12636nas a2204069 4500008004100000022001400041245010500055210006900160260001300229300001100242490000700253520123400260653001501494653001001509653001201519653001801531653001001549653002301559653003001582653003101612653001201643653003101655653001701686653003801703653003401741653001601775653001101791653002701802653003601829653002801865653003401893653003101927100001901958700002401977700002102001700001802022700002002040700002102060700002102081700002202102700002502124700001902149700002502168700001802193700002202211700002002233700001802253700001802271700001702289700002502306700003202331700002002363700002102383700001902404700002402423700002902447700001702476700001802493700001502511700002102526700002302547700001902570700001802589700002002607700001602627700002402643700002602667700001202693700002202705700001902727700003502746700001802781700001102799700002502810700002202835700001902857700002402876700002002900700001302920700002302933700001802956700002002974700002502994700002003019700002703039700002203066700002403088700002003112700002003132700002103152700001903173700002003192700002103212700002303233700002303256700001903279700002103298700002103319700002303340700002503363700002403388700002203412700001803434700002703452700002703479700002203506700001803528700001903546700002303565700002303588700002203611700001903633700002003652700001803672700001903690700002303709700002003732700002203752700002303774700002803797700002103825700002103846700001703867700002703884700001703911700002203928700002303950700002703973700001804000700002004018700002004038700001804058700002104076700001904097700001604116700002804132700002204160700002204182700002004204700002004224700002204244700002104266700002204287700002404309700001904333700001604352700001404368700001504382700002304397700002304420700001604443700002104459700001904480700002504499700001904524700002104543700002004564700001804584700002304602700002104625700002204646700002404668700002104692700001204713700002304725700001904748700002104767700002204788700003604810700002304846700002404869700002004893700002304913700001804936700001704954700002504971700002104996700002205017700001905039700001905058700002405077700001905101700001705120700001605137700002305153700002305176700002205199700002005221700001905241700002305260700001905283700002705302700001905329700001905348700002305367700002105390700001805411700002505429700002005454700002305474700002105497700001805518700002005536700002605556700001905582700002105601700002205622700002205644700001805666700002205684700001705706700002005723700001705743700002205760700002205782700002505804700002505829700002105854700001905875700002205894700002305916700001605939700001505955700001905970700002805989700002006017700002106037700001706058700001806075700002206093700002806115700002106143700001606164700001806180700002706198700002206225700002306247700002006270700002106290700001906311700002206330700001706352700001806369700002306387700001906410700002306429700002906452700002306481700002406504700002006528700002206548700001806570700001906588700002506607700002306632700002006655700002006675700002706695700002106722700002406743700002606767700002006793700002006813700002406833700002506857700001906882700002206901700001906923700002306942700001806965700002506983700002607008700002207034700001507056700002007071700001707091700002007108700001807128700002007146700002007166700002107186700002407207700002207231700001907253700001907272700001907291700002807310700002307338700001807361700001607379700002007395700002207415700002007437700002107457700002407478700002407502700002407526700002107550700002307571700001907594700002107613700002207634700002407656700002707680700002307707700002007730700002407750700002507774700002007799700002007819700002807839700002107867700002307888700002407911700001707935700002007952700002407972700001707996700001908013700002708032700002408059700002408083700002008107700002008127700002508147700002508172700001908197700002208216700002508238700002008263700001608283700002108299700002208320700002008342700001908362710002308381710002108404710002808425710005308453710002408506856003608530 2010 eng d a1546-171800aNew genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.0 aNew genetic loci implicated in fasting glucose homeostasis and t c2010 Feb a105-160 v423 a
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
10aAdolescent10aAdult10aAlleles10aBlood Glucose10aChild10aDatabases, Genetic10aDiabetes Mellitus, Type 210aDNA Copy Number Variations10aFasting10aGene Expression Regulation10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeostasis10aHumans10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aReproducibility of Results1 aDupuis, Josée1 aLangenberg, Claudia1 aProkopenko, Inga1 aSaxena, Richa1 aSoranzo, Nicole1 aJackson, Anne, U1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aGloyn, Anna, L1 aLindgren, Cecilia, M1 aMägi, Reedik1 aMorris, Andrew, P1 aRandall, Joshua1 aJohnson, Toby1 aElliott, Paul1 aRybin, Denis1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aHenneman, Peter1 aGrallert, Harald1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aFranklin, Christopher, S1 aNavarro, Pau1 aSong, Kijoung1 aGoel, Anuj1 aPerry, John, R B1 aEgan, Josephine, M1 aLajunen, Taina1 aGrarup, Niels1 aSparsø, Thomas1 aDoney, Alex1 aVoight, Benjamin, F1 aStringham, Heather, M1 aLi, Man1 aKanoni, Stavroula1 aShrader, Peter1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aQi, Lu1 aTimpson, Nicholas, J1 aGieger, Christian1 aZabena, Carina1 aRocheleau, Ghislain1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aPayne, Felicity1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aArdlie, Kristin1 aAriyurek, Yavuz1 aBalkau, Beverley1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBonnefond, Amélie1 aBonnycastle, Lori, L1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aCharpentier, Guillaume1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCornelis, Marilyn1 aCrawford, Gabe1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aDina, Christian1 aErdos, Michael, R1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFox, Caroline, S1 aFrants, Rune1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGroves, Christopher, J1 aGrundy, Scott1 aGwilliam, Rhian1 aGyllensten, Ulf1 aHadjadj, Samy1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHerder, Christian1 aHicks, Andrew, A1 aHillman, David, R1 aHingorani, Aroon, D1 aHofman, Albert1 aHui, Jennie1 aHung, Joe1 aIsomaa, Bo1 aJohnson, Paul, R V1 aJørgensen, Torben1 aJula, Antti1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aLyssenko, Valeriya1 aMahley, Robert1 aMangino, Massimo1 aManning, Alisa, K1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcCulloch, Laura, J1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, Braxton, D1 aMorken, Mario, A1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNarisu, Narisu1 aNeville, Matthew, J1 aOostra, Ben, A1 aOrrù, Marco1 aPakyz, Ruth1 aPalmer, Colin, N A1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPerola, Markus1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRathmann, Wolfgang1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRoden, Michael1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aScott, Laura, J1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurethsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTanaka, Toshiko1 aThorand, Barbara1 aTichet, Jean1 aTönjes, Anke1 aTuomi, Tiinamaija1 aUitterlinden, André, G1 aDijk, Ko Willems1 aHoek, Mandy1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWalters, Bragi, G1 aWard, Kim, L1 aWatkins, Hugh1 aWeedon, Michael, N1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZeggini, Eleftheria1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aLoos, Ruth, J F1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aHattersley, Andrew, T1 aSilander, Kaisa1 aSalomaa, Veikko1 aSmith, George Davey1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aDedoussis, George, V1 aSerrano-Ríos, Manuel1 aMorris, Andrew, D1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPankow, James, S1 aSampson, Michael, J1 aKuusisto, Johanna1 aLaakso, Markku1 aHansen, Torben1 aPedersen, Oluf1 aPramstaller, Peter Paul1 aWichmann, Erich, H1 aIllig, Thomas1 aRudan, Igor1 aWright, Alan, F1 aStumvoll, Michael1 aCampbell, Harry1 aWilson, James, F1 aBergman, Richard, N1 aBuchanan, Thomas, A1 aCollins, Francis, S1 aMohlke, Karen, L1 aTuomilehto, Jaakko1 aValle, Timo, T1 aAltshuler, David1 aRotter, Jerome, I1 aSiscovick, David, S1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aDeloukas, Panos1 aSpector, Timothy, D1 aFrayling, Timothy, M1 aFerrucci, Luigi1 aKong, Augustine1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAulchenko, Yurii, S1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aWaterworth, Dawn, M1 aVollenweider, Peter1 aPeltonen, Leena1 aMooser, Vincent1 aAbecasis, Goncalo, R1 aWareham, Nicholas, J1 aSladek, Robert1 aFroguel, Philippe1 aWatanabe, Richard, M1 aMeigs, James, B1 aGroop, Leif1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aFlorez, Jose, C1 aBarroso, Inês1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal BPgen Consortium1 aAnders Hamsten on behalf of Procardis Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/116003101nas a2200493 4500008004100000022001400041245016400055210006900219260001600288300001200304490000700316520162000323653001001943653002201953653000901975653002801984653004002012653001502052653001102067653003802078653001102116653000902127653001602136653003602152100002002188700002102208700002102229700001702250700002402267700001802291700002302309700002302332700001802355700002102373700001902394700001902413700002202432700003002454700002102484700001702505700002402522700002502546856003602571 2011 eng d a1460-208300aA gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium.0 agenecentric association scan for Coagulation Factor VII levels i c2011 Sep 01 a3525-340 v203 aPolymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
10aAdult10aAfrican Americans10aAged10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFactor VII10aFemale10aGenetic Predisposition to Disease10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aTaylor, Kira, C1 aLange, Leslie, A1 aZabaneh, Delilah1 aLange, Ethan1 aKeating, Brendan, J1 aTang, Weihong1 aSmith, Nicholas, L1 aDelaney, Joseph, A1 aKumari, Meena1 aHingorani, Aroon1 aNorth, Kari, E1 aKivimaki, Mika1 aTracy, Russell, P1 aO'Donnell, Christopher, J1 aFolsom, Aaron, R1 aGreen, David1 aHumphries, Steve, E1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/156813785nas a2204513 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2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium 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2011 eng d a1546-171800aGenetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.0 aGenetic variation near IRS1 associates with reduced adiposity an c2011 Jun 26 a753-600 v433 aGenome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
10aAdiponectin10aAdiposity10aAlleles10aBody Fat Distribution10aBody Mass Index10aBody Weight10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aInsulin Receptor Substrate Proteins10aIntracellular Signaling Peptides and Proteins10aMale10aMembrane Proteins10aMeta-Analysis as Topic10aMetabolome10aObesity10aPolymorphism, Single Nucleotide10aSubcutaneous Fat1 aKilpeläinen, Tuomas, O1 aZillikens, Carola, M1 aStančáková, Alena1 aFinucane, Francis, M1 aRied, Janina, S1 aLangenberg, Claudia1 aZhang, Weihua1 aBeckmann, Jacques, S1 aLuan, Jian'an1 aVandenput, Liesbeth1 aStyrkarsdottir, Unnur1 aZhou, Yanhua1 aSmith, Albert, Vernon1 aZhao, Jing-Hua1 aAmin, Najaf1 aVedantam, Sailaja1 aShin, So-Youn1 aHaritunians, Talin1 aFu, Mao1 aFeitosa, Mary, F1 aKumari, Meena1 aHalldorsson, Bjarni, V1 aTikkanen, Emmi1 aMangino, Massimo1 aHayward, Caroline1 aSong, Ci1 aArnold, Alice, M1 aAulchenko, Yurii, S1 aOostra, Ben, A1 aCampbell, Harry1 aCupples, Adrienne, L1 aDavis, Kathryn, E1 aDöring, Angela1 aEiriksdottir, Gudny1 aEstrada, Karol1 aFernández-Real, José, Manuel1 aGarcia, Melissa1 aGieger, Christian1 aGlazer, Nicole, L1 aGuiducci, Candace1 aHofman, Albert1 aHumphries, Steve, E1 aIsomaa, Bo1 aJacobs, Leonie, C1 aJula, Antti1 aKarasik, David1 aKarlsson, Magnus, K1 aKhaw, Kay-Tee1 aKim, Lauren, J1 aKivimaki, Mika1 aKlopp, Norman1 aKuhnel, Brigitte1 aKuusisto, Johanna1 aLiu, Yongmei1 aLjunggren, Osten1 aLorentzon, Mattias1 aLuben, Robert, N1 aMcKnight, Barbara1 aMellström, Dan1 aMitchell, Braxton, D1 aMooser, Vincent1 aMoreno, José, Maria1 aMännistö, Satu1 aO'Connell, Jeffery, R1 aPascoe, Laura1 aPeltonen, Leena1 aPeral, Belén1 aPerola, Markus1 aPsaty, Bruce, M1 aSalomaa, Veikko1 aSavage, David, B1 aSemple, Robert, K1 aSkaric-Juric, Tatjana1 aSigurdsson, Gunnar1 aSong, Kijoung, S1 aSpector, Timothy, D1 aSyvänen, Ann-Christine1 aTalmud, Philippa, J1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVidal-Puig, Antonio1 aWild, Sarah, H1 aWright, Alan, F1 aClegg, Deborah, J1 aSchadt, Eric1 aWilson, James, F1 aRudan, Igor1 aRipatti, Samuli1 aBorecki, Ingrid, B1 aShuldiner, Alan, R1 aIngelsson, Erik1 aJansson, John-Olov1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aGroop, Leif1 aKiel, Douglas, P1 aRivadeneira, Fernando1 aWalker, Mark1 aBarroso, Inês1 aVollenweider, Peter1 aWaeber, Gérard1 aChambers, John, C1 aKooner, Jaspal, S1 aSoranzo, Nicole1 aHirschhorn, Joel, N1 aStefansson, Kari1 aWichmann, H-Erich1 aOhlsson, Claes1 aO'Rahilly, Stephen1 aWareham, Nicholas, J1 aSpeliotes, Elizabeth, K1 aFox, Caroline, S1 aLaakso, Markku1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/130103421nas a2200829 4500008004100000022001400041245004600055210004200101260001300143300001600156490000700172520116200179653001001341653003801351653003401389653001301423653001101436653001401447100001901461700001601480700002301496700002301519700002201542700001801564700002401582700002101606700002001627700002301647700001701670700001201687700001801699700002401717700001901741700002101760700002101781700001801802700002401820700002001844700002201864700002301886700001901909700001901928700002101947700001901968700002001987700002202007700002002029700002202049700002202071700002302093700002002116700002002136700002202156700002002178700002602198700002102224700002002245700002002265700002502285700002502310700002902335700002202364700002002386700002402406700001902430700001702449700002402466700002002490700002202510700002302532856003602555 2011 eng d a1558-149700aA genome-wide association study of aging.0 agenomewide association study of aging c2011 Nov a2109.e15-280 v323 aHuman longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.
10aAging10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLongevity1 aWalter, Stefan1 aAtzmon, Gil1 aDemerath, Ellen, W1 aGarcia, Melissa, E1 aKaplan, Robert, C1 aKumari, Meena1 aLunetta, Kathryn, L1 aMilaneschi, Yuri1 aTanaka, Toshiko1 aTranah, Gregory, J1 aVölker, Uwe1 aYu, Lei1 aArnold, Alice1 aBenjamin, Emelia, J1 aBiffar, Reiner1 aBuchman, Aron, S1 aBoerwinkle, Eric1 aCouper, David1 aDe Jager, Philip, L1 aEvans, Denis, A1 aHarris, Tamara, B1 aHoffmann, Wolfgang1 aHofman, Albert1 aKarasik, David1 aKiel, Douglas, P1 aKocher, Thomas1 aKuningas, Maris1 aLauner, Lenore, J1 aLohman, Kurt, K1 aLutsey, Pamela, L1 aMackenbach, Johan1 aMarciante, Kristin1 aPsaty, Bruce, M1 aReiman, Eric, M1 aRotter, Jerome, I1 aSeshadri, Sudha1 aShardell, Michelle, D1 aSmith, Albert, V1 aDuijn, Cornelia1 aWalston, Jeremy1 aZillikens, Carola, M1 aBandinelli, Stefania1 aBaumeister, Sebastian, E1 aBennett, David, A1 aFerrucci, Luigi1 aGudnason, Vilmundur1 aKivimaki, Mika1 aLiu, Yongmei1 aMurabito, Joanne, M1 aNewman, Anne, B1 aTiemeier, Henning1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/130708958nas a2202881 4500008004100000022001400041245014400055210006900199260001300268300001300281490000700294520091900301653001001220653001201230653001801242653001201260653001101272653001901283653003401302653001101336653001201347653000901359653003601368653000901404653002601413653002801439100002101467700002001488700001901508700002101527700002201548700001801570700001801588700002501606700001901631700002301650700002201673700003101695700001601726700002101742700002001763700001801783700001801801700002301819700001901842700001801861700002001879700001801899700002501917700002401942700001601966700002101982700002002003700002202023700001702045700001902062700002502081700002002106700002302126700001302149700002502162700001602187700002402203700001402227700002202241700001702263700001802280700002602298700002302324700002202347700002202369700001602391700002102407700002002428700001502448700002402463700002502487700001402512700002502526700002202551700002102573700002002594700001702614700001802631700002502649700002102674700002102695700002102716700002002737700002602757700001802783700002002801700001902821700001502840700002102855700001302876700003002889700002802919700002102947700002102968700002002989700002903009700002403038700002103062700001903083700002103102700002003123700001803143700002003161700002103181700001703202700002103219700002203240700002003262700001403282700002503296700002003321700001803341700001903359700002203378700002403400700002003424700001603444700002103460700001803481700001903499700001703518700002003535700001903555700001903574700002603593700002803619700002303647700002103670700002303691700002203714700002003736700001903756700002503775700002003800700002103820700002403841700002203865700001803887700002203905700002203927700002503949700001903974700002303993700002304016700002104039700002004060700002204080700002304102700002004125700002604145700002504171700002304196700002404219700001604243700002004259700001804279700002004297700002204317700002004339700002404359700002404383700002404407700002304431700002504454700001904479700002304498700001904521700001904540700002004559700002404579700002104603700002004624700001804644700002104662700002004683700002704703700002204730700001904752700002104771700002504792700002004817700002004837700001504857700002104872700002304893700002304916700002204939700001804961700002404979700002005003700001905023700002205042700001905064700002505083700002405108700001905132700002105151700002005172700002405192700002005216700001805236700001805254700002005272700002405292700001905316700002105335700003705356700002205393700002305415700002105438700001505459700001905474700002305493700001905516700002205535700002105557700002005578700002005598700002105618700002105639700002205660700001805682700002705700700002505727700002505752700002205777700002005799700002005819700002405839700002005863700002405883700002005907700002105927700001905948710007305967856003606040 2012 eng d a1546-171800aLarge-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.0 aLargescale association analyses identify new loci influencing gl c2012 Sep a991-10050 v443 aThrough genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
10aAdult10aAnimals10aBlood Glucose10aFasting10aFemale10aGene Frequency10aGenome-Wide Association Study10aHumans10aInsulin10aMale10aMetabolic Networks and Pathways10aMice10aOsmolar Concentration10aQuantitative Trait Loci1 aScott, Robert, A1 aLagou, Vasiliki1 aWelch, Ryan, P1 aWheeler, Eleanor1 aMontasser, May, E1 aLuan, Jian'an1 aMägi, Reedik1 aStrawbridge, Rona, J1 aRehnberg, Emil1 aGustafsson, Stefan1 aKanoni, Stavroula1 aRasmussen-Torvik, Laura, J1 aYengo, Loic1 aLecoeur, Cécile1 aShungin, Dmitry1 aSanna, Serena1 aSidore, Carlo1 aJohnson, Paul, C D1 aJukema, Wouter1 aJohnson, Toby1 aMahajan, Anubha1 aVerweij, Niek1 aThorleifsson, Gudmar1 aHottenga, Jouke-Jan1 aShah, Sonia1 aSmith, Albert, V1 aSennblad, Bengt1 aGieger, Christian1 aSalo, Perttu1 aPerola, Markus1 aTimpson, Nicholas, J1 aEvans, David, M1 aSt Pourcain, Beate1 aWu, Ying1 aAndrews, Jeanette, S1 aHui, Jennie1 aBielak, Lawrence, F1 aZhao, Wei1 aHorikoshi, Momoko1 aNavarro, Pau1 aIsaacs, Aaron1 aO'Connell, Jeffrey, R1 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aCaulfield, Mark1 aAntti, Jula1 aMangino, Massimo1 aSmall, Kerrin1 aMiljkovic, Iva1 aLiu, Yongmei1 aAtalay, Mustafa1 aKiess, Wieland1 aJames, Alan, L1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aPalmer, Colin, N A1 aDoney, Alex, S F1 aWillemsen, Gonneke1 aSmit, Johannes, H1 aCampbell, Susan1 aPolasek, Ozren1 aBonnycastle, Lori, L1 aHercberg, Serge1 aDimitriou, Maria1 aBolton, Jennifer, L1 aFowkes, Gerard, R1 aKovacs, Peter1 aLindström, Jaana1 aZemunik, Tatijana1 aBandinelli, Stefania1 aWild, Sarah, H1 aBasart, Hanneke, V1 aRathmann, Wolfgang1 aGrallert, Harald1 aMaerz, Winfried1 aKleber, Marcus, E1 aBoehm, Bernhard, O1 aPeters, Annette1 aPramstaller, Peter, P1 aProvince, Michael, A1 aBorecki, Ingrid, B1 aHastie, Nicholas, D1 aRudan, Igor1 aCampbell, Harry1 aWatkins, Hugh1 aFarrall, Martin1 aStumvoll, Michael1 aFerrucci, Luigi1 aWaterworth, Dawn, M1 aBergman, Richard, N1 aCollins, Francis, S1 aTuomilehto, Jaakko1 aWatanabe, Richard, M1 aGeus, Eco, J C1 aPenninx, Brenda, W1 aHofman, Albert1 aOostra, Ben, A1 aPsaty, Bruce, M1 aVollenweider, Peter1 aWilson, James, F1 aWright, Alan, F1 aHovingh, Kees1 aMetspalu, Andres1 aUusitupa, Matti1 aMagnusson, Patrik, K E1 aKyvik, Kirsten, O1 aKaprio, Jaakko1 aPrice, Jackie, F1 aDedoussis, George, V1 aDeloukas, Panos1 aMeneton, Pierre1 aLind, Lars1 aBoehnke, Michael1 aShuldiner, Alan, R1 aDuijn, Cornelia, M1 aMorris, Andrew, D1 aToenjes, Anke1 aPeyser, Patricia, A1 aBeilby, John, P1 aKörner, Antje1 aKuusisto, Johanna1 aLaakso, Markku1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aLakka, Timo, A1 aRauramaa, Rainer1 aAdair, Linda, S1 aSmith, George Davey1 aSpector, Tim, D1 aIllig, Thomas1 ade Faire, Ulf1 aHamsten, Anders1 aGudnason, Vilmundur1 aKivimaki, Mika1 aHingorani, Aroon1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aBoomsma, Dorret, I1 aStefansson, Kari1 aHarst, Pim1 aDupuis, Josée1 aPedersen, Nancy, L1 aSattar, Naveed1 aHarris, Tamara, B1 aCucca, Francesco1 aRipatti, Samuli1 aSalomaa, Veikko1 aMohlke, 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2012 eng d a1553-740400aNovel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.0 aNovel loci for adiponectin levels and their influence on type 2 c2012 ae10026070 v83 aCirculating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
10aAdiponectin10aAfrican Americans10aAsian Continental Ancestry Group10aCholesterol, HDL10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aFemale10aGene Expression10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlucose Tolerance Test10aHumans10aInsulin Resistance10aMale10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aWaist-Hip Ratio1 aDastani, Zari1 aHivert, Marie-France1 aTimpson, Nicholas1 aPerry, John, R B1 aYuan, Xin1 aScott, Robert, A1 aHenneman, Peter1 aHeid, Iris, M1 aKizer, Jorge, R1 aLyytikäinen, Leo-Pekka1 aFuchsberger, Christian1 aTanaka, Toshiko1 aMorris, Andrew, P1 aSmall, Kerrin1 aIsaacs, Aaron1 aBeekman, Marian1 aCoassin, Stefan1 aLohman, Kurt1 aQi, Lu1 aKanoni, Stavroula1 aPankow, James, S1 aUh, Hae-Won1 aWu, Ying1 aBidulescu, Aurelian1 aRasmussen-Torvik, Laura, J1 aGreenwood, Celia, M T1 aLadouceur, Martin1 aGrimsby, Jonna1 aManning, Alisa, K1 aLiu, Ching-Ti1 aKooner, Jaspal1 aMooser, Vincent, E1 aVollenweider, Peter1 aKapur, Karen, A1 aChambers, John1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aFrants, Rune1 aWillems-Vandijk, Ko1 aOostra, Ben, A1 aWillems, Sara, M1 aLamina, Claudia1 aWinkler, Thomas, W1 aPsaty, Bruce, M1 aTracy, Russell, P1 aBrody, Jennifer1 aChen, Ida1 aViikari, Jorma1 aKähönen, Mika1 aPramstaller, Peter, P1 aEvans, David, M1 aSt Pourcain, Beate1 aSattar, Naveed1 aWood, Andrew, R1 aBandinelli, Stefania1 aCarlson, Olga, D1 aEgan, Josephine, M1 aBöhringer, Stefan1 avan Heemst, Diana1 aKedenko, Lyudmyla1 aKristiansson, Kati1 aNuotio, Marja-Liisa1 aLoo, Britt-Marie1 aHarris, Tamara1 aGarcia, Melissa1 aKanaya, Alka1 aHaun, Margot1 aKlopp, Norman1 aWichmann, H-Erich1 aDeloukas, Panos1 aKatsareli, Efi1 aCouper, David, J1 aDuncan, Bruce, B1 aKloppenburg, Margreet1 aAdair, Linda, S1 aBorja, Judith, B1 aWilson, James, G1 aMusani, Solomon1 aGuo, Xiuqing1 aJohnson, Toby1 aSemple, Robert1 aTeslovich, Tanya, M1 aAllison, Matthew, A1 aRedline, Susan1 aBuxbaum, Sarah, G1 aMohlke, Karen, L1 aMeulenbelt, Ingrid1 aBallantyne, Christie, M1 aDedoussis, George, V1 aHu, Frank, B1 aLiu, Yongmei1 aPaulweber, Bernhard1 aSpector, Timothy, D1 aSlagboom, Eline1 aFerrucci, Luigi1 aJula, Antti1 aPerola, Markus1 aRaitakari, Olli1 aFlorez, Jose, C1 aSalomaa, Veikko1 aEriksson, Johan, G1 aFrayling, Timothy, M1 aHicks, Andrew, A1 aLehtimäki, Terho1 aSmith, George Davey1 aSiscovick, David, S1 aKronenberg, Florian1 aDuijn, Cornelia1 aLoos, Ruth, J F1 aWaterworth, Dawn, M1 aMeigs, James, B1 aDupuis, Josée1 aRichards, Brent1 aVoight, Benjamin, F1 aScott, Laura, J1 aSteinthorsdottir, Valgerdur1 aDina, Christian1 aWelch, Ryan, P1 aZeggini, Eleftheria1 aHuth, Cornelia1 aAulchenko, Yurii, S1 aThorleifsson, Gudmar1 aMcCulloch, Laura, J1 aFerreira, Teresa1 aGrallert, Harald1 aAmin, Najaf1 aWu, Guanming1 aWiller, Cristen, J1 aRaychaudhuri, Soumya1 aMcCarroll, Steve, A1 aHofmann, Oliver, M1 aSegrè, Ayellet, V1 aHoek, Mandy1 aNavarro, Pau1 aArdlie, Kristin1 aBalkau, Beverley1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBlagieva, Roza1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBoström, Kristina, Bengtsson1 aBravenboer, Bert1 aBumpstead, Suzannah1 aBurtt, Noel, P1 aCharpentier, Guillaume1 aChines, Peter, S1 aCornelis, Marilyn1 aCrawford, Gabe1 aDoney, Alex, S F1 aElliott, Katherine, S1 aElliott, Amanda, L1 aErdos, Michael, R1 aFox, Caroline, S1 aFranklin, Christopher, S1 aGanser, Martha1 aGieger, Christian1 aGrarup, Niels1 aGreen, Todd1 aGriffin, Simon1 aGroves, Christopher, J1 aGuiducci, Candace1 aHadjadj, Samy1 aHassanali, Neelam1 aHerder, Christian1 aIsomaa, Bo1 aJackson, Anne, U1 aJohnson, Paul, R V1 aJørgensen, Torben1 aKao, Wen, H L1 aKong, Augustine1 aKraft, Peter1 aKuusisto, Johanna1 aLauritzen, Torsten1 aLi, Man1 aLieverse, Aloysius1 aLindgren, Cecilia, M1 aLyssenko, Valeriya1 aMarre, Michel1 aMeitinger, Thomas1 aMidthjell, Kristian1 aMorken, Mario, A1 aNarisu, Narisu1 aNilsson, Peter1 aOwen, Katharine, R1 aPayne, Felicity1 aPetersen, Ann-Kristin1 aPlatou, Carl1 aProença, Christine1 aProkopenko, Inga1 aRathmann, Wolfgang1 aRayner, William1 aRobertson, Neil, R1 aRocheleau, Ghislain1 aRoden, Michael1 aSampson, Michael, J1 aSaxena, Richa1 aShields, Beverley, M1 aShrader, Peter1 aSigurdsson, Gunnar1 aSparsø, Thomas1 aStrassburger, Klaus1 aStringham, Heather, M1 aSun, Qi1 aSwift, Amy, J1 aThorand, Barbara1 aTichet, Jean1 aTuomi, Tiinamaija1 avan Dam, Rob, M1 avan Haeften, Timon, W1 avan Herpt, Thijs1 avan Vliet-Ostaptchouk, Jana, V1 aWalters, Bragi, G1 aWeedon, Michael, N1 aWijmenga, Cisca1 aWitteman, Jacqueline1 aBergman, Richard, N1 aCauchi, Stephane1 aCollins, Francis, S1 aGloyn, Anna, L1 aGyllensten, Ulf1 aHansen, Torben1 aHide, Winston, A1 aHitman, Graham, A1 aHofman, Albert1 aHunter, David, J1 aHveem, Kristian1 aLaakso, Markku1 aMorris, Andrew, D1 aPalmer, Colin, N A1 aRudan, Igor1 aSijbrands, Eric1 aStein, Lincoln, D1 aTuomilehto, Jaakko1 aUitterlinden, Andre1 aWalker, Mark1 aWatanabe, Richard, M1 aAbecasis, Goncalo, R1 aBoehm, Bernhard, O1 aCampbell, Harry1 aDaly, Mark, J1 aHattersley, Andrew, T1 aPedersen, Oluf1 aBarroso, Inês1 aGroop, Leif1 aSladek, Rob1 aThorsteinsdottir, Unnur1 aWilson, James, F1 aIllig, Thomas1 aFroguel, Philippe1 aDuijn, Cornelia, M1 aStefansson, Kari1 aAltshuler, David1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aSoranzo, Nicole1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aMägi, Reedik1 aRandall, Joshua1 aElliott, Paul1 aRybin, Denis1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aSong, Kijoung1 aGoel, Anuj1 aLajunen, Taina1 aDoney, Alex1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aTimpson, Nicholas, J1 aZabena, Carina1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aAriyurek, Yavuz1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBergmann, Sven1 aBochud, Murielle1 aBonnefond, Amélie1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, Eco, J C1 aDelplanque, Jerome1 aFedson, Annette, C1 aFischer-Rosinsky, Antje1 aForouhi, Nita, G1 aFranzosi, Maria Grazia1 aGalan, Pilar1 aGoodarzi, Mark, O1 aGraessler, Jürgen1 aGrundy, Scott1 aGwilliam, Rhian1 aHallmans, Göran1 aHammond, Naomi1 aHan, Xijing1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeath, Simon, C1 aHercberg, Serge1 aHillman, David, R1 aHingorani, Aroon, D1 aHui, Jennie1 aHung, Joe1 aKaakinen, Marika1 aKaprio, Jaakko1 aKesaniemi, Antero, Y1 aKivimaki, Mika1 aKnight, Beatrice1 aKoskinen, Seppo1 aKovacs, Peter1 aKyvik, Kirsten Ohm1 aLathrop, Mark, G1 aLawlor, Debbie, A1 aLe Bacquer, Olivier1 aLecoeur, Cécile1 aLi, Yun1 aMahley, Robert1 aMangino, Massimo1 aMartínez-Larrad, María Teresa1 aMcAteer, Jarred, B1 aMcPherson, Ruth1 aMeisinger, Christa1 aMelzer, David1 aMeyre, David1 aMitchell, 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Guillaume1 aLauner, Lenore, J1 aLakatta, Edward, G1 aLaaksonen, Reijo1 aKyvik, Kirsten, O1 aKönig, Inke, R1 aKhaw, Kay-Tee1 aKaplan, Lee, M1 aJohansson, Asa1 aJanssens, Cecile, J W1 aIgl, Wilmar1 aHovingh, Kees1 aHengstenberg, Christian1 aHavulinna, Aki, S1 aHastie, Nicholas, D1 aHarris, Tamara, B1 aHaritunians, Talin1 aHall, Alistair, S1 aGroop, Leif, C1 aGonzalez, Elena1 aFreimer, Nelson, B1 aErdmann, Jeanette1 aEjebe, Kenechi, G1 aDöring, Angela1 aDominiczak, Anna, F1 aDemissie, Serkalem1 aDeloukas, Panagiotis1 ade Faire, Ulf1 aCrawford, Gabriel1 aChen, Yii-der, I1 aCaulfield, Mark, J1 aBoekholdt, Matthijs1 aAssimes, Themistocles, L1 aQuertermous, Thomas1 aSeielstad, Mark1 aWong, Tien, Y1 aTai, E-Shyong1 aFeranil, Alan, B1 aKuzawa, Christopher, W1 aTaylor, Herman, A1 aGabriel, Stacey, B1 aHolm, Hilma1 aGudnason, Vilmundur1 aKrauss, Ronald, M1 aOrdovas, Jose, M1 aMunroe, Patricia, B1 aKooner, Jaspal, S1 aTall, Alan, R1 aHegele, Robert, A1 aKastelein, John, J P1 aSchadt, Eric, E1 aStrachan, David, P1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aKathiresan, Sekar1 aDIAGRAM+ Consortium1 aMAGIC Consortium1 aGLGC Investigators1 aMuTHER Consortium1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal B Pgen Consortium1 aProcardis Consortium1 aMAGIC investigators1 aGLGC Consortium uhttps://chs-nhlbi.org/node/137810597nas a2203385 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2013 eng d a1546-171800aCommon variants associated with plasma triglycerides and risk for coronary artery disease.0 aCommon variants associated with plasma triglycerides and risk fo c2013 Nov a1345-520 v453 aTriglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
10aBiological Transport10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors10aTriglycerides1 aDo, Ron1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aGao, Chi1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 aKesäniemi, Antero1 aKivimaki, Mika1 aKooner, Jaspal, S1 aKoudstaal, Peter, J1 aKrauss, Ronald, M1 aKuh, Diana1 aKuusisto, Johanna1 aKyvik, Kirsten, O1 aLaakso, Markku1 aLakka, Timo, A1 aLind, Lars1 aLindgren, Cecilia, M1 aMartin, Nicholas, G1 aMärz, Winfried1 aMcCarthy, Mark, I1 aMcKenzie, Colin, A1 aMeneton, Pierre1 aMetspalu, Andres1 aMoilanen, Leena1 aMorris, Andrew, D1 aMunroe, Patricia, B1 aNjølstad, Inger1 aPedersen, Nancy, L1 aPower, Chris1 aPramstaller, Peter, P1 aPrice, Jackie, F1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRauramaa, Rainer1 aSaleheen, Danish1 aSalomaa, Veikko1 aSanghera, Dharambir, K1 aSaramies, Jouko1 aSchwarz, Peter, E H1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aSiegbahn, Agneta1 aSpector, Tim, D1 aStefansson, Kari1 aStrachan, David, P1 aTayo, Bamidele, O1 aTremoli, Elena1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aDuijn, Cornelia, M1 aVollenweider, Peter1 aWallentin, Lars1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWolffenbuttel, Bruce, H R1 aAltshuler, David1 aOrdovas, Jose, M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aDaly, Mark, J1 aNeale, Benjamin, M1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/801410661nas a2203397 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2013 eng d a1546-171800aDiscovery and refinement of loci associated with lipid levels.0 aDiscovery and refinement of loci associated with lipid levels c2013 Nov a1274-12830 v453 aLevels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
10aAfrican Continental Ancestry Group10aAsian Continental Ancestry Group10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLipids10aTriglycerides1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDo, Ron1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 aKesäniemi, Antero1 aKivimaki, Mika1 aKooner, Jaspal, S1 aKoudstaal, Peter, J1 aKrauss, Ronald, M1 aKuh, Diana1 aKuusisto, Johanna1 aKyvik, Kirsten, O1 aLaakso, Markku1 aLakka, Timo, A1 aLind, Lars1 aLindgren, Cecilia, M1 aMartin, Nicholas, G1 aMärz, Winfried1 aMcCarthy, Mark, I1 aMcKenzie, Colin, A1 aMeneton, Pierre1 aMetspalu, Andres1 aMoilanen, Leena1 aMorris, Andrew, D1 aMunroe, Patricia, B1 aNjølstad, Inger1 aPedersen, Nancy, L1 aPower, Chris1 aPramstaller, Peter, P1 aPrice, Jackie, F1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRauramaa, Rainer1 aSaleheen, Danish1 aSalomaa, Veikko1 aSanghera, Dharambir, K1 aSaramies, Jouko1 aSchwarz, Peter, E H1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aSiegbahn, Agneta1 aSpector, Tim, D1 aStefansson, Kari1 aStrachan, David, P1 aTayo, Bamidele, O1 aTremoli, Elena1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aDuijn, Cornelia, M1 aVollenweider, Peter1 aWallentin, Lars1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWolffenbuttel, Bruce, H R1 aOrdovas, Jose, M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aKathiresan, Sekar1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aGlobal Lipids Genetics Consortium uhttps://chs-nhlbi.org/node/615412626nas a2204177 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2013 eng d a1546-171800aGenome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.0 aGenomewide metaanalysis identifies 11 new loci for anthropometri c2013 May a501-120 v453 aApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
10aAnthropometry10aBody Height10aBody Mass Index10aCase-Control Studies10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMeta-Analysis as Topic10aObesity10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aWaist-Hip Ratio1 aBerndt, Sonja, I1 aGustafsson, Stefan1 aMägi, Reedik1 aGanna, Andrea1 aWheeler, Eleanor1 aFeitosa, Mary, F1 aJustice, Anne, E1 aMonda, Keri, L1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aEsko, Tõnu1 aFall, Tove1 aFerreira, Teresa1 aGentilini, Davide1 aJackson, Anne, U1 aLuan, Jian'an1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWiller, Cristen, J1 aWinkler, Thomas, W1 aWood, Andrew, R1 aWorkalemahu, Tsegaselassie1 aHu, Yi-Juan1 aLee, Sang, Hong1 aLiang, Liming1 aLin, Dan-Yu1 aMin, Josine, L1 aNeale, Benjamin, M1 aThorleifsson, Gudmar1 aYang, Jian1 aAlbrecht, Eva1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aHeijer, Martin, den1 aEklund, Niina1 aFischer, Krista1 aGoel, Anuj1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aJarick, Ivonne1 aJohansson, Asa1 aJohnson, Toby1 aKanoni, Stavroula1 aKleber, Marcus, E1 aKönig, Inke, R1 aKristiansson, Kati1 aKutalik, Zoltán1 aLamina, Claudia1 aLecoeur, Cécile1 aLi, Guo1 aMangino, Massimo1 aMcArdle, Wendy, L1 aMedina-Gómez, Carolina1 aMüller-Nurasyid, Martina1 aNgwa, Julius, S1 aNolte, Ilja, M1 aPaternoster, Lavinia1 aPechlivanis, Sonali1 aPerola, Markus1 aPeters, Marjolein, J1 aPreuss, Michael1 aRose, Lynda, M1 aShi, Jianxin1 aShungin, Dmitry1 aSmith, Albert, Vernon1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTeumer, Alexander1 aTrip, Mieke, D1 aTyrer, Jonathan1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aWaite, Lindsay, L1 aZhao, Jing Hua1 aAbsher, Devin1 aAsselbergs, Folkert, W1 aAtalay, Mustafa1 aAttwood, Antony, P1 aBalmforth, Anthony, J1 aBasart, Hanneke1 aBeilby, John1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBruinenberg, Marcel1 aCampbell, Harry1 aChasman, Daniel, I1 aChines, Peter, S1 aCollins, Francis, S1 aConnell, John, M1 aCookson, William, O1 ade Faire, Ulf1 ade Vegt, Femmie1 aDei, Mariano1 aDimitriou, Maria1 aEdkins, Sarah1 aEstrada, Karol1 aEvans, David, M1 aFarrall, Martin1 aFerrario, Marco, M1 aFerrieres, Jean1 aFranke, Lude1 aFrau, Francesca1 aGejman, Pablo, V1 aGrallert, Harald1 aGrönberg, Henrik1 aGudnason, Vilmundur1 aHall, Alistair, S1 aHall, Per1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHeath, Andrew, C1 aHebebrand, Johannes1 aHomuth, Georg1 aHu, Frank, B1 aHunt, Sarah, E1 aHyppönen, Elina1 aIribarren, Carlos1 aJacobs, Kevin, B1 aJansson, John-Olov1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKee, Frank1 aKhaw, Kay-Tee1 aKivimaki, Mika1 aKoenig, Wolfgang1 aKraja, Aldi, T1 aKumari, Meena1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaitinen, Jaana, H1 aLakka, Timo, A1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLind, Lars1 aLindström, Jaana1 aLiu, Jianjun1 aLiuzzi, Antonio1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aMadden, Pamela, A1 aMagnusson, Patrik, K1 aManunta, Paolo1 aMarek, Diana1 aMärz, Winfried1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMihailov, Evelin1 aMilani, Lili1 aMontgomery, Grant, W1 aMooser, Vincent1 aMühleisen, Thomas, W1 aMunroe, Patricia, B1 aMusk, Arthur, W1 aNarisu, Narisu1 aNavis, Gerjan1 aNicholson, George1 aNohr, Ellen, A1 aOng, Ken, K1 aOostra, Ben, A1 aPalmer, Colin, N A1 aPalotie, Aarno1 aPeden, John, F1 aPedersen, Nancy1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aProkopenko, Inga1 aPütter, Carolin1 aRadhakrishnan, Aparna1 aRaitakari, Olli1 aRendon, Augusto1 aRivadeneira, Fernando1 aRudan, Igor1 aSaaristo, Timo, E1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSanna, Serena1 aSaramies, Jouko1 aSchipf, Sabine1 aSchreiber, Stefan1 aSchunkert, Heribert1 aShin, So-Youn1 aSignorini, Stefano1 aSinisalo, Juha1 aSkrobek, Boris1 aSoranzo, Nicole1 aStančáková, Alena1 aStark, Klaus1 aStephens, Jonathan, C1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStumvoll, Michael1 aSwift, Amy, J1 aTheodoraki, Eirini, V1 aThorand, Barbara1 aTrégouët, David-Alexandre1 aTremoli, Elena1 avan der Klauw, Melanie, M1 avan Meurs, Joyce, B J1 aVermeulen, Sita, H1 aViikari, Jorma1 aVirtamo, Jarmo1 aVitart, Veronique1 aWaeber, Gérard1 aWang, Zhaoming1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWinkelmann, Bernhard, R1 aWitteman, Jacqueline, C M1 aWolffenbuttel, Bruce, H R1 aWong, Andrew1 aWright, Alan, F1 aZillikens, Carola, M1 aAmouyel, Philippe1 aBoehm, Bernhard, O1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCupples, Adrienne, L1 aCusi, Daniele1 aDedoussis, George, V1 aErdmann, Jeanette1 aEriksson, Johan, G1 aFranks, Paul, W1 aFroguel, Philippe1 aGieger, Christian1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHingorani, Aroon1 aHinney, Anke1 aHofman, Albert1 aHovingh, Kees, G1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aJöckel, Karl-Heinz1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKiemeney, Lambertus, A1 aKuh, Diana1 aLaakso, Markku1 aLehtimäki, Terho1 aLevinson, Douglas, F1 aMartin, Nicholas, G1 aMetspalu, Andres1 aMorris, Andrew, D1 aNieminen, Markku, S1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aOuwehand, Willem, H1 aPalmer, Lyle, J1 aPenninx, Brenda1 aPower, Chris1 aProvince, Michael, A1 aPsaty, Bruce, M1 aQi, Lu1 aRauramaa, Rainer1 aRidker, Paul, M1 aRipatti, Samuli1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSnieder, Harold1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aTönjes, Anke1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aHarst, Pim1 aVollenweider, Peter1 aWallaschofski, Henri1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWichmann, H-Erich1 aWilson, James, F1 aAbecasis, Goncalo, R1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunian, Talin1 aHeid, Iris, M1 aHunter, David1 aKaplan, Robert, C1 aKarpe, Fredrik1 aMoffatt, Miriam, F1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPawitan, Yudi1 aSchadt, Eric, E1 aSchlessinger, David1 aSteinthorsdottir, Valgerdur1 aStrachan, David, P1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aVisscher, Peter, M1 aDi Blasio, Anna, Maria1 aHirschhorn, Joel, N1 aLindgren, Cecilia, M1 aMorris, Andrew, P1 aMeyre, David1 aScherag, Andre1 aMcCarthy, Mark, I1 aSpeliotes, Elizabeth, K1 aNorth, Kari, E1 aLoos, Ruth, J F1 aIngelsson, Erik uhttps://chs-nhlbi.org/node/615211009nas a2203553 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2013 eng d a1546-171800aIdentification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.0 aIdentification of heart rateassociated loci and their effects on c2013 Jun a621-310 v453 aElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
10aAnimals10aArrhythmias, Cardiac10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHeart Rate10aHumans10aMetabolic Networks and Pathways10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aHoed, Marcel, den1 aEijgelsheim, Mark1 aEsko, Tõnu1 aBrundel, Bianca, J J M1 aPeal, David, S1 aEvans, David, M1 aNolte, Ilja, M1 aSegrè, Ayellet, V1 aHolm, Hilma1 aHandsaker, Robert, E1 aWestra, Harm-Jan1 aJohnson, Toby1 aIsaacs, Aaron1 aYang, Jian1 aLundby, Alicia1 aZhao, Jing Hua1 aKim, Young, Jin1 aGo, Min Jin1 aAlmgren, Peter1 aBochud, Murielle1 aBoucher, Gabrielle1 aCornelis, Marilyn, C1 aGudbjartsson, Daniel1 aHadley, David1 aHarst, Pim1 aHayward, Caroline1 aHeijer, Martin, den1 aIgl, Wilmar1 aJackson, Anne, U1 aKutalik, Zoltán1 aLuan, Jian'an1 aKemp, John, P1 aKristiansson, Kati1 aLadenvall, Claes1 aLorentzon, Mattias1 aMontasser, May, E1 aNjajou, Omer, T1 aO'Reilly, Paul, F1 aPadmanabhan, Sandosh1 aSt Pourcain, Beate1 aRankinen, Tuomo1 aSalo, Perttu1 aTanaka, Toshiko1 aTimpson, Nicholas, J1 aVitart, Veronique1 aWaite, Lindsay1 aWheeler, William1 aZhang, Weihua1 aDraisma, Harmen, H M1 aFeitosa, Mary, F1 aKerr, Kathleen, F1 aLind, Penelope, A1 aMihailov, Evelin1 aOnland-Moret, Charlotte, N1 aSong, Ci1 aWeedon, Michael, N1 aXie, Weijia1 aYengo, Loic1 aAbsher, Devin1 aAlbert, Christine, M1 aAlonso, Alvaro1 aArking, Dan, E1 ade Bakker, Paul, I W1 aBalkau, Beverley1 aBarlassina, Cristina1 aBenaglio, Paola1 aBis, Joshua, C1 aBouatia-Naji, Nabila1 aBrage, Søren1 aChanock, Stephen, J1 aChines, Peter, S1 aChung, Mina1 aDarbar, Dawood1 aDina, Christian1 aDörr, Marcus1 aElliott, Paul1 aFelix, Stephan, B1 aFischer, Krista1 aFuchsberger, Christian1 aGeus, Eco, J C1 aGoyette, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aHofman, Albert1 aHolewijn, Suzanne1 aHoogstra-Berends, Femke1 aHottenga, Jouke-Jan1 aJensen, Majken, K1 aJohansson, Asa1 aJunttila, Juhani1 aKääb, Stefan1 aKanon, Bart1 aKetkar, Shamika1 aKhaw, Kay-Tee1 aKnowles, Joshua, W1 aKooner, Angrad, S1 aKors, Jan, A1 aKumari, Meena1 aMilani, Lili1 aLaiho, Päivi1 aLakatta, Edward, G1 aLangenberg, Claudia1 aLeusink, Maarten1 aLiu, Yongmei1 aLuben, Robert, N1 aLunetta, Kathryn, L1 aLynch, Stacey, N1 aMarkus, Marcello, R P1 aMarques-Vidal, Pedro1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcCarroll, Steven, A1 aMedland, Sarah, E1 aMiller, Kathryn, A1 aMontgomery, Grant, W1 aMorrison, Alanna, C1 aMüller-Nurasyid, Martina1 aNavarro, Pau1 aNelis, Mari1 aO'Connell, Jeffrey, R1 aO'Donnell, Christopher, J1 aOng, Ken, K1 aNewman, Anne, B1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aRao, Dabeeru, C1 aRing, Susan, M1 aRossin, Elizabeth, J1 aRudan, Diana1 aSanna, Serena1 aScott, Robert, A1 aSehmi, Jaban, S1 aSharp, Stephen1 aShin, Jordan, T1 aSingleton, Andrew, B1 aSmith, Albert, V1 aSoranzo, Nicole1 aSpector, Tim, D1 aStewart, Chip1 aStringham, Heather, M1 aTarasov, Kirill, V1 aUitterlinden, André, G1 aVandenput, Liesbeth1 aHwang, Shih-Jen1 aWhitfield, John, B1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWitteman, Jacqueline, C M1 aWong, Andrew1 aWong, Quenna1 aJamshidi, Yalda1 aZitting, Paavo1 aBoer, Jolanda, M A1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aEkelund, Ulf1 aForouhi, Nita, G1 aFroguel, Philippe1 aHingorani, Aroon1 aIngelsson, Erik1 aKivimaki, Mika1 aKronmal, Richard, A1 aKuh, Diana1 aLind, Lars1 aMartin, Nicholas, G1 aOostra, Ben, A1 aPedersen, Nancy, L1 aQuertermous, Thomas1 aRotter, Jerome, I1 aSchouw, Yvonne, T1 aVerschuren, W, M Monique1 aWalker, Mark1 aAlbanes, Demetrius1 aArnar, David, O1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBoehnke, Michael1 ade Boer, Rudolf, A1 aBouchard, Claude1 aCaulfield, W, L Mark1 aChambers, John, C1 aCurhan, Gary1 aCusi, Daniele1 aEriksson, Johan1 aFerrucci, Luigi1 aGilst, Wiek, H1 aGlorioso, Nicola1 ade Graaf, Jacqueline1 aGroop, Leif1 aGyllensten, Ulf1 aHsueh, Wen-Chi1 aHu, Frank, B1 aHuikuri, Heikki, V1 aHunter, David, J1 aIribarren, Carlos1 aIsomaa, Bo1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKiemeney, Lambertus, A1 avan der Klauw, Melanie, M1 aKooner, Jaspal, S1 aKraft, Peter1 aIacoviello, Licia1 aLehtimäki, Terho1 aLokki, Marja-Liisa, L1 aMitchell, Braxton, D1 aNavis, Gerjan1 aNieminen, Markku, S1 aOhlsson, Claes1 aPoulter, Neil, R1 aQi, Lu1 aRaitakari, Olli, T1 aRimm, Eric, B1 aRioux, John, D1 aRizzi, Federica1 aRudan, Igor1 aSalomaa, Veikko1 aSever, Peter, S1 aShields, Denis, C1 aShuldiner, Alan, R1 aSinisalo, Juha1 aStanton, Alice, V1 aStolk, Ronald, P1 aStrachan, David, P1 aTardif, Jean-Claude1 aThorsteinsdottir, Unnur1 aTuomilehto, Jaako1 avan Veldhuisen, Dirk, J1 aVirtamo, Jarmo1 aViikari, Jorma1 aVollenweider, Peter1 aWaeber, Gérard1 aWiden, Elisabeth1 aCho, Yoon Shin1 aOlsen, Jesper, V1 aVisscher, Peter, M1 aWiller, Cristen1 aFranke, Lude1 aErdmann, Jeanette1 aThompson, John, R1 aPfeufer, Arne1 aSotoodehnia, Nona1 aNewton-Cheh, Christopher1 aEllinor, Patrick, T1 aStricker, Bruno, H Ch1 aMetspalu, Andres1 aPerola, Markus1 aBeckmann, Jacques, S1 aSmith, George Davey1 aStefansson, Kari1 aWareham, Nicholas, J1 aMunroe, Patricia, B1 aSibon, Ody, C M1 aMilan, David, J1 aSnieder, Harold1 aSamani, Nilesh, J1 aLoos, Ruth, J F1 aGlobal BPgen Consortium1 aCARDIoGRAM consortium1 aPR GWAS Consortium1 aQRS GWAS Consortium1 aQT-IGC consortium1 aCHARGE-AF Consortium uhttps://chs-nhlbi.org/node/801511004nas a2203505 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2013 eng d a1553-740400aSex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.0 aSexstratified genomewide association studies including 270000 in c2013 Jun ae10035000 v93 aGiven the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
10aAnthropometry10aBody Height10aBody Mass Index10aBody Weight10aBody Weights and Measures10aFemale10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aPolymorphism, Single Nucleotide10aSex Characteristics10aWaist Circumference10aWaist-Hip Ratio1 aRandall, Joshua, C1 aWinkler, Thomas, W1 aKutalik, Zoltán1 aBerndt, Sonja, I1 aJackson, Anne, U1 aMonda, Keri, L1 aKilpeläinen, Tuomas, O1 aEsko, Tõnu1 aMägi, Reedik1 aLi, Shengxu1 aWorkalemahu, Tsegaselassie1 aFeitosa, Mary, F1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aFall, Tove1 aFerreira, Teresa1 aGustafsson, Stefan1 aLocke, Adam, E1 aMathieson, Iain1 aScherag, Andre1 aVedantam, Sailaja1 aWood, Andrew, R1 aLiang, Liming1 aSteinthorsdottir, Valgerdur1 aThorleifsson, Gudmar1 aDermitzakis, Emmanouil, T1 aDimas, Antigone, S1 aKarpe, Fredrik1 aMin, Josine, L1 aNicholson, George1 aClegg, Deborah, J1 aPerson, Thomas1 aKrohn, Jon, P1 aBauer, Sabrina1 aBuechler, Christa1 aEisinger, Kristina1 aBonnefond, Amélie1 aFroguel, Philippe1 aHottenga, Jouke-Jan1 aProkopenko, Inga1 aWaite, Lindsay, L1 aHarris, Tamara, B1 aSmith, Albert, Vernon1 aShuldiner, Alan, R1 aMcArdle, Wendy, L1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aGrönberg, Henrik1 aChen, Yii-Der Ida1 aLi, Guo1 aBeckmann, Jacques, S1 aJohnson, Toby1 aThorsteinsdottir, Unnur1 aTeder-Laving, Maris1 aKhaw, Kay-Tee1 aWareham, Nicholas, J1 aZhao, Jing Hua1 aAmin, Najaf1 aOostra, Ben, A1 aKraja, Aldi, T1 aProvince, Michael, A1 aCupples, Adrienne, L1 aHeard-Costa, Nancy, L1 aKaprio, Jaakko1 aRipatti, Samuli1 aSurakka, Ida1 aCollins, Francis, S1 aSaramies, Jouko1 aTuomilehto, Jaakko1 aJula, Antti1 aSalomaa, Veikko1 aErdmann, Jeanette1 aHengstenberg, Christian1 aLoley, Christina1 aSchunkert, Heribert1 aLamina, Claudia1 aWichmann, Erich, H1 aAlbrecht, Eva1 aGieger, Christian1 aHicks, Andrew, A1 aJohansson, Asa1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aSpeliotes, Elizabeth, K1 aPenninx, Brenda1 aHartikainen, Anna-Liisa1 aJarvelin, Marjo-Riitta1 aGyllensten, Ulf1 aBoomsma, Dorret, I1 aCampbell, Harry1 aWilson, James, F1 aChanock, Stephen, J1 aFarrall, Martin1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aRivadeneira, Fernando1 aEstrada, Karol1 aUitterlinden, André, G1 aHofman, Albert1 aZillikens, Carola, M1 aHeijer, Martin, den1 aKiemeney, Lambertus, A1 aMaschio, Andrea1 aHall, Per1 aTyrer, Jonathan1 aTeumer, Alexander1 aVölzke, Henry1 aKovacs, Peter1 aTönjes, Anke1 aMangino, Massimo1 aSpector, Tim, D1 aHayward, Caroline1 aRudan, Igor1 aHall, Alistair, S1 aSamani, Nilesh, J1 aAttwood, Antony, Paul1 aSambrook, Jennifer, G1 aHung, Joseph1 aPalmer, Lyle, J1 aLokki, Marja-Liisa1 aSinisalo, Juha1 aBoucher, Gabrielle1 aHuikuri, Heikki1 aLorentzon, Mattias1 aOhlsson, Claes1 aEklund, Niina1 aEriksson, Johan, G1 aBarlassina, Cristina1 aRivolta, Carlo1 aNolte, Ilja, M1 aSnieder, Harold1 avan der Klauw, Melanie, M1 avan Vliet-Ostaptchouk, Jana, V1 aGejman, Pablo, V1 aShi, Jianxin1 aJacobs, Kevin, B1 aWang, Zhaoming1 aBakker, Stephan, J L1 aLeach, Irene, Mateo1 aNavis, Gerjan1 aHarst, Pim1 aMartin, Nicholas, G1 aMedland, Sarah, E1 aMontgomery, Grant, W1 aYang, Jian1 aChasman, Daniel, I1 aRidker, Paul, M1 aRose, Lynda, M1 aLehtimäki, Terho1 aRaitakari, Olli1 aAbsher, Devin1 aIribarren, Carlos1 aBasart, Hanneke1 aHovingh, Kees, G1 aHyppönen, Elina1 aPower, Chris1 aAnderson, Denise1 aBeilby, John, P1 aHui, Jennie1 aJolley, Jennifer1 aSager, Hendrik1 aBornstein, Stefan, R1 aSchwarz, Peter, E H1 aKristiansson, Kati1 aPerola, Markus1 aLindström, Jaana1 aSwift, Amy, J1 aUusitupa, Matti1 aAtalay, Mustafa1 aLakka, Timo, A1 aRauramaa, Rainer1 aBolton, Jennifer, L1 aFowkes, Gerry1 aFraser, Ross, M1 aPrice, Jackie, F1 aFischer, Krista1 aKov, Kaarel, Krjutå1 aMetspalu, Andres1 aMihailov, Evelin1 aLangenberg, Claudia1 aLuan, Jian'an1 aOng, Ken, K1 aChines, Peter, S1 aKeinanen-Kiukaanniemi, Sirkka, M1 aSaaristo, Timo, E1 aEdkins, Sarah1 aFranks, Paul, W1 aHallmans, Göran1 aShungin, Dmitry1 aMorris, Andrew, David1 aPalmer, Colin, N A1 aErbel, Raimund1 aMoebus, Susanne1 aNöthen, Markus, M1 aPechlivanis, Sonali1 aHveem, Kristian1 aNarisu, Narisu1 aHamsten, Anders1 aHumphries, Steve, E1 aStrawbridge, Rona, J1 aTremoli, Elena1 aGrallert, Harald1 aThorand, Barbara1 aIllig, Thomas1 aKoenig, Wolfgang1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aBoehm, Bernhard, O1 aKleber, Marcus, E1 aMärz, Winfried1 aWinkelmann, Bernhard, R1 aKuusisto, Johanna1 aLaakso, Markku1 aArveiler, Dominique1 aCesana, Giancarlo1 aKuulasmaa, Kari1 aVirtamo, Jarmo1 aYarnell, John, W G1 aKuh, Diana1 aWong, Andrew1 aLind, Lars1 ade Faire, Ulf1 aGigante, Bruna1 aMagnusson, Patrik, K E1 aPedersen, Nancy, L1 aDedoussis, George1 aDimitriou, Maria1 aKolovou, Genovefa1 aKanoni, Stavroula1 aStirrups, Kathleen1 aBonnycastle, Lori, L1 aNjølstad, Inger1 aWilsgaard, Tom1 aGanna, Andrea1 aRehnberg, Emil1 aHingorani, Aroon1 aKivimaki, Mika1 aKumari, Meena1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David1 aIngelsson, Erik1 aKaplan, Robert1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aStrachan, David, P1 aStefansson, Kari1 aDuijn, Cornelia, M1 aAbecasis, Goncalo, R1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aQi, Lu1 aLoos, Ruth, J F1 aLindgren, Cecilia, M1 aNorth, Kari, E1 aHeid, Iris, M1 aDIAGRAM Consortium1 aMAGIC investigators uhttps://chs-nhlbi.org/node/602808212nas a2202197 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2014 eng d a1756-183300aAssociation between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.0 aAssociation between alcohol and cardiovascular disease Mendelian c2014 Jul 10 ag41640 v3493 aOBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.
DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.
PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.
MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.
RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).
CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
10aAdult10aAged10aAlcohol Dehydrogenase10aAlcohol Drinking10aBiomarkers10aCoronary Disease10aFemale10aGenetic Markers10aGenotype10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aModels, Statistical10aPolymorphism, Single Nucleotide10aStroke1 aHolmes, Michael, V1 aDale, Caroline, E1 aZuccolo, Luisa1 aSilverwood, Richard, J1 aGuo, Yiran1 aYe, Zheng1 aPrieto-Merino, David1 aDehghan, Abbas1 aTrompet, Stella1 aWong, Andrew1 aCavadino, Alana1 aDrogan, Dagmar1 aPadmanabhan, Sandosh1 aLi, Shanshan1 aYesupriya, Ajay1 aLeusink, Maarten1 aSundström, Johan1 aHubacek, Jaroslav, A1 aPikhart, Hynek1 aSwerdlow, Daniel, I1 aPanayiotou, Andrie, G1 aBorinskaya, Svetlana, A1 aFinan, Chris1 aShah, Sonia1 aKuchenbaecker, Karoline, B1 aShah, Tina1 aEngmann, Jorgen1 aFolkersen, Lasse1 aEriksson, Per1 aRicceri, Fulvio1 aMelander, Olle1 aSacerdote, Carlotta1 aGamble, Dale, M1 aRayaprolu, Sruti1 aRoss, Owen, A1 aMcLachlan, Stela1 aVikhireva, Olga1 aSluijs, Ivonne1 aScott, Robert, A1 aAdamkova, Vera1 aFlicker, Leon1 avan Bockxmeer, Frank, M1 aPower, Christine1 aMarques-Vidal, Pedro1 aMeade, Tom1 aMarmot, Michael, G1 aFerro, Jose, M1 aPaulos-Pinheiro, Sofia1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aLeach, Irene, Mateo1 aVerweij, Niek1 aLinneberg, Allan1 aSkaaby, Tea1 aDoevendans, Pieter, A1 aCramer, Maarten, J1 aHarst, Pim1 aKlungel, Olaf, H1 aDowling, Nicole, F1 aDominiczak, Anna, F1 aKumari, Meena1 aNicolaides, Andrew, N1 aWeikert, Cornelia1 aBoeing, Heiner1 aEbrahim, Shah1 aGaunt, Tom, R1 aPrice, Jackie, F1 aLannfelt, Lars1 aPeasey, Anne1 aKubinova, Ruzena1 aPajak, Andrzej1 aMalyutina, Sofia1 aVoevoda, Mikhail, I1 aTamosiunas, Abdonas1 avan der Zee, Anke, H Maitland1 aNorman, Paul, E1 aHankey, Graeme, J1 aBergmann, Manuela, M1 aHofman, Albert1 aFranco, Oscar, H1 aCooper, Jackie1 aPalmen, Jutta1 aSpiering, Wilko1 ade Jong, Pim, A1 aKuh, Diana1 aHardy, Rebecca1 aUitterlinden, André, G1 aIkram, Arfan, M1 aFord, Ian1 aHyppönen, Elina1 aAlmeida, Osvaldo, P1 aWareham, Nicholas, J1 aKhaw, Kay-Tee1 aHamsten, Anders1 aHusemoen, Lise, Lotte N1 aTjønneland, Anne1 aTolstrup, Janne, S1 aRimm, Eric1 aBeulens, Joline, W J1 aVerschuren, W, M Monique1 aOnland-Moret, Charlotte, N1 aHofker, Marten, H1 aWannamethee, Goya1 aWhincup, Peter, H1 aMorris, Richard1 aVicente, Astrid, M1 aWatkins, Hugh1 aFarrall, Martin1 aJukema, Wouter1 aMeschia, James1 aCupples, Adrienne, L1 aSharp, Stephen, J1 aFornage, Myriam1 aKooperberg, Charles1 aLaCroix, Andrea, Z1 aDai, James, Y1 aLanktree, Matthew, B1 aSiscovick, David, S1 aJorgenson, Eric1 aSpring, Bonnie1 aCoresh, Josef1 aLi, Yun, R1 aBuxbaum, Sarah, G1 aSchreiner, Pamela, J1 aEllison, Curtis1 aTsai, Michael, Y1 aPatel, Sanjay, R1 aRedline, Susan1 aJohnson, Andrew, D1 aHoogeveen, Ron, C1 aHakonarson, Hakon1 aRotter, Jerome, I1 aBoerwinkle, Eric1 ade Bakker, Paul, I W1 aKivimaki, Mika1 aAsselbergs, Folkert, W1 aSattar, Naveed1 aLawlor, Debbie, A1 aWhittaker, John1 aSmith, George, Davey1 aMukamal, Kenneth1 aPsaty, Bruce, M1 aWilson, James, G1 aLange, Leslie, A1 aHamidovic, Ajna1 aHingorani, Aroon, D1 aNordestgaard, Børge, G1 aBobak, Martin1 aLeon, David, A1 aLangenberg, Claudia1 aPalmer, Tom, M1 aReiner, Alex, P1 aKeating, Brendan, J1 aDudbridge, Frank1 aCasas, Juan, P1 aInterAct Consortium uhttps://chs-nhlbi.org/node/656910059nas a2203157 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2014 eng d a1546-171800aGenetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.0 aGenetic association study of QT interval highlights role for cal c2014 Aug a826-360 v463 aThe QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
10aAdult10aAged10aArrhythmias, Cardiac10aCalcium Signaling10aDeath, Sudden, Cardiac10aElectrocardiography10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHeart Ventricles10aHumans10aLong QT Syndrome10aMale10aMiddle Aged10aMyocardium10aPolymorphism, Single Nucleotide1 aArking, Dan, E1 aPulit, Sara, L1 aCrotti, Lia1 aHarst, Pim1 aMunroe, Patricia, B1 aKoopmann, Tamara, T1 aSotoodehnia, Nona1 aRossin, Elizabeth, J1 aMorley, Michael1 aWang, Xinchen1 aJohnson, Andrew, D1 aLundby, Alicia1 aGudbjartsson, Daniel, F1 aNoseworthy, Peter, A1 aEijgelsheim, Mark1 aBradford, Yuki1 aTarasov, Kirill, V1 aDörr, Marcus1 aMüller-Nurasyid, Martina1 aLahtinen, Annukka, M1 aNolte, Ilja, M1 aSmith, Albert, Vernon1 aBis, Joshua, C1 aIsaacs, Aaron1 aNewhouse, Stephen, J1 aEvans, Daniel, S1 aPost, Wendy, S1 aWaggott, Daryl1 aLyytikäinen, Leo-Pekka1 aHicks, Andrew, A1 aEisele, Lewin1 aEllinghaus, David1 aHayward, Caroline1 aNavarro, Pau1 aUlivi, Sheila1 aTanaka, Toshiko1 aTester, David, J1 aChatel, Stéphanie1 aGustafsson, Stefan1 aKumari, Meena1 aMorris, Richard, W1 aNaluai, Åsa, T1 aPadmanabhan, Sandosh1 aKluttig, Alexander1 aStrohmer, Bernhard1 aPanayiotou, Andrie, G1 aTorres, Maria1 aKnoflach, Michael1 aHubacek, Jaroslav, A1 aSlowikowski, Kamil1 aRaychaudhuri, Soumya1 aKumar, Runjun, D1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShuldiner, Alan, R1 aAlonso, Alvaro1 aBader, Joel, S1 aEhret, Georg1 aHuang, Hailiang1 aKao, Linda, W H1 aStrait, James, B1 aMacfarlane, Peter, W1 aBrown, Morris1 aCaulfield, Mark, J1 aSamani, Nilesh, J1 aKronenberg, Florian1 aWilleit, Johann1 aSmith, Gustav1 aGreiser, Karin, H1 aSchwabedissen, Henriette, Meyer Zu1 aWerdan, Karl1 aCarella, Massimo1 aZelante, Leopoldo1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aKolcic, Ivana1 aPolasek, Ozren1 aWright, Alan, F1 aGriffin, Maura1 aDaly, Mark, J1 aArnar, David, O1 aHolm, Hilma1 aThorsteinsdottir, Unnur1 aDenny, Joshua, C1 aRoden, Dan, M1 aZuvich, Rebecca, L1 aEmilsson, Valur1 aPlump, Andrew, S1 aLarson, Martin, G1 aO'Donnell, Christopher, J1 aYin, Xiaoyan1 aBobbo, Marco1 aD'Adamo, Adamo, P1 aIorio, Annamaria1 aSinagra, Gianfranco1 aCarracedo, Angel1 aCummings, Steven, R1 aNalls, Michael, A1 aJula, Antti1 aKontula, Kimmo, K1 aMarjamaa, Annukka1 aOikarinen, Lasse1 aPerola, Markus1 aPorthan, Kimmo1 aErbel, Raimund1 aHoffmann, Per1 aJöckel, Karl-Heinz1 aKälsch, Hagen1 aNöthen, Markus, M1 aHoed, Marcel, den1 aLoos, Ruth, J F1 aThelle, Dag, S1 aGieger, Christian1 aMeitinger, Thomas1 aPerz, Siegfried1 aPeters, Annette1 aPrucha, Hanna1 aSinner, Moritz, F1 aWaldenberger, Melanie1 ade Boer, Rudolf, A1 aFranke, Lude1 avan der Vleuten, Pieter, A1 aBeckmann, Britt, Maria1 aMartens, Eimo1 aBardai, Abdennasser1 aHofman, Nynke1 aWilde, Arthur, A M1 aBehr, Elijah, R1 aDalageorgou, Chrysoula1 aGiudicessi, John, R1 aMedeiros-Domingo, Argelia1 aBarc, Julien1 aKyndt, Florence1 aProbst, Vincent1 aGhidoni, Alice1 aInsolia, Roberto1 aHamilton, Robert, M1 aScherer, Stephen, W1 aBrandimarto, Jeffrey1 aMargulies, Kenneth1 aMoravec, Christine, E1 aM, Fabiola, del Greco1 aFuchsberger, Christian1 aO'Connell, Jeffrey, R1 aLee, Wai, K1 aWatt, Graham, C M1 aCampbell, Harry1 aWild, Sarah, H1 aMokhtari, Nour, E El1 aFrey, Norbert1 aAsselbergs, Folkert, W1 aLeach, Irene, Mateo1 aNavis, Gerjan1 avan den Berg, Maarten, P1 avan Veldhuisen, Dirk, J1 aKellis, Manolis1 aKrijthe, Bouwe, P1 aFranco, Oscar, H1 aHofman, Albert1 aKors, Jan, A1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aKedenko, Lyudmyla1 aLamina, Claudia1 aOostra, Ben, A1 aAbecasis, Goncalo, R1 aLakatta, Edward, G1 aMulas, Antonella1 aOrrù, Marco1 aSchlessinger, David1 aUda, Manuela1 aMarkus, Marcello, R P1 aVölker, Uwe1 aSnieder, Harold1 aSpector, Timothy, D1 aArnlöv, Johan1 aLind, Lars1 aSundström, Johan1 aSyvänen, Ann-Christine1 aKivimaki, Mika1 aKähönen, Mika1 aMononen, Nina1 aRaitakari, Olli, T1 aViikari, Jorma, S1 aAdamkova, Vera1 aKiechl, Stefan1 aBrion, Maria1 aNicolaides, Andrew, N1 aPaulweber, Bernhard1 aHaerting, Johannes1 aDominiczak, Anna, F1 aNyberg, Fredrik1 aWhincup, Peter, H1 aHingorani, Aroon, D1 aSchott, Jean-Jacques1 aBezzina, Connie, R1 aIngelsson, Erik1 aFerrucci, Luigi1 aGasparini, Paolo1 aWilson, James, F1 aRudan, Igor1 aFranke, Andre1 aMühleisen, Thomas, W1 aPramstaller, Peter, P1 aLehtimäki, Terho, J1 aPaterson, Andrew, D1 aParsa, Afshin1 aLiu, Yongmei1 aDuijn, Cornelia, M1 aSiscovick, David, S1 aGudnason, Vilmundur1 aJamshidi, Yalda1 aSalomaa, Veikko1 aFelix, Stephan, B1 aSanna, Serena1 aRitchie, Marylyn, D1 aStricker, Bruno, H1 aStefansson, Kari1 aBoyer, Laurie, A1 aCappola, Thomas, P1 aOlsen, Jesper, V1 aLage, Kasper1 aSchwartz, Peter, J1 aKääb, Stefan1 aChakravarti, Aravinda1 aAckerman, Michael, J1 aPfeufer, Arne1 ade Bakker, Paul, I W1 aNewton-Cheh, Christopher1 aCARe Consortium1 aCOGENT Consortium1 aDCCT/EDIC1 aeMERGE Consortium1 aHRGEN Consortium uhttps://chs-nhlbi.org/node/654408133nas a2201957 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2015 eng d a1474-547X00aHMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.0 aHMGcoenzyme A reductase inhibition type 2 diabetes and bodyweigh c2015 Jan 24 a351-610 v3853 aBACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).
INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
FUNDING: The funding sources are cited at the end of the paper.
10aAged10aBody Mass Index10aBody Weight10aCholesterol, HDL10aCholesterol, LDL10aDiabetes Mellitus, Type 210aFemale10aGenetic Testing10aHumans10aHydroxymethylglutaryl CoA Reductases10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRandomized Controlled Trials as Topic10aRisk Factors1 aSwerdlow, Daniel, I1 aPreiss, David1 aKuchenbaecker, Karoline, B1 aHolmes, Michael, V1 aEngmann, Jorgen, E L1 aShah, Tina1 aSofat, Reecha1 aStender, Stefan1 aJohnson, Paul, C D1 aScott, Robert, A1 aLeusink, Maarten1 aVerweij, Niek1 aSharp, Stephen, J1 aGuo, Yiran1 aGiambartolomei, Claudia1 aChung, Christina1 aPeasey, Anne1 aAmuzu, Antoinette1 aLi, KaWah1 aPalmen, Jutta1 aHoward, Philip1 aCooper, Jackie, A1 aDrenos, Fotios1 aLi, Yun, R1 aLowe, Gordon1 aGallacher, John1 aStewart, Marlene, C W1 aTzoulaki, Ioanna1 aBuxbaum, Sarah, G1 avan der A, Daphne, L1 aForouhi, Nita, G1 aOnland-Moret, Charlotte, N1 aSchouw, Yvonne, T1 aSchnabel, Renate, B1 aHubacek, Jaroslav, A1 aKubinova, Ruzena1 aBaceviciene, Migle1 aTamosiunas, Abdonas1 aPajak, Andrzej1 aTopor-Madry, Roman1 aStepaniak, Urszula1 aMalyutina, Sofia1 aBaldassarre, Damiano1 aSennblad, Bengt1 aTremoli, Elena1 ade Faire, Ulf1 aVeglia, Fabrizio1 aFord, Ian1 aJukema, Wouter1 aWestendorp, Rudi, G J1 ade Borst, Gert, Jan1 ade Jong, Pim, A1 aAlgra, Ale1 aSpiering, Wilko1 avan der Zee, Anke, H Maitland1 aKlungel, Olaf, H1 ade Boer, Anthonius1 aDoevendans, Pieter, A1 aEaton, Charles, B1 aRobinson, Jennifer, G1 aDuggan, David1 aKjekshus, John1 aDowns, John, R1 aGotto, Antonio, M1 aKeech, Anthony, C1 aMarchioli, Roberto1 aTognoni, Gianni1 aSever, Peter, S1 aPoulter, Neil, R1 aWaters, David, D1 aPedersen, Terje, R1 aAmarenco, Pierre1 aNakamura, Haruo1 aMcMurray, John, J V1 aLewsey, James, D1 aChasman, Daniel, I1 aRidker, Paul, M1 aMaggioni, Aldo, P1 aTavazzi, Luigi1 aRay, Kausik, K1 aSeshasai, Sreenivasa, Rao Kondap1 aManson, JoAnn, E1 aPrice, Jackie, F1 aWhincup, Peter, H1 aMorris, Richard, W1 aLawlor, Debbie, A1 aSmith, George Davey1 aBen-Shlomo, Yoav1 aSchreiner, Pamela, J1 aFornage, Myriam1 aSiscovick, David, S1 aCushman, Mary1 aKumari, Meena1 aWareham, Nick, J1 aVerschuren, W, M Monique1 aRedline, Susan1 aPatel, Sanjay, R1 aWhittaker, John, C1 aHamsten, Anders1 aDelaney, Joseph, A1 aDale, Caroline1 aGaunt, Tom, R1 aWong, Andrew1 aKuh, Diana1 aHardy, Rebecca1 aKathiresan, Sekar1 aCastillo, Berta, A1 aHarst, Pim1 aBrunner, Eric, J1 aTybjaerg-Hansen, Anne1 aMarmot, Michael, G1 aKrauss, Ronald, M1 aTsai, Michael1 aCoresh, Josef1 aHoogeveen, Ronald, C1 aPsaty, Bruce, M1 aLange, Leslie, A1 aHakonarson, Hakon1 aDudbridge, Frank1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aKivimaki, Mika1 aTimpson, Nicholas, J1 aLangenberg, Claudia1 aAsselbergs, Folkert, W1 aVoevoda, Mikhail1 aBobak, Martin1 aPikhart, Hynek1 aWilson, James, G1 aReiner, Alex, P1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aSattar, Naveed1 aDIAGRAM Consortium1 aMAGIC Consortium1 aInterAct Consortium uhttps://chs-nhlbi.org/node/686305080nas a2201129 4500008004100000022001400041245007200055210006900127260001600196300001100212490000700223520191200230653002502142653002102167653002802188653001102216653001902227653001302246653002602259653001102285653000902296653003702305653001602342653003602358653002002394653001802414100002302432700002702455700001902482700001902501700002502520700002702545700002202572700002502594700001702619700002402636700002302660700002602683700002802709700001602737700002102753700001502774700002002789700002802809700001502837700002102852700001802873700002102891700002602912700002602938700002202964700001902986700002103005700002203026700001803048700002003066700002103086700001903107700002403126700002103150700002603171700002203197700002403219700002103243700002203264700001903286700002403305700002003329700002103349700001803370700001803388700001803406700002003424700002103444700002103465700001803486700002403504700001903528700001803547700002003565700002103585700002103606700002503627700002103652700002503673700002003698700002403718700001903742700002203761700002103783700002203804700002403826700002403850700001903874710002103893856003603914 2015 eng d a1522-964500aMendelian randomization of blood lipids for coronary heart disease.0 aMendelian randomization of blood lipids for coronary heart disea c2015 Mar 01 a539-500 v363 aAIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.
METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).
CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
10aCase-Control Studies10aCholesterol, HDL10aCoronary Artery Disease10aFemale10aGene Frequency10aGenotype10aGenotyping Techniques10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Assessment10aTriglycerides1 aHolmes, Michael, V1 aAsselbergs, Folkert, W1 aPalmer, Tom, M1 aDrenos, Fotios1 aLanktree, Matthew, B1 aNelson, Christopher, P1 aDale, Caroline, E1 aPadmanabhan, Sandosh1 aFinan, Chris1 aSwerdlow, Daniel, I1 aTragante, Vinicius1 avan Iperen, Erik, P A1 aSivapalaratnam, Suthesh1 aShah, Sonia1 aElbers, Clara, C1 aShah, Tina1 aEngmann, Jorgen1 aGiambartolomei, Claudia1 aWhite, Jon1 aZabaneh, Delilah1 aSofat, Reecha1 aMcLachlan, Stela1 aDoevendans, Pieter, A1 aBalmforth, Anthony, J1 aHall, Alistair, S1 aNorth, Kari, E1 aAlmoguera, Berta1 aHoogeveen, Ron, C1 aCushman, Mary1 aFornage, Myriam1 aPatel, Sanjay, R1 aRedline, Susan1 aSiscovick, David, S1 aTsai, Michael, Y1 aKarczewski, Konrad, J1 aHofker, Marten, H1 aVerschuren, Monique1 aBots, Michiel, L1 aSchouw, Yvonne, T1 aMelander, Olle1 aDominiczak, Anna, F1 aMorris, Richard1 aBen-Shlomo, Yoav1 aPrice, Jackie1 aKumari, Meena1 aBaumert, Jens1 aPeters, Annette1 aThorand, Barbara1 aKoenig, Wolfgang1 aGaunt, Tom, R1 aHumphries, Steve, E1 aClarke, Robert1 aWatkins, Hugh1 aFarrall, Martin1 aWilson, James, G1 aRich, Stephen, S1 ade Bakker, Paul, I W1 aLange, Leslie, A1 aSmith, George, Davey1 aReiner, Alex, P1 aTalmud, Philippa, J1 aKivimaki, Mika1 aLawlor, Debbie, A1 aDudbridge, Frank1 aSamani, Nilesh, J1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aCasas, Juan, P1 aUCLEB consortium uhttps://chs-nhlbi.org/node/656803683nas a2200757 4500008004100000022001400041245011200055210006900167260000900236300000700245490000700252520150800259100002401767700002201791700002101813700001601834700001601850700002701866700002501893700002101918700002201939700001601961700001901977700001701996700002402013700001802037700002302055700001802078700002802096700002302124700002602147700002002173700002202193700002302215700002002238700002302258700002302281700002002304700003102324700001802355700001802373700002702391700002002418700002402438700001802462700002202480700002202502700001802524700002102542700002102563700002002584700001902604700002802623700002002651700002402671700002202695700002102717700001902738700001802757700002002775700001902795700002702814700002402841700002402865856003602889 2017 eng d a1756-038100aDiscovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.0 aDiscovery and replication of SNPSNP interactions for quantitativ c2017 a250 v103 aBACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).
RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.
CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
1 aHolzinger, Emily, R1 aVerma, Shefali, S1 aMoore, Carrie, B1 aHall, Molly1 aDe, Rishika1 aGilbert-Diamond, Diane1 aLanktree, Matthew, B1 aPankratz, Nathan1 aAmuzu, Antoinette1 aBurt, Amber1 aDale, Caroline1 aDudek, Scott1 aFurlong, Clement, E1 aGaunt, Tom, R1 aKim, Daniel, Seung1 aRiess, Helene1 aSivapalaratnam, Suthesh1 aTragante, Vinicius1 avan Iperen, Erik, P A1 aBrautbar, Ariel1 aCarrell, David, S1 aCrosslin, David, R1 aJarvik, Gail, P1 aKuivaniemi, Helena1 aKullo, Iftikhar, J1 aLarson, Eric, B1 aRasmussen-Torvik, Laura, J1 aTromp, Gerard1 aBaumert, Jens1 aCruickshanks, Karen, J1 aFarrall, Martin1 aHingorani, Aroon, D1 aHovingh, G, K1 aKleber, Marcus, E1 aKlein, Barbara, E1 aKlein, Ronald1 aKoenig, Wolfgang1 aLange, Leslie, A1 aMӓrz, Winfried1 aNorth, Kari, E1 aOnland-Moret, Charlotte1 aReiner, Alex, P1 aTalmud, Philippa, J1 aSchouw, Yvonne, T1 aWilson, James, G1 aKivimaki, Mika1 aKumari, Meena1 aMoore, Jason, H1 aDrenos, Fotios1 aAsselbergs, Folkert, W1 aKeating, Brendan, J1 aRitchie, Marylyn, D uhttps://chs-nhlbi.org/node/756606994nas a2202101 4500008004100000022001400041245009900055210006900154260001600223300001000239490000600249520104500255100001901300700001901319700002301338700002201361700001701383700001601400700002801416700002201444700001901466700001801485700002201503700002701525700002201552700002301574700001901597700002001616700001801636700002201654700002301676700002201699700002001721700002801741700002801769700002201797700002001819700002701839700003001866700001901896700001701915700002201932700002201954700001801976700001701994700002102011700002702032700002202059700002302081700002202104700001902126700001702145700001802162700002002180700002202200700002502222700002102247700001802268700002102286700002002307700002302327700002202350700002702372700002102399700002102420700002402441700001902465700002102484700002002505700002102525700001902546700002502565700001902590700002602609700002602635700002102661700001902682700002402701700002002725700002602745700001902771700002102790700002002811700002402831700001702855700001802872700002402890700002102914700002202935700001302957700001202970700001902982700002403001700001803025700002503043700002203068700002003090700002203110700003903132700002103171700001803192700002203210700001903232700001803251700002003269700001703289700001903306700002403325700001703349700002003366700002003386700002003406700002303426700002703449700002203476700002103498700002203519700002303541700002403564700002203588700002103610700002203631700002303653700003203676700002403708700002203732700002003754700002803774700002403802700002003826700002203846700002503868700002203893700002803915700002403943700001803967700002603985700002404011700002304035700001704058700002004075700002304095700001804118700002204136700002304158700001504181700002104196700002004217700002704237700001904264700002004283700001904303700002404322700001504346700002204361700001504383700002804398700002404426700002904450700002004479700002504499700002204524700002204546700001904568700002204587700001704609700002304626700002204649700002604671700002704697700002704724700002304751700002104774700002204795700002004817700001904837856003604856 2017 eng d a2041-172300aGenetic loci associated with heart rate variability and their effects on cardiac disease risk.0 aGenetic loci associated with heart rate variability and their ef c2017 Jun 14 a158050 v83 aReduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses. Carotid 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. In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.