Rozenn, N1 aFelix, Janine, F1 aJaddoe, Vincent, W V1 aWu, Ying1 aMohlke, Karen, L1 aLehtimäki, Terho1 aWang, Carol, A1 aPennell, Craig, E1 aSchunkert, Heribert1 aKessler, Thorsten1 aZeng, Lingyao1 aWillenborg, Christina1 aPeters, Annette1 aLieb, Wolfgang1 aGrote, Veit1 aRzehak, Peter1 aKoletzko, Berthold1 aErdmann, Jeanette1 aMunz, Matthias1 aWu, Tangchun1 aHe, Meian1 aYu, Caizheng1 aLecoeur, Cécile1 aFroguel, Philippe1 aCorella, Dolores1 aMoreno, Luis, A1 aLai, Chao-Qiang1 aPitkänen, Niina1 aBoreham, Colin, A1 aRidker, Paul, M1 aRosendaal, Frits, R1 ade Mutsert, Renée1 aPower, Chris1 aPaternoster, Lavinia1 aSørensen, Thorkild, I A1 aTjønneland, Anne1 aOvervad, Kim1 aDjoussé, Luc1 aRivadeneira, Fernando1 aLee, Nanette, R1 aRaitakari, Olli, T1 aKähönen, Mika1 aViikari, Jorma1 aLanghendries, Jean-Paul1 aEscribano, Joaquin1 aVerduci, Elvira1 aDedoussis, George1 aKönig, Inke1 aBalkau, Beverley1 aColtell, Oscar1 aDallongeville, Jean1 aMeirhaeghe, Aline1 aAmouyel, Philippe1 aGottrand, Frédéric1 aPahkala, Katja1 aNiinikoski, Harri1 aHyppönen, Elina1 aMärz, Winfried1 aMackey, David, A1 aGruszfeld, Dariusz1 aTucker, Katherine, L1 aFumeron, Frédéric1 aEstruch, Ramon1 aOrdovas, Jose, M1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aMozaffarian, Dariush1 aPsaty, Bruce, M1 aNorth, Kari, E1 aChasman, Daniel, I1 aQi, Lu uhttps://chs-nhlbi.org/node/841007958nas a2202377 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2020 eng d a2041-172300aMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.0 aMultiancestry GWAS of the electrocardiographic PR interval ident c2020 May 21 a25420 v113 aThe electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
1 aNtalla, Ioanna1 aWeng, Lu-Chen1 aCartwright, James, H1 aHall, Amelia, Weber1 aSveinbjornsson, Gardar1 aTucker, Nathan, R1 aChoi, Seung, Hoan1 aChaffin, Mark, D1 aRoselli, Carolina1 aBarnes, Michael, R1 aMifsud, Borbala1 aWarren, Helen, R1 aHayward, Caroline1 aMarten, Jonathan1 aCranley, James, J1 aConcas, Maria, Pina1 aGasparini, Paolo1 aBoutin, Thibaud1 aKolcic, Ivana1 aPolasek, Ozren1 aRudan, Igor1 aAraujo, Nathalia, M1 aLima-Costa, Maria, Fernanda1 aRibeiro, Antonio, Luiz P1 aSouza, Renan, P1 aTarazona-Santos, Eduardo1 aGiedraitis, Vilmantas1 aIngelsson, Erik1 aMahajan, Anubha1 aMorris, Andrew, P1 aM, Fabiola, del Greco1 aFoco, Luisa1 aGögele, Martin1 aHicks, Andrew, A1 aCook, James, P1 aLind, Lars1 aLindgren, Cecilia, M1 aSundström, Johan1 aNelson, Christopher, P1 aRiaz, Muhammad, B1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aUlivi, Sheila1 aKähönen, Mika1 aMishra, Pashupati, P1 aMononen, Nina1 aNikus, Kjell1 aCaulfield, Mark, J1 aDominiczak, Anna1 aPadmanabhan, Sandosh1 aMontasser, May, E1 aO'Connell, Jeff, R1 aRyan, Kathleen1 aShuldiner, Alan, R1 aAeschbacher, Stefanie1 aConen, David1 aRisch, Lorenz1 aThériault, Sébastien1 aHutri-Kähönen, Nina1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aRaitakari, Olli, T1 aBarnes, Catriona, L K1 aCampbell, Harry1 aJoshi, Peter, K1 aWilson, James, F1 aIsaacs, Aaron1 aKors, Jan, A1 aDuijn, Cornelia, M1 aHuang, Paul, L1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSmith, Albert, V1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aNadkarni, Girish, N1 aPreuss, Michael, H1 aCorrea, Adolfo1 aMei, Hao1 aWilson, James1 aMeitinger, Thomas1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aWaldenberger, Melanie1 aMangino, Massimo1 aSpector, Timothy, D1 aRienstra, Michiel1 avan de Vegte, Yordi, J1 aHarst, Pim1 aVerweij, Niek1 aKääb, Stefan1 aSchramm, Katharina1 aSinner, Moritz, F1 aStrauch, Konstantin1 aCutler, Michael, J1 aFatkin, Diane1 aLondon, Barry1 aOlesen, Morten1 aRoden, Dan, M1 aShoemaker, Benjamin1 aSmith, Gustav1 aBiggs, Mary, L1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aRice, Kenneth1 aSotoodehnia, Nona1 aDe Grandi, Alessandro1 aFuchsberger, Christian1 aPattaro, Cristian1 aPramstaller, Peter, P1 aFord, Ian1 aJukema, Wouter1 aMacfarlane, Peter, W1 aTrompet, Stella1 aDörr, Marcus1 aFelix, Stephan, B1 aVölker, Uwe1 aWeiss, Stefan1 aHavulinna, Aki, S1 aJula, Antti1 aSääksjärvi, Katri1 aSalomaa, Veikko1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aLin, Henry, J1 aRotter, Jerome, I1 aTaylor, Kent, D1 aYao, Jie1 ade Mutsert, Renée1 aMaan, Arie, C1 aMook-Kanamori, Dennis, O1 aNoordam, Raymond1 aCucca, Francesco1 aDing, Jun1 aLakatta, Edward, G1 aQian, Yong1 aTarasov, Kirill, V1 aLevy, Daniel1 aLin, Honghuang1 aNewton-Cheh, Christopher, H1 aLunetta, Kathryn, L1 aMurray, Alison, D1 aPorteous, David, J1 aSmith, Blair, H1 aStricker, Bruno, H1 aUitterlinden, Andre1 avan den Berg, Marten, E1 aHaessler, Jeffrey1 aJackson, Rebecca, D1 aKooperberg, Charles1 aPeters, Ulrike1 aReiner, Alexander, P1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBoerwinkle, Eric1 aEhret, Georg, B1 aSoliman, Elsayed, Z1 aAvery, Christy, L1 aGogarten, Stephanie, M1 aKerr, Kathleen, F1 aLaurie, Cathy, C1 aSeyerle, Amanda, A1 aStilp, Adrienne1 aAssa, Solmaz1 aSaid, Abdullah1 avan der Ende, Yldau1 aLambiase, Pier, D1 aOrini, Michele1 aRamirez, Julia1 aVan Duijvenboden, Stefan1 aArnar, David, O1 aGudbjartsson, Daniel, F1 aHolm, Hilma1 aSulem, Patrick1 aThorleifsson, Gudmar1 aThorolfsdottir, Rosa, B1 aThorsteinsdottir, Unnur1 aBenjamin, Emelia, J1 aTinker, Andrew1 aStefansson, Kari1 aEllinor, Patrick, T1 aJamshidi, Yalda1 aLubitz, Steven, A1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/836803741nas 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/840711212nas a2203445 4500008004100000022001400041245008000055210006900135260001300204300001200217490000800229520148100237100002301718700001801741700001901759700002701778700002401805700001601829700002501845700002301870700001801893700002601911700002901937700002401966700002601990700002302016700001902039700002202058700002002080700001802100700002202118700001502140700003102155700001902186700002802205700002302233700002002256700002002276700002302296700002002319700002502339700001502364700002102379700002502400700002202425700002502447700001802472700002302490700002102513700002402534700002602558700002502584700002602609700002302635700001802658700002602676700002802702700001902730700002102749700002102770700002102791700002202812700002302834700002102857700002302878700001702901700002102918700002102939700002002960700002202980700002003002700002403022700002903046700001903075700001803094700002103112700001603133700002003149700002003169700002103189700001803210700002403228700002403252700002303276700002403299700002303323700001603346700002303362700001703385700002103402700001603423700002303439700002103462700002003483700002303503700002503526700002803551700002403579700003103603700002203634700002103656700002103677700002803698700002403726700002003750700002703770700002303797700001403820700002203834700001603856700001203872700001903884700002303903700002003926700002303946700001403969700001803983700002304001700002404024700002704048700002004075700002004095700001904115700002404134700002704158700002104185700002204206700001804228700002404246700001704270700002304287700002104310700002304331700002404354700002404378700002204402700002104424700002304445700002304468700001604491700002104507700002104528700002204549700001804571700001704589700001504606700001804621700001804639700002704657700002104684700002004705700001804725700002104743700002404764700001804788700002204806700002204828700002304850700002204873700002004895700002104915700001704936700002004953700002504973700002904998700002105027700002205048700001905070700001905089700001705108700002105125700001905146700002005165700002205185700001905207700002205226700001905248700002305267700002305290700002005313700001905333700002305352700001905375700002005394700002005414700001805434700001705452700002105469700002005490700001905510700002305529700001905552700002405571700002105595700001605616700001705632700002205649700002005671700002605691700002105717700001805738700002205756700002105778700002405799700002505823700002605848700002605874700002305900700001905923700002305942700002105965700002005986700002306006700002106029700002406050700002006074700002206094700001906116700001906135700002606154700002406180700002606204700002506230700002006255700002106275700002206296700002806318700002506346700002106371700002106392700002506413700002206438700002106460700002806481700001806509700002206527700002206549700001706571700002406588700001906612700001406631700002506645700002506670700001906695700002106714700002106735700002306756700002106779700003006800700001706830700002006847700001406867700001906881700002006900700001506920700001706935700002106952700002006973700001806993700002907011700002707040700001607067700003107083700002207114700002107136700002407157700002207181700002407203700002307227700002307250700002107273700002107294700002507315700001507340700002407355700001607379700002107395700001707416700001707433700002107450710006007471710002307531710002607554710004707580710002607627710002707653710002407680710002607704856003607730 2021 eng d a1476-468700aGenetic insights into biological mechanisms governing human ovarian ageing.0 aGenetic insights into biological mechanisms governing human ovar c2021 Aug a393-3970 v5963 aReproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
1 aRuth, Katherine, S1 aDay, Felix, R1 aHussain, Jazib1 aMartínez-Marchal, Ana1 aAiken, Catherine, E1 aAzad, Ajuna1 aThompson, Deborah, J1 aKnoblochova, Lucie1 aAbe, Hironori1 aTarry-Adkins, Jane, L1 aGonzalez, Javier, Martin1 aFontanillas, Pierre1 aClaringbould, Annique1 aBakker, Olivier, B1 aSulem, Patrick1 aWalters, Robin, G1 aTerao, Chikashi1 aTuron, Sandra1 aHorikoshi, Momoko1 aLin, Kuang1 aOnland-Moret, Charlotte, N1 aSankar, Aditya1 aHertz, Emil, Peter Thra1 aTimshel, Pascal, N1 aShukla, Vallari1 aBorup, Rehannah1 aOlsen, Kristina, W1 aAguilera, Paula1 aFerrer-Roda, Mònica1 aHuang, Yan1 aStankovic, Stasa1 aTimmers, Paul, R H J1 aAhearn, Thomas, U1 aAlizadeh, Behrooz, Z1 aNaderi, Elnaz1 aAndrulis, Irene, L1 aArnold, Alice, M1 aAronson, Kristan, J1 aAugustinsson, Annelie1 aBandinelli, Stefania1 aBarbieri, Caterina, M1 aBeaumont, Robin, N1 aBecher, Heiko1 aBeckmann, Matthias, W1 aBenonisdottir, Stefania1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBojesen, Stig, E1 aBolla, Manjeet, K1 aBoomsma, Dorret, I1 aBowker, Nicholas1 aBrody, Jennifer, A1 aBroer, Linda1 aBuring, Julie, E1 aCampbell, Archie1 aCampbell, Harry1 aCastelao, Jose, E1 aCatamo, Eulalia1 aChanock, Stephen, J1 aChenevix-Trench, Georgia1 aCiullo, Marina1 aCorre, Tanguy1 aCouch, Fergus, J1 aCox, Angela1 aCrisponi, Laura1 aCross, Simon, S1 aCucca, Francesco1 aCzene, Kamila1 aSmith, George Davey1 ade Geus, Eco, J C N1 ade Mutsert, Renée1 aDe Vivo, Immaculata1 aDemerath, Ellen, W1 aDennis, Joe1 aDunning, Alison, M1 aDwek, Miriam1 aEriksson, Mikael1 aEsko, Tõnu1 aFasching, Peter, A1 aFaul, Jessica, D1 aFerrucci, Luigi1 aFranceschini, Nora1 aFrayling, Timothy, M1 aGago-Dominguez, Manuela1 aMezzavilla, Massimo1 aGarcía-Closas, Montserrat1 aGieger, Christian1 aGiles, Graham, G1 aGrallert, Harald1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aGuénel, Pascal1 aHaiman, Christopher, A1 aHåkansson, Niclas1 aHall, Per1 aHayward, Caroline1 aHe, Chunyan1 aHe, Wei1 aHeiss, Gerardo1 aHøffding, Miya, K1 aHopper, John, L1 aHottenga, Jouke, J1 aHu, Frank1 aHunter, David1 aIkram, Mohammad, A1 aJackson, Rebecca, D1 aJoaquim, Micaella, D R1 aJohn, Esther, M1 aJoshi, Peter, K1 aKarasik, David1 aKardia, Sharon, L R1 aKartsonaki, Christiana1 aKarlsson, Robert1 aKitahara, Cari, M1 aKolcic, Ivana1 aKooperberg, Charles1 aKraft, Peter1 aKurian, Allison, W1 aKutalik, Zoltán1 aLa Bianca, Martina1 aLachance, Genevieve1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLaven, Joop, S E1 aLawlor, Deborah, A1 aLe Marchand, Loïc1 aLi, Jingmei1 aLindblom, Annika1 aLindström, Sara1 aLindstrom, Tricia1 aLinet, Martha1 aLiu, Yongmei1 aLiu, Simin1 aLuan, Jian'an1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMannermaa, Arto1 aMarco, Brumat1 aMarten, Jonathan1 aMartin, Nicholas, G1 aMbarek, Hamdi1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMeisinger, Christa1 aMeitinger, Thomas1 aMenni, Cristina1 aMetspalu, Andres1 aMilani, Lili1 aMilne, Roger, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMulas, Antonella1 aMulligan, Anna, M1 aMurray, Alison1 aNalls, Mike, A1 aNewman, Anne1 aNoordam, Raymond1 aNutile, Teresa1 aNyholt, Dale, R1 aOlshan, Andrew, F1 aOlsson, Håkan1 aPainter, Jodie, N1 aPatel, Alpa, V1 aPedersen, Nancy, L1 aPerjakova, Natalia1 aPeters, Annette1 aPeters, Ulrike1 aPharoah, Paul, D P1 aPolasek, Ozren1 aPorcu, Eleonora1 aPsaty, Bruce, M1 aRahman, Iffat1 aRennert, Gad1 aRennert, Hedy, S1 aRidker, Paul, M1 aRing, Susan, M1 aRobino, Antonietta1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRossouw, Jacques1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aSala, Cinzia, F1 aSaloustros, Emmanouil1 aSandler, Dale, P1 aSanna, Serena1 aSawyer, Elinor, J1 aSarnowski, Chloe1 aSchlessinger, David1 aSchmidt, Marjanka, K1 aSchoemaker, Minouk, J1 aSchraut, Katharina, E1 aScott, Christopher1 aShekari, Saleh1 aShrikhande, Amruta1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSorice, Rossella1 aSouthey, Melissa, C1 aSpector, Tim, D1 aSpinelli, John, J1 aStampfer, Meir1 aStöckl, Doris1 avan Meurs, Joyce, B J1 aStrauch, Konstantin1 aStyrkarsdottir, Unnur1 aSwerdlow, Anthony, J1 aTanaka, Toshiko1 aTeras, Lauren, R1 aTeumer, Alexander1 aÞorsteinsdottir, Unnur1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTraglia, Michela1 aTroester, Melissa, A1 aTruong, Thérèse1 aTyrrell, Jessica1 aUitterlinden, André, G1 aUlivi, Sheila1 aVachon, Celine, M1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVölzke, Henry1 aWang, Qin1 aWareham, Nicholas, J1 aWeinberg, Clarice, R1 aWeir, David, R1 aWilcox, Amber, N1 aDijk, Ko Willems1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWolk, Alicja1 aWood, Andrew, R1 aZhao, Wei1 aZygmunt, Marek1 aChen, Zhengming1 aLi, Liming1 aFranke, Lude1 aBurgess, Stephen1 aDeelen, Patrick1 aPers, Tune, H1 aGrøndahl, Marie, Louise1 aAndersen, Claus, Yding1 aPujol, Anna1 aLopez-Contreras, Andres, J1 aDaniel, Jeremy, A1 aStefansson, Kari1 aChang-Claude, Jenny1 aSchouw, Yvonne, T1 aLunetta, Kathryn, L1 aChasman, Daniel, I1 aEaston, Douglas, F1 aVisser, Jenny, A1 aOzanne, Susan, E1 aNamekawa, Satoshi, H1 aSolc, Petr1 aMurabito, Joanne, M1 aOng, Ken, K1 aHoffmann, Eva, R1 aMurray, Anna1 aRoig, Ignasi1 aPerry, John, R B1 aBiobank-based Integrative Omics Study (BIOS) Consortium1 aeQTLGen Consortium1 aBioBank Japan Project1 aChina Kadoorie Biobank Collaborative Group1 akConFab Investigators1 aLifeLines Cohort Study1 aInterAct Consortium1 a23andMe Research Team uhttps://chs-nhlbi.org/node/883506260nas a2201741 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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/900506233nas a2201609 4500008004100000022001400041245009500055210006900150260001600219520178500235100001702020700002102037700001902058700002102077700002302098700001502121700001802136700002002154700002202174700002002196700002802216700001802244700002202262700002402284700002102308700002002329700002002349700001502369700002502384700001702409700003102426700002002457700002302477700002302500700002102523700001702544700002002561700002102581700002702602700001902629700002402648700002602672700002102698700001802719700001702737700001902754700002802773700002002801700002402821700002202845700002202867700001902889700001402908700002102922700002102943700002502964700002002989700002203009700001803031700002203049700002003071700001903091700002303110700002003133700002803153700001603181700001503197700001703212700001403229700002003243700002303263700001903286700001603305700002003321700001703341700002103358700001903379700001303398700001703411700002203428700002403450700002903474700002003503700001503523700002303538700002403561700002203585700002003607700001803627700001703645700002103662700001903683700002103702700001603723700001503739700002603754700002003780700002403800700002203824700002103846700001703867700001803884700001703902700002203919700002203941700002003963700002603983700002204009700001904031700001504050700002004065700002204085700002404107700002404131700002604155700002004181700002004201700002304221700001804244700002104262700002204283700002104305700001804326700002404344700001804368700001904386700001604405700001904421700001804440700002004458700002704478700002104505700002004526700001904546700002204565856003604587 2021 eng d a1476-557800aMulti-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.0 aMultiancestry genomewide genesleep interactions identify novel l c2021 Apr 153 aLong and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
1 aWang, Heming1 aNoordam, Raymond1 aCade, Brian, E1 aSchwander, Karen1 aWinkler, Thomas, W1 aLee, Jiwon1 aSung, Yun, Ju1 aBentley, Amy, R1 aManning, Alisa, K1 aAschard, Hugues1 aKilpeläinen, Tuomas, O1 aIlkov, Marjan1 aBrown, Michael, R1 aHorimoto, Andrea, R1 aRichard, Melissa1 aBartz, Traci, M1 aVojinovic, Dina1 aLim, Elise1 aNierenberg, Jovia, L1 aLiu, Yongmei1 aChitrala, Kumaraswamynaidu1 aRankinen, Tuomo1 aMusani, Solomon, K1 aFranceschini, Nora1 aRauramaa, Rainer1 aAlver, Maris1 aZee, Phyllis, C1 aHarris, Sarah, E1 avan der Most, Peter, J1 aNolte, Ilja, M1 aMunroe, Patricia, B1 aPalmer, Nicholette, D1 aKuhnel, Brigitte1 aWeiss, Stefan1 aWen, Wanqing1 aHall, Kelly, A1 aLyytikäinen, Leo-Pekka1 aO'Connell, Jeff1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 ade Vries, Paul, S1 aArking, Dan, E1 aChen, Han1 aBoerwinkle, Eric1 aKrieger, Jose, E1 aSchreiner, Pamela, J1 aSidney, Stephen1 aShikany, James, M1 aRice, Kenneth1 aChen, Yii-Der Ida1 aGharib, Sina, A1 aBis, Joshua, C1 aLuik, Annemarie, I1 aIkram, Arfan, M1 aUitterlinden, André, G1 aAmin, Najaf1 aXu, Hanfei1 aLevy, Daniel1 aHe, Jiang1 aLohman, Kurt, K1 aZonderman, Alan, B1 aRice, Treva, K1 aSims, Mario1 aWilson, Gregory1 aSofer, Tamar1 aRich, Stephen, S1 aPalmas, Walter1 aYao, Jie1 aGuo, Xiuqing1 aRotter, Jerome, I1 aBiermasz, Nienke, R1 aMook-Kanamori, Dennis, O1 aMartin, Lisa, W1 aBarac, Ana1 aWallace, Robert, B1 aGottlieb, Daniel, J1 aKomulainen, Pirjo1 aHeikkinen, Sami1 aMägi, Reedik1 aMilani, Lili1 aMetspalu, Andres1 aStarr, John, M1 aMilaneschi, Yuri1 aWaken, R, J1 aGao, Chuan1 aWaldenberger, Melanie1 aPeters, Annette1 aStrauch, Konstantin1 aMeitinger, Thomas1 aRoenneberg, Till1 aVölker, Uwe1 aDörr, Marcus1 aShu, Xiao-Ou1 aMukherjee, Sutapa1 aHillman, David, R1 aKähönen, Mika1 aWagenknecht, Lynne, E1 aGieger, Christian1 aGrabe, Hans, J1 aZheng, Wei1 aPalmer, Lyle, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aMorrison, Alanna, C1 aPereira, Alexandre, C1 aFornage, Myriam1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLiu, Ching-Ti1 aKelly, Tanika, N1 aEvans, Michele, K1 aBouchard, Claude1 aFox, Ervin, R1 aKooperberg, Charles1 aZhu, Xiaofeng1 aLakka, Timo, A1 aEsko, Tõnu1 aNorth, Kari, E1 aDeary, Ian, J1 aSnieder, Harold1 aPenninx, Brenda, W J H1 aGauderman, James1 aRao, Dabeeru, C1 aRedline, Susan1 avan Heemst, Diana uhttps://chs-nhlbi.org/node/871402876nas a2200337 4500008004100000022001400041245014800055210006900203260000900272300001100281490000700292520184000299100002002139700001802159700002102177700002102198700002202219700002302241700001602264700002202280700002302302700002202325700002402347700002202371700002002393700002302413700001902436700002502455700002202480856003602502 2021 eng d a1663-981200aThe Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction.0 aPharmacogenetics of Statin Therapy on Clinical Events No Evidenc c2021 a6798570 v123 aThe pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with -values <5.0 × 10 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. In stage-1 meta-analysis (eight studies, = 10,769, 4,212 cases), we observed no genome-wide significant results ( < 5.0 × 10). A total of 144 genetic variants were followed-up in the second stage (three studies, = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.
1 aTrompet, Stella1 aPostmus, Iris1 aWarren, Helen, R1 aNoordam, Raymond1 aSmit, Roelof, A J1 aTheusch, Elizabeth1 aLi, Xiaohui1 aArsenault, Benoit1 aChasman, Daniel, I1 aHitman, Graham, A1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aKrauss, Ron, M1 aCupples, Adrienne, L1 aJukema, Wouter, J uhttps://chs-nhlbi.org/node/898012282nas a2204021 4500008004100000022001400041245011000055210006900165260001600234300000800250490000600258520108400264653001501348653002201363653002701385653003401412653003101446653001101477653001101488100002301499700002101522700002201543700002001565700002001585700002201605700002301627700001801650700002101668700001901689700001901708700002101727700001801748700001901766700002301785700001701808700001201825700001901837700002401856700002101880700002701901700001601928700001901944700001901963700001301982700002001995700002002015700001902035700001902054700001802073700002002091700002402111700002302135700002102158700002902179700002602208700002902234700001802263700001802281700002102299700002102320700002202341700001802363700001702381700002402398700002002422700001902442700002002461700002102481700002302502700002402525700001702549700002002566700001802586700002002604700002502624700001802649700002602667700002002693700001702713700002702730700002602757700002002783700002502803700002302828700002202851700002802873700003002901700002602931700002502957700001902982700002803001700002003029700002003049700002203069700002003091700002703111700002203138700002603160700003203186700002303218700002303241700002803264700002203292700002103314700002003335700002303355700002403378700002403402700002903426700002203455700001703477700001703494700002103511700001703532700002403549700001803573700002003591700002003611700001403631700002603645700002303671700002703694700001703721700002003738700001903758700002103777700002003798700002403818700002503842700002503867700002003892700002003912700002103932700001203953700002603965700002003991700001704011700002104028700001604049700002004065700001804085700001604103700001904119700002104138700002304159700001804182700001904200700002104219700002004240700002104260700001904281700002204300700002804322700002304350700002204373700001704395700001204412700002004424700001904444700002204463700002604485700002204511700002204533700002304555700002104578700002104599700001804620700001904638700002604657700002304683700002104706700002104727700002204748700002204770700002204792700002104814700002004835700001404855700001704869700002004886700002404906700001904930700002004949700001504969700002004984700003105004700002305035700002605058700002205084700002805106700002105134700002105155700001905176700002005195700001805215700002205233700002905255700002405284700001905308700001905327700002505346700001905371700002105390700001905411700002405430700002005454700002305474700002105497700002105518700001905539700002405558700002005582700002005602700002005622700002105642700002005663700002605683700001805709700002005727700002105747700002305768700002205791700002505813700002205838700002805860700001905888700002005907700002105927700001905948700002105967700002105988700002106009700002706030700002406057700002306081700002606104700002006130700001906150700001806169700002606187700001806213700001806231700002106249700001906270700002306289700001906312700001906331700002106350700002506371700001906396700002706415700001806442700002006460700001706480700002106497700002006518700001806538700002606556700001906582700002406601700001506625700002206640700002106662700002106683700001306704700002106717700001806738700002206756700002306778700001706801700002006818700002306838700002306861700002006884700002706904700002006931700002506951700002506976700002607001700002107027700002107048700002007069700001907089700002207108700002107130700001807151700002507169700001607194700001907210700002407229700001907253700001807272700002807290700002207318700002307340700002207363700001907385700002007404700002107424700001607445700001907461700002807480700001707508700002807525700002007553700002207573700002607595700002407621700002507645700001507670700001807685700001707703700001907720700002007739700002107759700001907780700001507799700001707814700001907831700002507850700002007875700002307895700002007918700002107938700001207959700002007971700002107991700002308012700002108035700002408056700001908080700002208099700001808121710002708139710002708166710003108193856003608224 2022 eng d a2399-364200aDifferential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.0 aDifferential and shared genetic effects on kidney function betwe c2022 Jun 13 a5800 v53 aReduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
10aCreatinine10aDiabetes Mellitus10aDiabetic Nephropathies10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney1 aWinkler, Thomas, W1 aRasheed, Humaira1 aTeumer, Alexander1 aGorski, Mathias1 aRowan, Bryce, X1 aStanzick, Kira, J1 aThomas, Laurent, F1 aTin, Adrienne1 aHoppmann, Anselm1 aChu, Audrey, Y1 aTayo, Bamidele1 aThio, Chris, H L1 aCusi, Daniele1 aChai, Jin-Fang1 aSieber, Karsten, B1 aHorn, Katrin1 aLi, Man1 aScholz, Markus1 aCocca, Massimiliano1 aWuttke, Matthias1 avan der Most, Peter, J1 aYang, Qiong1 aGhasemi, Sahar1 aNutile, Teresa1 aLi, Yong1 aPontali, Giulia1 aGünther, Felix1 aDehghan, Abbas1 aCorrea, Adolfo1 aParsa, Afshin1 aFeresin, Agnese1 ade Vries, Aiko, P J1 aZonderman, Alan, B1 aSmith, Albert, V1 aOldehinkel, Albertine, J1 aDe Grandi, Alessandro1 aRosenkranz, Alexander, R1 aFranke, Andre1 aTeren, Andrej1 aMetspalu, Andres1 aHicks, Andrew, A1 aMorris, Andrew, P1 aTönjes, Anke1 aMorgan, Anna1 aPodgornaia, Anna, I1 aPeters, Annette1 aKörner, Antje1 aMahajan, Anubha1 aCampbell, Archie1 aFreedman, Barry, I1 aSpedicati, Beatrice1 aPonte, Belen1 aSchöttker, Ben1 aBrumpton, Ben1 aBanas, Bernhard1 aKrämer, Bernhard, K1 aJung, Bettina1 aÅsvold, Bjørn, Olav1 aSmith, Blair, H1 aNing, Boting1 aPenninx, Brenda, W J H1 aVanderwerff, Brett, R1 aPsaty, Bruce, M1 aKammerer, Candace, M1 aLangefeld, Carl, D1 aHayward, Caroline1 aSpracklen, Cassandra, N1 aRobinson-Cohen, Cassianne1 aHartman, Catharina, A1 aLindgren, Cecilia, M1 aWang, Chaolong1 aSabanayagam, Charumathi1 aHeng, Chew-Kiat1 aLanzani, Chiara1 aKhor, Chiea-Chuen1 aCheng, Ching-Yu1 aFuchsberger, Christian1 aGieger, Christian1 aShaffer, Christian, M1 aSchulz, Christina-Alexandra1 aWiller, Cristen, J1 aChasman, Daniel, I1 aGudbjartsson, Daniel, F1 aRuggiero, Daniela1 aToniolo, Daniela1 aCzamara, Darina1 aPorteous, David, J1 aWaterworth, Dawn, M1 aMascalzoni, Deborah1 aMook-Kanamori, Dennis, O1 aReilly, Dermot, F1 aDaw, Warwick1 aHofer, Edith1 aBoerwinkle, Eric1 aSalvi, Erika1 aBottinger, Erwin, P1 aTai, E-Shyong1 aCatamo, Eulalia1 aRizzi, Federica1 aGuo, Feng1 aRivadeneira, Fernando1 aGuilianini, Franco1 aSveinbjornsson, Gardar1 aEhret, Georg1 aWaeber, Gérard1 aBiino, Ginevra1 aGirotto, Giorgia1 aPistis, Giorgio1 aNadkarni, Girish, N1 aDelgado, Graciela, E1 aMontgomery, Grant, W1 aSnieder, Harold1 aCampbell, Harry1 aWhite, Harvey, D1 aGao, He1 aStringham, Heather, M1 aSchmidt, Helena1 aLi, Hengtong1 aBrenner, Hermann1 aHolm, Hilma1 aKirsten, Holgen1 aKramer, Holly1 aRudan, Igor1 aNolte, Ilja, M1 aTzoulaki, Ioanna1 aOlafsson, Isleifur1 aMartins, Jade1 aCook, James, P1 aWilson, James, F1 aHalbritter, Jan1 aFelix, Janine, F1 aDivers, Jasmin1 aKooner, Jaspal, S1 aLee, Jeannette, Jen-Mai1 aO'Connell, Jeffrey1 aRotter, Jerome, I1 aLiu, Jianjun1 aXu, Jie1 aThiery, Joachim1 aArnlöv, Johan1 aKuusisto, Johanna1 aJakobsdottir, Johanna1 aTremblay, Johanne1 aChambers, John, C1 aWhitfield, John, B1 aGaziano, John, M1 aMarten, Jonathan1 aCoresh, Josef1 aJonas, Jost, B1 aMychaleckyj, Josyf, C1 aChristensen, Kaare1 aEckardt, Kai-Uwe1 aMohlke, Karen, L1 aEndlich, Karlhans1 aDittrich, Katalin1 aRyan, Kathleen, A1 aRice, Kenneth, M1 aTaylor, Kent, D1 aHo, Kevin1 aNikus, Kjell1 aMatsuda, Koichi1 aStrauch, Konstantin1 aMiliku, Kozeta1 aHveem, Kristian1 aLind, Lars1 aWallentin, Lars1 aYerges-Armstrong, Laura, M1 aRaffield, Laura, M1 aPhillips, Lawrence, S1 aLauner, Lenore, J1 aLyytikäinen, Leo-Pekka1 aLange, Leslie, A1 aCitterio, Lorena1 aKlaric, Lucija1 aIkram, Arfan, M1 aIsing, Marcus1 aKleber, Marcus, E1 aFrancescatto, Margherita1 aConcas, Maria, Pina1 aCiullo, Marina1 aPiratsu, Mario1 aOrho-Melander, Marju1 aLaakso, Markku1 aLoeffler, Markus1 aPerola, Markus1 ade Borst, Martin, H1 aGögele, Martin1 aLa Bianca, Martina1 aLukas, Mary, Ann1 aFeitosa, Mary, F1 aBiggs, Mary, L1 aWojczynski, Mary, K1 aKavousi, Maryam1 aKanai, Masahiro1 aAkiyama, Masato1 aYasuda, Masayuki1 aNauck, Matthias1 aWaldenberger, Melanie1 aChee, Miao-Li1 aChee, Miao-Ling1 aBoehnke, Michael1 aPreuss, Michael, H1 aStumvoll, Michael1 aProvince, Michael, A1 aEvans, Michele, K1 aO'Donoghue, Michelle, L1 aKubo, Michiaki1 aKähönen, Mika1 aKastarinen, Mika1 aNalls, Mike, A1 aKuokkanen, Mikko1 aGhanbari, Mohsen1 aBochud, Murielle1 aJosyula, Navya, Shilpa1 aMartin, Nicholas, G1 aTan, Nicholas, Y Q1 aPalmer, Nicholette, D1 aPirastu, Nicola1 aSchupf, Nicole1 aVerweij, Niek1 aHutri-Kähönen, Nina1 aMononen, Nina1 aBansal, Nisha1 aDevuyst, Olivier1 aMelander, Olle1 aRaitakari, Olli, T1 aPolasek, Ozren1 aManunta, Paolo1 aGasparini, Paolo1 aMishra, Pashupati, P1 aSulem, Patrick1 aMagnusson, Patrik, K E1 aElliott, Paul1 aRidker, Paul, M1 aHamet, Pavel1 aSvensson, Per, O1 aJoshi, Peter, K1 aKovacs, Peter1 aPramstaller, Peter, P1 aRossing, Peter1 aVollenweider, Peter1 aHarst, Pim1 aDorajoo, Rajkumar1 aSim, Ralene, Z H1 aBurkhardt, Ralph1 aTao, Ran1 aNoordam, Raymond1 aMägi, Reedik1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aRueedi, Rico1 avan Dam, Rob, M1 aCarroll, Robert, J1 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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 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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, 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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/910408759nas a2202509 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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/953505138nas a2201357 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2023 eng d a2041-172300aGenetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.0 aGenetic architecture of spatial electrical biomarkers for cardia c2023 Mar 14 a14110 v143 aThe 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
10aArrhythmias, Cardiac10aAtrioventricular Block10aBiomarkers10aCardiovascular Diseases10aElectrocardiography10aGenome-Wide Association Study10aHumans10aRisk Factors1 aYoung, William, J1 aHaessler, Jeffrey1 aBenjamins, Jan-Walter1 aRepetto, Linda1 aYao, Jie1 aIsaacs, Aaron1 aHarper, Andrew, R1 aRamirez, Julia1 aGarnier, Sophie1 aVan Duijvenboden, Stefan1 aBaldassari, Antoine, R1 aConcas, Maria, Pina1 aDuong, ThuyVy1 aFoco, Luisa1 aIsaksen, Jonas, L1 aMei, Hao1 aNoordam, Raymond1 aNursyifa, Casia1 aRichmond, Anne1 aSantolalla, Meddly, L1 aSitlani, Colleen, M1 aSoroush, Negin1 aThériault, Sébastien1 aTrompet, Stella1 aAeschbacher, Stefanie1 aAhmadizar, Fariba1 aAlonso, Alvaro1 aBrody, Jennifer, A1 aCampbell, Archie1 aCorrea, Adolfo1 aDarbar, Dawood1 aDe Luca, Antonio1 aDeleuze, Jean-Francois1 aEllervik, Christina1 aFuchsberger, Christian1 aGoel, Anuj1 aGrace, Christopher1 aGuo, Xiuqing1 aHansen, Torben1 aHeckbert, Susan, R1 aJackson, Rebecca, D1 aKors, Jan, A1 aLima-Costa, Maria, Fernanda1 aLinneberg, Allan1 aMacfarlane, Peter, W1 aMorrison, Alanna, C1 aNavarro, Pau1 aPorteous, David, J1 aPramstaller, Peter, P1 aReiner, Alexander, P1 aRisch, Lorenz1 aSchotten, Ulrich1 aShen, Xia1 aSinagra, Gianfranco1 aSoliman, Elsayed, Z1 aStoll, Monika1 aTarazona-Santos, Eduardo1 aTinker, Andrew1 aTrajanoska, Katerina1 aVillard, Eric1 aWarren, Helen, R1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aArking, Dan, E1 aAvery, Christy, L1 aConen, David1 aGirotto, Giorgia1 aGrarup, Niels1 aHayward, Caroline1 aJukema, Wouter1 aMook-Kanamori, Dennis, O1 aOlesen, Morten, Salling1 aPadmanabhan, Sandosh1 aPsaty, Bruce, M1 aPattaro, Cristian1 aRibeiro, Antonio, Luiz P1 aRotter, Jerome, I1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aWilson, James, G1 aOrini, Michele1 aCharron, Philippe1 aWatkins, Hugh1 aKooperberg, Charles1 aLin, Henry, J1 aWilson, James, F1 aKanters, Jørgen, K1 aSotoodehnia, Nona1 aMifsud, Borbala1 aLambiase, Pier, D1 aTereshchenko, Larisa, G1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/932203534nas a2200649 4500008004100000245010900041210006900150260001600219520168900235100002201924700001601946700002001962700002201982700001402004700002202018700001602040700002202056700002402078700002002102700002202122700001702144700002402161700001802185700002102203700002302224700002402247700001902271700002102290700002002311700001902331700002202350700002002372700001902392700002002411700001702431700001902448700001702467700002502484700002402509700001902533700002302552700001902575700002302594700002002617700002102637700001802658700002002676700002202696700002402718700002102742700002002763700001802783700001402801700001702815700001602832856003602848 2023 eng d00aGenome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.0 aGenomeWide Interaction Analysis with DASH Diet Score Identified c2023 Nov 113 aOBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).
METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.
RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1.
CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.
1 aGuirette, Melanie1 aLan, Jessie1 aMcKeown, Nicola1 aBrown, Michael, R1 aChen, Han1 ade Vries, Paul, S1 aKim, Hyunju1 aRebholz, Casey, M1 aMorrison, Alanna, C1 aBartz, Traci, M1 aFretts, Amanda, M1 aGuo, Xiuqing1 aLemaitre, Rozenn, N1 aLiu, Ching-Ti1 aNoordam, Raymond1 ade Mutsert, Renée1 aRosendaal, Frits, R1 aWang, Carol, A1 aBeilin, Lawrence1 aMori, Trevor, A1 aOddy, Wendy, H1 aPennell, Craig, E1 aChai, Jin, Fang1 aWhitton, Clare1 avan Dam, Rob, M1 aLiu, Jianjun1 aTai, Shyong, E1 aSim, Xueling1 aNeuhouser, Marian, L1 aKooperberg, Charles1 aTinker, Lesley1 aFranceschini, Nora1 aHuan, Tianxiao1 aWinkler, Thomas, W1 aBentley, Amy, R1 aGauderman, James1 aHeerkens, Luc1 aTanaka, Toshiko1 avan Rooij, Jeroen1 aMunroe, Patricia, B1 aWarren, Helen, R1 aVoortman, Trudy1 aChen, Honglei1 aRao, D, C1 aLevy, Daniel1 aMa, Jiantao uhttps://chs-nhlbi.org/node/958313865nas 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/938505739nas a2200901 4500008004100000245012500041210006900166260001600235520316300251100002003414700003103434700002303465700002103488700001803509700001503527700002303542700001303565700001703578700002203595700001803617700001803635700002303653700001503676700002203691700001703713700001803730700002503748700001703773700001803790700002103808700001903829700002203848700002003870700001503890700002003905700001603925700002503941700002403966700001903990700002404009700002404033700002504057700002104082700002404103700002404127700002204151700002004173700002104193700002104214700003004235700002004265700002104285700001204306700002104318700001904339700002004358700001904378700002104397700002304418700002104441700001604462700002504478700002104503700002404524700001904548700002204567700002004589700002304609700002304632700002404655700001904679700002104698700002204719700001804741700002204759700002004781856003604801 2023 eng d00aTime-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.0 aTimetoEvent GenomeWide Association Study for Incident Cardiovasc c2023 Jul 283 aBACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.
METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.
RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0×10 ).
CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.
CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.
1 aKwak, Soo, Heon1 aHernandez-Cancela, Ryan, B1 aDiCorpo, Daniel, A1 aCondon, David, E1 aMerino, Jordi1 aWu, Peitao1 aBrody, Jennifer, A1 aYao, Jie1 aGuo, Xiuqing1 aAhmadizar, Fariba1 aMeyer, Mariah1 aSincan, Murat1 aMercader, Josep, M1 aLee, Sujin1 aHaessler, Jeffrey1 aVy, Ha, My T1 aLin, Zhaotong1 aArmstrong, Nicole, D1 aGu, Shaopeng1 aTsao, Noah, L1 aLange, Leslie, A1 aWang, Ningyuan1 aWiggins, Kerri, L1 aTrompet, Stella1 aLiu, Simin1 aLoos, Ruth, J F1 aJudy, Renae1 aSchroeder, Philip, H1 aHasbani, Natalie, R1 aBos, Maxime, M1 aMorrison, Alanna, C1 aJackson, Rebecca, D1 aReiner, Alexander, P1 aManson, JoAnn, E1 aChaudhary, Ninad, S1 aCarmichael, Lynn, K1 aChen, Yii-Der Ida1 aTaylor, Kent, D1 aGhanbari, Mohsen1 avan Meurs, Joyce1 aPitsillides, Achilleas, N1 aPsaty, Bruce, M1 aNoordam, Raymond1 aDo, Ron1 aPark, Kyong, Soo1 aJukema, Wouter1 aKavousi, Maryam1 aCorrea, Adolfo1 aRich, Stephen, S1 aDamrauer, Scott, M1 aHajek, Catherine1 aCho, Nam, H1 aIrvin, Marguerite, R1 aPankow, James, S1 aNadkarni, Girish, N1 aSladek, Robert1 aGoodarzi, Mark, O1 aFlorez, Jose, C1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aKooperberg, Charles1 aDupuis, Josée1 aMalhotra, Rajeev1 ade Vries, Paul, S1 aLiu, Ching-Ti1 aRotter, Jerome, I1 aMeigs, James, B uhttps://chs-nhlbi.org/node/945007212nas a2201753 4500008004100000245012700041210006900168260001600237520220800253100002502461700001902486700001602505700001902521700002302540700001902563700002302582700002102605700001802626700002002644700002402664700002302688700002902711700002302740700002002763700002102783700002102804700002102825700002402846700002202870700001902892700001502911700002102926700002002947700001802967700001902985700002103004700002503025700002603050700002103076700001903097700001903116700002803135700002203163700002203185700001903207700002003226700001803246700001703264700001503281700002003296700002803316700001703344700001703361700002703378700002503405700002003430700002003450700002003470700002403490700001203514700001603526700002003542700002803562700001603590700002103606700001903627700002103646700002703667700002103694700002403715700001603739700002203755700002403777700002503801700001703826700001403843700002103857700002003878700002203898700001903920700002003939700001503959700002003974700002203994700002404016700002004040700001804060700002004078700002704098700001804125700001704143700002104160700001604181700001804197700002404215700002004239700002004259700002604279700001904305700002004324700002304344700002304367700002504390700002004415700003004435700001804465700002304483700001804506700002104524700001904545700002004564700001804584700001904602700002304621700002204644700002004666700001904686700002204705700002004727700001904747700002304766700002104789700002004810700002304830700002504853700002904878700002904907700001904936700002604955700001904981700002205000700002005022700002405042700002005066700001705086700001805103700002105121700001305142700003205155700002305187700002205210700002205232700002505254700002405279700002305303710003105326710006505357856003605422 2023 eng d00aWhole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.0 aWhole genome analysis of plasma fibrinogen reveals populationdif c2023 Jun 123 aUNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
1 aHuffman, Jennifer, E1 aNicolas, Jayna1 aHahn, Julie1 aHeath, Adam, S1 aRaffield, Laura, M1 aYanek, Lisa, R1 aBrody, Jennifer, A1 aThibord, Florian1 aAlmasy, Laura1 aBartz, Traci, M1 aBielak, Lawrence, F1 aBowler, Russell, P1 aCarrasquilla, Germán, D1 aChasman, Daniel, I1 aChen, Ming-Huei1 aEmmert, David, B1 aGhanbari, Mohsen1 aHaessle, Jeffery1 aHottenga, Jouke-Jan1 aKleber, Marcus, E1 aLe, Ngoc-Quynh1 aLee, Jiwon1 aLewis, Joshua, P1 aLi-Gao, Ruifang1 aLuan, Jian'an1 aMalmberg, Anni1 aMangino, Massimo1 aMarioni, Riccardo, E1 aMartinez-Perez, Angel1 aPankratz, Nathan1 aPolasek, Ozren1 aRichmond, Anne1 aRodriguez, Benjamin, At1 aRotter, Jerome, I1 aSteri, Maristella1 aSuchon, Pierre1 aTrompet, Stella1 aWeiss, Stefan1 aZare, Marjan1 aAuer, Paul1 aCho, Michael, H1 aChristofidou, Paraskevi1 aDavies, Gail1 ade Geus, Eco1 aDeleuze, Jean-Francois1 aDelgado, Graciela, E1 aEkunwe, Lynette1 aFaraday, Nauder1 aGögele, Martin1 aGreinacher, Andreas1 aHe, Gao1 aHoward, Tom1 aJoshi, Peter, K1 aKilpeläinen, Tuomas, O1 aLahti, Jari1 aLinneberg, Allan1 aNaitza, Silvia1 aNoordam, Raymond1 aPaüls-Vergés, Ferran1 aRich, Stephen, S1 aRosendaal, Frits, R1 aRudan, Igor1 aRyan, Kathleen, A1 aSouto, Juan, Carlos1 avan Rooij, Frank, Ja1 aWang, Heming1 aZhao, Wei1 aBecker, Lewis, C1 aBeswick, Andrew1 aBrown, Michael, R1 aCade, Brian, E1 aCampbell, Harry1 aCho, Kelly1 aCrapo, James, D1 aCurran, Joanne, E1 ade Maat, Moniek, Pm1 aDoyle, Margaret1 aElliott, Paul1 aFloyd, James, S1 aFuchsberger, Christian1 aGrarup, Niels1 aGuo, Xiuqing1 aHarris, Sarah, E1 aHou, Lifang1 aKolcic, Ivana1 aKooperberg, Charles1 aMenni, Cristina1 aNauck, Matthias1 aO'Connell, Jeffrey, R1 aOrrù, Valeria1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aSmith, Jennifer, A1 aSoria, José, Manuel1 aStott, David, J1 aVlieg, Astrid, van Hylcka1 aWatkins, Hugh1 aWillemsen, Gonneke1 aWilson, Peter1 aBen-Shlomo, Yoav1 aBlangero, John1 aBoomsma, Dorret1 aCox, Simon, R1 aDehghan, Abbas1 aEriksson, Johan, G1 aFiorillo, Edoardo1 aFornage, Myriam1 aHansen, Torben1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, Lr1 aLange, Leslie, A1 aMärz, Winfried1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aMook-Kanamori, Dennis, O1 aMorange, Pierre-Emmanuel1 aPedersen, Oluf1 aPramstaller, Peter, P1 aRedline, Susan1 aReiner, Alexander1 aRidker, Paul, M1 aSilverman, Edwin, K1 aSpector, Tim, D1 aVölker, Uwe1 aWareham, Nick1 aWilson, James, F1 aYao, Jie1 aTrégouët, David-Alexandre1 aJohnson, Andrew, D1 aWolberg, Alisa, S1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aMorrison, Alanna, C1 aSmith, Nicholas, L1 aVA Million Veteran Program1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/944914002nas 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/961907235nas a2202173 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2024 eng d a2041-172300aX-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.0 aXchromosome and kidney function evidence from a multitrait genet c2024 Jan 18 a5860 v153 aX-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
10aAndrogens10aChromosomes, Human, X10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aKidney10aMale10aPolymorphism, Single Nucleotide10aResponse Elements10aTetraspanins1 aScholz, Markus1 aHorn, Katrin1 aPott, Janne1 aWuttke, Matthias1 aKühnapfel, Andreas1 aNasr, Kamal1 aKirsten, Holger1 aLi, Yong1 aHoppmann, Anselm1 aGorski, Mathias1 aGhasemi, Sahar1 aLi, Man1 aTin, Adrienne1 aChai, Jin-Fang1 aCocca, Massimiliano1 aWang, Judy1 aNutile, Teresa1 aAkiyama, Masato1 aÅsvold, Bjørn, Olav1 aBansal, Nisha1 aBiggs, Mary, L1 aBoutin, Thibaud1 aBrenner, Hermann1 aBrumpton, Ben1 aBurkhardt, Ralph1 aCai, Jianwen1 aCampbell, Archie1 aCampbell, Harry1 aChalmers, John1 aChasman, Daniel, I1 aChee, Miao, Ling1 aChee, Miao, Li1 aChen, Xu1 aCheng, Ching-Yu1 aCifkova, Renata1 aDaviglus, Martha1 aDelgado, Graciela1 aDittrich, Katalin1 aEdwards, Todd, L1 aEndlich, Karlhans1 aGaziano, Michael1 aGiri, Ayush1 aGiulianini, Franco1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aHallan, Stein1 aHamet, Pavel1 aHartman, Catharina, A1 aHayward, Caroline1 aHeid, Iris, M1 aHellwege, Jacklyn, N1 aHolleczek, Bernd1 aHolm, Hilma1 aHutri-Kähönen, Nina1 aHveem, Kristian1 aIsermann, Berend1 aJonas, Jost, B1 aJoshi, Peter, K1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKastarinen, Mika1 aKhor, Chiea, Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKörner, Antje1 aKovacs, Peter1 aKrajcoviechova, Alena1 aKramer, Holly1 aKrämer, Bernhard, K1 aKuokkanen, Mikko1 aKähönen, Mika1 aLange, Leslie, A1 aLash, James, P1 aLehtimäki, Terho1 aLi, Hengtong1 aLin, Bridget, M1 aLiu, Jianjun1 aLoeffler, Markus1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMartin, Nicholas, G1 aMatsuda, Koichi1 aMilaneschi, Yuri1 aMishra, Pashupati, P1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMychaleckyj, Josyf, C1 aMärz, Winfried1 aNauck, Matthias1 aNikus, Kjell1 aNolte, Ilja, M1 aNoordam, Raymond1 aOkada, Yukinori1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPirastu, Nicola1 aPolasek, Ozren1 aPorteous, David, J1 aPoulain, Tanja1 aPsaty, Bruce, M1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRasheed, Humaira1 aReilly, Dermot, F1 aRice, Kenneth, M1 aRichmond, Anne1 aRidker, Paul, M1 aRotter, Jerome, I1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSchneiderman, Neil1 aSchöttker, Ben1 aSims, Mario1 aSnieder, Harold1 aStark, Klaus, J1 aStefansson, Kari1 aStocker, Hannah1 aStumvoll, Michael1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSvensson, Per, O1 aTai, E-Shyong1 aTaylor, Kent, D1 aTayo, Bamidele, O1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomas, Laurent, F1 aTremblay, Johanne1 aTönjes, Anke1 avan der Most, Peter, J1 aVitart, Veronique1 aVölker, Uwe1 aWang, Ya, Xing1 aWang, Chaolong1 aBin Wei, Wen1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWinkler, Thomas, W1 aWong, Tien-Yin1 aWoodward, Mark1 aSim, Xueling1 aChu, Audrey, Y1 aFeitosa, Mary, F1 aThorsteinsdottir, Unnur1 aHung, Adriana, M1 aTeumer, Alexander1 aFranceschini, Nora1 aParsa, Afshin1 aKöttgen, Anna1 aSchlosser, Pascal1 aPattaro, Cristian uhttps://chs-nhlbi.org/node/9579