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Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
10aBody Height10aBody Mass Index10aBody Size10aBody Weight10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aObesity10aPolymorphism, Single Nucleotide1 aSpeliotes, Elizabeth, K1 aWiller, Cristen, J1 aBerndt, Sonja, I1 aMonda, Keri, L1 aThorleifsson, Gudmar1 aJackson, Anne, U1 aAllen, Hana, Lango1 aLindgren, Cecilia, M1 aLuan, Jian'an1 aMägi, Reedik1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWinkler, Thomas, W1 aQi, Lu1 aWorkalemahu, Tsegaselassie1 aHeid, Iris, M1 aSteinthorsdottir, Valgerdur1 aStringham, Heather, M1 aWeedon, Michael, N1 aWheeler, Eleanor1 aWood, Andrew, R1 aFerreira, Teresa1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aEstrada, Karol1 aLiang, Liming1 aNemesh, James1 aPark, Ju-Hyun1 aGustafsson, Stefan1 aKilpeläinen, Tuomas, O1 aYang, Jian1 aBouatia-Naji, Nabila1 aEsko, Tõnu1 aFeitosa, Mary, F1 aKutalik, Zoltán1 aMangino, Massimo1 aRaychaudhuri, Soumya1 aScherag, Andre1 aSmith, Albert, 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aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBergmann, Sven1 aBiebermann, Heike1 aBlakemore, Alexandra, I F1 aBoes, Tanja1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBrown, Morris, J1 aBuchanan, Thomas, A1 aBusonero, Fabio1 aCampbell, Harry1 aCappuccio, Francesco, P1 aCavalcanti-Proença, Christine1 aChen, Yii-Der Ida1 aChen, Chih-Mei1 aChines, Peter, S1 aClarke, Robert1 aCoin, Lachlan1 aConnell, John1 aDay, Ian, N M1 aHeijer, Martin, den1 aDuan, Jubao1 aEbrahim, Shah1 aElliott, Paul1 aElosua, Roberto1 aEiriksdottir, Gudny1 aErdos, Michael, R1 aEriksson, Johan, G1 aFacheris, Maurizio, F1 aFelix, Stephan, B1 aFischer-Posovszky, Pamela1 aFolsom, Aaron, R1 aFriedrich, Nele1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGejman, Pablo, V1 aGeus, Eco, J C1 aGieger, Christian1 aGjesing, Anette, P1 aGoel, Anuj1 aGoyette, Philippe1 aGrallert, Harald1 aGrässler, Jürgen1 aGreenawalt, Danielle, M1 aGroves, Christopher, J1 aGudnason, Vilmundur1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 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aTeslovich, Tanya, M1 aThompson, John, R1 aThomson, Brian1 aTönjes, Anke1 aTuomi, Tiinamaija1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aViikari, Jorma1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogel, Carla, I G1 aVoight, Benjamin, F1 aWaite, Lindsay, L1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWiegand, Susanna1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aWitteman, Jacqueline, C1 aXu, Jianfeng1 aZhang, Qunyuan1 aZgaga, Lina1 aZiegler, Andreas1 aZitting, Paavo1 aBeilby, John, P1 aFarooqi, Sadaf1 aHebebrand, Johannes1 aHuikuri, Heikki, V1 aJames, Alan, L1 aKähönen, Mika1 aLevinson, Douglas, F1 aMacciardi, Fabio1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRidker, Paul, M1 aStumvoll, Michael1 aBeckmann, Jacques, S1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCollins, Francis, S1 aCupples, Adrienne, L1 aSmith, George Davey1 aErdmann, Jeanette1 aFroguel, 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aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aFrayling, Timothy, M1 aThorsteinsdottir, Unnur1 aAbecasis, Goncalo, R1 aBarroso, Inês1 aBoehnke, Michael1 aStefansson, Kari1 aNorth, Kari, E1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aIngelsson, Erik1 aLoos, Ruth, J F1 aMAGIC1 aProcardis Consortium uhttps://chs-nhlbi.org/node/123712636nas a2204069 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2010 eng d a1546-171800aNew genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.0 aNew genetic loci implicated in fasting glucose homeostasis and t c2010 Feb a105-160 v423 aLevels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
10aAdolescent10aAdult10aAlleles10aBlood Glucose10aChild10aDatabases, Genetic10aDiabetes Mellitus, Type 210aDNA Copy Number Variations10aFasting10aGene Expression Regulation10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHomeostasis10aHumans10aMeta-Analysis as Topic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aReproducibility of Results1 aDupuis, Josée1 aLangenberg, Claudia1 aProkopenko, Inga1 aSaxena, Richa1 aSoranzo, Nicole1 aJackson, Anne, U1 aWheeler, Eleanor1 aGlazer, Nicole, L1 aBouatia-Naji, Nabila1 aGloyn, Anna, L1 aLindgren, Cecilia, M1 aMägi, Reedik1 aMorris, Andrew, P1 aRandall, Joshua1 aJohnson, Toby1 aElliott, Paul1 aRybin, Denis1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aHenneman, Peter1 aGrallert, Harald1 aDehghan, Abbas1 aHottenga, Jouke Jan1 aFranklin, Christopher, S1 aNavarro, Pau1 aSong, Kijoung1 aGoel, Anuj1 aPerry, John, R B1 aEgan, Josephine, M1 aLajunen, Taina1 aGrarup, Niels1 aSparsø, Thomas1 aDoney, Alex1 aVoight, Benjamin, F1 aStringham, Heather, M1 aLi, Man1 aKanoni, Stavroula1 aShrader, Peter1 aCavalcanti-Proença, Christine1 aKumari, Meena1 aQi, Lu1 aTimpson, Nicholas, J1 aGieger, Christian1 aZabena, Carina1 aRocheleau, Ghislain1 aIngelsson, Erik1 aAn, Ping1 aO'Connell, Jeffrey1 aLuan, Jian'an1 aElliott, Amanda1 aMcCarroll, Steven, A1 aPayne, Felicity1 aRoccasecca, Rosa Maria1 aPattou, François1 aSethupathy, Praveen1 aArdlie, Kristin1 aAriyurek, Yavuz1 aBalkau, Beverley1 aBarter, Philip1 aBeilby, John, P1 aBen-Shlomo, Yoav1 aBenediktsson, Rafn1 aBennett, Amanda, J1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBonnefond, Amélie1 aBonnycastle, Lori, L1 aBorch-Johnsen, Knut1 aBöttcher, Yvonne1 aBrunner, Eric1 aBumpstead, Suzannah, J1 aCharpentier, Guillaume1 aChen, Yii-Der Ida1 aChines, Peter1 aClarke, Robert1 aCoin, Lachlan, J M1 aCooper, Matthew, N1 aCornelis, Marilyn1 aCrawford, Gabe1 aCrisponi, Laura1 aDay, Ian, N M1 aGeus, 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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 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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 a1546-171800aGenome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.0 aGenomewide association study identifies six new loci influencing c2011 Sep 11 a1005-110 v433 aNumerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
10aArteries10aBlood Pressure10aCase-Control Studies10aFollow-Up Studies10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide1 aWain, Louise, V1 aVerwoert, Germaine, C1 aO'Reilly, Paul, F1 aShi, Gang1 aJohnson, Toby1 aJohnson, Andrew, D1 aBochud, Murielle1 aRice, Kenneth, M1 aHenneman, Peter1 aSmith, Albert, V1 aEhret, Georg, B1 aAmin, Najaf1 aLarson, Martin, G1 aMooser, Vincent1 aHadley, David1 aDörr, Marcus1 aBis, Joshua, C1 aAspelund, Thor1 aEsko, Tõnu1 aJanssens, Cecile, J W1 aZhao, Jing Hua1 aHeath, Simon1 aLaan, Maris1 aFu, Jingyuan1 aPistis, Giorgio1 aLuan, Jian'an1 aArora, Pankaj1 aLucas, Gavin1 aPirastu, Nicola1 aPichler, Irene1 aJackson, Anne, U1 aWebster, Rebecca, J1 aZhang, Feng1 aPeden, John, F1 aSchmidt, Helena1 aTanaka, Toshiko1 aCampbell, Harry1 aIgl, Wilmar1 aMilaneschi, Yuri1 aHottenga, Jouke-Jan1 aVitart, Veronique1 aChasman, Daniel, I1 aTrompet, Stella1 aBragg-Gresham, Jennifer, L1 aAlizadeh, Behrooz, Z1 aChambers, John, C1 aGuo, Xiuqing1 aLehtimäki, Terho1 aKuhnel, Brigitte1 aLopez, Lorna, M1 aPolasek, Ozren1 aBoban, Mladen1 aNelson, Christopher, P1 aMorrison, Alanna, C1 aPihur, Vasyl1 aGanesh, Santhi, K1 aHofman, Albert1 aKundu, Suman1 aMattace-Raso, Francesco, U S1 aRivadeneira, Fernando1 aSijbrands, Eric, J G1 aUitterlinden, André, G1 aHwang, Shih-Jen1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aLaitinen, Jaana1 aPouta, Anneli1 aZitting, Paavo1 aMcArdle, Wendy, L1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGlazer, Nicole, L1 aTaylor, Kent, D1 aHarris, Tamara, B1 aAlavere, Helene1 aHaller, Toomas1 aKeis, Aime1 aTammesoo, Mari-Liis1 aAulchenko, Yurii1 aBarroso, Inês1 aKhaw, Kay-Tee1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aEyheramendy, Susana1 aOrg, Elin1 aSõber, Siim1 aLu, Xiaowen1 aNolte, Ilja, M1 aPenninx, Brenda, W1 aCorre, Tanguy1 aMasciullo, Corrado1 aSala, Cinzia1 aGroop, Leif1 aVoight, Benjamin, F1 aMelander, Olle1 aO'Donnell, Christopher, J1 aSalomaa, Veikko1 ad'Adamo, Adamo, Pio1 aFabretto, Antonella1 aFaletra, Flavio1 aUlivi, Sheila1 aDel Greco, Fabiola, M1 aFacheris, Maurizio1 aCollins, Francis, S1 aBergman, Richard, N1 aBeilby, John, P1 aHung, Joseph1 aMusk, William1 aMangino, Massimo1 aShin, So-Youn1 aSoranzo, Nicole1 aWatkins, Hugh1 aGoel, Anuj1 aHamsten, Anders1 aGider, Pierre1 aLoitfelder, Marisa1 aZeginigg, Marion1 aHernandez, Dena1 aNajjar, Samer, S1 aNavarro, Pau1 aWild, Sarah, H1 aCorsi, Anna Maria1 aSingleton, Andrew1 aGeus, Eco, J C1 aWillemsen, Gonneke1 aParker, Alex, N1 aRose, Lynda, M1 aBuckley, Brendan1 aStott, David1 aOrrù, Marco1 aUda, Manuela1 avan der Klauw, Melanie, M1 aZhang, Weihua1 aLi, Xinzhong1 aScott, James1 aChen, Yii-Der Ida1 aBurke, Gregory, L1 aKähönen, Mika1 aViikari, Jorma1 aDöring, Angela1 aMeitinger, Thomas1 aDavies, Gail1 aStarr, John, M1 aEmilsson, Valur1 aPlump, Andrew1 aLindeman, Jan, H1 aHoen, Peter, A C 't1 aKönig, Inke, R1 aFelix, Janine, F1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aBreteler, Monique1 aDebette, Stephanie1 aDeStefano, Anita, L1 aFornage, Myriam1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aHolm, Hilma1 aStefansson, Kari1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aSamani, Nilesh, J1 aPreuss, Michael1 aRudan, Igor1 aHayward, Caroline1 aDeary, Ian, J1 aWichmann, H-Erich1 aRaitakari, Olli, T1 aPalmas, Walter1 aKooner, Jaspal, S1 aStolk, Ronald, P1 aJukema, Wouter1 aWright, Alan, F1 aBoomsma, Dorret, I1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWilson, James, F1 aFerrucci, Luigi1 aSchmidt, Reinhold1 aFarrall, Martin1 aSpector, Tim, D1 aPalmer, Lyle, J1 aTuomilehto, Jaakko1 aPfeufer, Arne1 aGasparini, Paolo1 aSiscovick, David1 aAltshuler, David1 aLoos, Ruth, J F1 aToniolo, Daniela1 aSnieder, Harold1 aGieger, Christian1 aMeneton, Pierre1 aWareham, Nicholas, J1 aOostra, Ben, A1 aMetspalu, Andres1 aLauner, Lenore1 aRettig, Rainer1 aStrachan, David, P1 aBeckmann, Jacques, S1 aWitteman, Jacqueline, C M1 aErdmann, Jeanette1 aDijk, Ko Willems1 aBoerwinkle, Eric1 aBoehnke, Michael1 aRidker, Paul, M1 aJarvelin, Marjo-Riitta1 aChakravarti, Aravinda1 aAbecasis, Goncalo, R1 aGudnason, Vilmundur1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aRao, Dabeeru, C1 aTobin, Martin, D1 aElliott, Paul1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aEchoGen consortium1 aAortaGen Consortium1 aCHARGE Consortium Heart Failure Working Group1 aKidneyGen Consortium1 aCKDGen Consortium1 aCardiogenics consortium1 aCardioGram uhttps://chs-nhlbi.org/node/132408598nas a2202365 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2012 eng d a1476-468700aFTO genotype is associated with phenotypic variability of body mass index.0 aFTO genotype is associated with phenotypic variability of body m c2012 Oct 11 a267-720 v4903 aThere is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Height10aBody Mass Index10aCo-Repressor Proteins10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteins10aRepressor Proteins1 aYang, Jian1 aLoos, Ruth, J F1 aPowell, Joseph, E1 aMedland, Sarah, E1 aSpeliotes, Elizabeth, K1 aChasman, Daniel, I1 aRose, Lynda, M1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aMägi, Reedik1 aWaite, Lindsay1 aSmith, Albert, Vernon1 aYerges-Armstrong, Laura, M1 aMonda, Keri, L1 aHadley, David1 aMahajan, Anubha1 aLi, Guo1 aKapur, Karen1 aVitart, Veronique1 aHuffman, Jennifer, E1 aWang, Sophie, R1 aPalmer, Cameron1 aEsko, Tõnu1 aFischer, Krista1 aZhao, Jing Hua1 aDemirkan, Ayse1 aIsaacs, Aaron1 aFeitosa, Mary, F1 aLuan, Jian'an1 aHeard-Costa, Nancy, L1 aWhite, Charles1 aJackson, Anne, U1 aPreuss, Michael1 aZiegler, Andreas1 aEriksson, Joel1 aKutalik, Zoltán1 aFrau, Francesca1 aNolte, Ilja, M1 avan Vliet-Ostaptchouk, Jana, V1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aVerweij, Niek1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aEstrada, Karol1 aBragg-Gresham, Jennifer, Lynn1 aSanna, Serena1 aSidore, Carlo1 aTyrer, Jonathan1 aTeumer, Alexander1 aProkopenko, Inga1 aMangino, Massimo1 aLindgren, Cecilia, M1 aAssimes, Themistocles, L1 aShuldiner, Alan, R1 aHui, Jennie1 aBeilby, John, P1 aMcArdle, Wendy, L1 aHall, Per1 aHaritunians, Talin1 aZgaga, Lina1 aKolcic, Ivana1 aPolasek, Ozren1 aZemunik, Tatijana1 aOostra, Ben, A1 aJunttila, Juhani1 aGrönberg, Henrik1 aSchreiber, Stefan1 aPeters, Annette1 aHicks, Andrew, A1 aStephens, Jonathan1 aFoad, Nicola, S1 aLaitinen, Jaana1 aPouta, Anneli1 aKaakinen, Marika1 aWillemsen, Gonneke1 aVink, Jacqueline, M1 aWild, Sarah, H1 aNavis, Gerjan1 aAsselbergs, Folkert, W1 aHomuth, Georg1 aJohn, Ulrich1 aIribarren, Carlos1 aHarris, Tamara1 aLauner, Lenore1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBoerwinkle, Eric1 aCadby, Gemma1 aPalmer, Lyle, J1 aJames, Alan, L1 aMusk, Arthur, W1 aIngelsson, Erik1 aPsaty, Bruce, M1 aBeckmann, Jacques, S1 aWaeber, Gérard1 aVollenweider, Peter1 aHayward, Caroline1 aWright, Alan, F1 aRudan, Igor1 aGroop, Leif, C1 aMetspalu, Andres1 aKhaw, Kay, Tee1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aProvince, Michael, A1 aWareham, Nicholas, J1 aTardif, Jean-Claude1 aHuikuri, Heikki, V1 aCupples, Adrienne, L1 aAtwood, Larry, D1 aFox, Caroline, S1 aBoehnke, Michael1 aCollins, Francis, S1 aMohlke, Karen, L1 aErdmann, Jeanette1 aSchunkert, Heribert1 aHengstenberg, Christian1 aStark, Klaus1 aLorentzon, Mattias1 aOhlsson, Claes1 aCusi, Daniele1 aStaessen, Jan, A1 avan der Klauw, Melanie, M1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aJolley, Jennifer, D1 aRipatti, Samuli1 aJarvelin, Marjo-Riitta1 aGeus, Eco, J C1 aBoomsma, Dorret, I1 aPenninx, Brenda1 aWilson, James, F1 aCampbell, Harry1 aChanock, Stephen, J1 aHarst, Pim1 aHamsten, Anders1 aWatkins, Hugh1 aHofman, Albert1 aWitteman, Jacqueline, C1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aZillikens, Carola, M1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aAbecasis, Goncalo, R1 aSchlessinger, David1 aSchipf, Sabine1 aStumvoll, Michael1 aTönjes, Anke1 aSpector, Tim, D1 aNorth, Kari, E1 aLettre, Guillaume1 aMcCarthy, Mark, I1 aBerndt, Sonja, I1 aHeath, Andrew, C1 aMadden, Pamela, A F1 aNyholt, Dale, R1 aMontgomery, Grant, W1 aMartin, Nicholas, G1 aMcKnight, Barbara1 aStrachan, David, P1 aHill, William, G1 aSnieder, Harold1 aRidker, Paul, M1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N1 aGoddard, Michael, E1 aVisscher, Peter, M uhttps://chs-nhlbi.org/node/617505960nas a2201525 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2012 eng d a1528-002000aGenome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.0 aGenomewide association study for circulating levels of PAI1 prov c2012 Dec 06 a4873-810 v1203 aWe conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
10aAdaptor Proteins, Signal Transducing10aARNTL Transcription Factors10aATPases Associated with Diverse Cellular Activities10aCell Line10aCell Line, Tumor10aCohort Studies10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aGene Expression Profiling10aGene Expression Regulation10aGene Frequency10aGenome-Wide Association Study10aGenotype10aHumans10aLIM Domain Proteins10aMeta-Analysis as Topic10aMonocytes10aMucin-310aPlasminogen Activator Inhibitor 110aPolymorphism, Single Nucleotide10aPPAR gamma10aProteasome Endopeptidase Complex10aRNA Interference10aTranscription Factors1 aHuang, Jie1 aSabater-Lleal, Maria1 aAsselbergs, Folkert, W1 aTregouet, David1 aShin, So-Youn1 aDing, Jingzhong1 aBaumert, Jens1 aOudot-Mellakh, Tiphaine1 aFolkersen, Lasse1 aJohnson, Andrew, D1 aSmith, Nicholas, L1 aWilliams, Scott, M1 aIkram, Mohammad, A1 aKleber, Marcus, E1 aBecker, Diane, M1 aTruong, Vinh1 aMychaleckyj, Josyf, C1 aTang, Weihong1 aYang, Qiong1 aSennblad, Bengt1 aMoore, Jason, H1 aWilliams, Frances, M K1 aDehghan, Abbas1 aSilbernagel, Günther1 aSchrijvers, Elisabeth, M C1 aSmith, Shelly1 aKarakas, Mahir1 aTofler, Geoffrey, H1 aSilveira, Angela1 aNavis, Gerjan, J1 aLohman, Kurt1 aChen, Ming-Huei1 aPeters, Annette1 aGoel, Anuj1 aHopewell, Jemma, C1 aChambers, John, C1 aSaleheen, Danish1 aLundmark, Per1 aPsaty, Bruce, M1 aStrawbridge, Rona, J1 aBoehm, Bernhard, O1 aCarter, Angela, M1 aMeisinger, Christa1 aPeden, John, F1 aBis, Joshua, C1 aMcKnight, Barbara1 aOhrvik, John1 aTaylor, Kent1 aFranzosi, Maria Grazia1 aSeedorf, Udo1 aCollins, Rory1 aFranco-Cereceda, Anders1 aSyvänen, Ann-Christine1 aGoodall, Alison, H1 aYanek, Lisa, R1 aCushman, Mary1 aMüller-Nurasyid, Martina1 aFolsom, Aaron, R1 aBasu, Saonli1 aMatijevic, Nena1 aGilst, Wiek, H1 aKooner, Jaspal, S1 aHofman, Albert1 aDanesh, John1 aClarke, Robert1 aMeigs, James, B1 aKathiresan, Sekar1 aReilly, Muredach, P1 aKlopp, Norman1 aHarris, Tamara, B1 aWinkelmann, Bernhard, R1 aGrant, Peter, J1 aHillege, Hans, L1 aWatkins, 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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.
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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, Braxton, D1 aMukherjee, Sutapa1 aNaitza, Silvia1 aNeville, Matthew, J1 aOrrù, Marco1 aPakyz, Ruth1 aPaolisso, Giuseppe1 aPattaro, Cristian1 aPearson, Daniel1 aPeden, John, F1 aPedersen, Nancy, L1 aPfeiffer, Andreas, F H1 aPichler, Irene1 aPolasek, Ozren1 aPosthuma, Danielle1 aPotter, Simon, C1 aPouta, Anneli1 aProvince, Michael, A1 aRayner, Nigel, W1 aRice, Kenneth1 aRipatti, Samuli1 aRivadeneira, Fernando1 aRolandsson, Olov1 aSandbaek, Annelli1 aSandhu, Manjinder1 aSanna, Serena1 aSayer, Avan Aihie1 aScheet, Paul1 aSeedorf, Udo1 aSharp, Stephen, J1 aShields, Beverley1 aSigurðsson, Gunnar1 aSijbrands, Eric, J G1 aSilveira, Angela1 aSimpson, Laila1 aSingleton, Andrew1 aSmith, Nicholas, L1 aSovio, Ulla1 aSwift, Amy1 aSyddall, Holly1 aSyvänen, Ann-Christine1 aTönjes, Anke1 aUitterlinden, André, G1 aDijk, Ko Willems1 aVarma, Dhiraj1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogelzangs, Nicole1 aWaeber, Gérard1 aWagner, Peter, J1 aWalley, Andrew1 aWard, Kim, L1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitteman, Jaqueline, C M1 aYarnell, John, W G1 aZelenika, Diana1 aZethelius, Björn1 aZhai, Guangju1 aZhao, Jing Hua1 aZillikens, Carola, M1 aBorecki, Ingrid, B1 aMeneton, Pierre1 aMagnusson, Patrik, K E1 aNathan, David, M1 aWilliams, Gordon, H1 aSilander, Kaisa1 aBornstein, Stefan, R1 aSchwarz, Peter1 aSpranger, Joachim1 aKarpe, Fredrik1 aShuldiner, Alan, R1 aCooper, Cyrus1 aSerrano-Ríos, Manuel1 aLind, Lars1 aPalmer, Lyle, J1 aHu, Frank, B1 aFranks, Paul, W1 aEbrahim, Shah1 aMarmot, Michael1 aKao, Linda, W H1 aPramstaller, Peter Paul1 aWright, Alan, F1 aStumvoll, Michael1 aHamsten, Anders1 aBuchanan, Thomas, A1 aValle, Timo, T1 aRotter, Jerome, I1 aPenninx, Brenda, W J H1 aBoomsma, Dorret, I1 aCao, Antonio1 aScuteri, Angelo1 aSchlessinger, David1 aUda, Manuela1 aRuokonen, Aimo1 aJarvelin, Marjo-Riitta1 aPeltonen, Leena1 aMooser, Vincent1 aSladek, Robert1 aMusunuru, Kiran1 aSmith, Albert, V1 aEdmondson, Andrew, C1 aStylianou, Ioannis, M1 aKoseki, Masahiro1 aPirruccello, James, P1 aChasman, Daniel, I1 aJohansen, Christopher, T1 aFouchier, Sigrid, W1 aPeloso, Gina, M1 aBarbalic, Maja1 aRicketts, Sally, L1 aBis, Joshua, C1 aFeitosa, Mary, F1 aOrho-Melander, Marju1 aMelander, Olle1 aLi, Xiaohui1 aLi, Mingyao1 aCho, Yoon Shin1 aGo, Min Jin1 aKim, Young, Jin1 aLee, Jong-Young1 aPark, Taesung1 aKim, Kyunga1 aSim, Xueling1 aOng, Rick Twee-Hee1 aCroteau-Chonka, Damien, C1 aLange, Leslie, A1 aSmith, Joshua, D1 aZiegler, Andreas1 aZhang, Weihua1 aZee, Robert, Y L1 aWhitfield, John, B1 aThompson, John, R1 aSurakka, Ida1 aSpector, Tim, D1 aSmit, Johannes, H1 aSinisalo, Juha1 aScott, James1 aSaharinen, Juha1 aSabatti, Chiara1 aRose, Lynda, M1 aRoberts, Robert1 aRieder, Mark1 aParker, Alex, N1 aParé, Guillaume1 aO'Donnell, Christopher, J1 aNieminen, Markku, S1 aNickerson, Deborah, A1 aMontgomery, Grant, W1 aMcArdle, Wendy1 aMasson, David1 aMartin, Nicholas, G1 aMarroni, Fabio1 aLucas, Gavin1 aLuben, Robert1 aLokki, Marja-Liisa1 aLettre, Guillaume1 aLauner, Lenore, J1 aLakatta, Edward, G1 aLaaksonen, Reijo1 aKyvik, Kirsten, O1 aKönig, Inke, R1 aKhaw, Kay-Tee1 aKaplan, Lee, M1 aJohansson, Asa1 aJanssens, Cecile, J W1 aIgl, Wilmar1 aHovingh, Kees1 aHengstenberg, Christian1 aHavulinna, Aki, S1 aHastie, Nicholas, D1 aHarris, Tamara, B1 aHaritunians, Talin1 aHall, Alistair, S1 aGroop, Leif, C1 aGonzalez, Elena1 aFreimer, Nelson, B1 aErdmann, Jeanette1 aEjebe, Kenechi, G1 aDöring, Angela1 aDominiczak, Anna, F1 aDemissie, Serkalem1 aDeloukas, Panagiotis1 ade Faire, Ulf1 aCrawford, Gabriel1 aChen, Yii-der, I1 aCaulfield, Mark, J1 aBoekholdt, Matthijs1 aAssimes, Themistocles, L1 aQuertermous, Thomas1 aSeielstad, Mark1 aWong, Tien, Y1 aTai, E-Shyong1 aFeranil, Alan, B1 aKuzawa, Christopher, W1 aTaylor, Herman, A1 aGabriel, Stacey, B1 aHolm, Hilma1 aGudnason, Vilmundur1 aKrauss, Ronald, M1 aOrdovas, Jose, M1 aMunroe, Patricia, B1 aKooner, Jaspal, S1 aTall, Alan, R1 aHegele, Robert, A1 aKastelein, John, J P1 aSchadt, Eric, E1 aStrachan, David, P1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aKathiresan, Sekar1 aDIAGRAM+ Consortium1 aMAGIC Consortium1 aGLGC Investigators1 aMuTHER Consortium1 aDIAGRAM Consortium1 aGIANT Consortium1 aGlobal B Pgen Consortium1 aProcardis Consortium1 aMAGIC investigators1 aGLGC Consortium uhttps://chs-nhlbi.org/node/137804481nas a2200937 4500008004100000022001400041245012400055210006900179260001300248300001100261490000700272520180500279653002802084653001002112653001702122653003802139653001302177653001702190653001102207653002602218653001702244100002602261700002102287700002502308700001702333700002002350700002302370700002202393700001402415700002302429700002502452700001902477700001502496700002102511700002002532700001902552700002202571700001902593700002202612700002002634700002002654700001902674700002102693700001502714700002302729700002202752700001902774700002102793700003102814700002202845700001702867700001902884700002202903700002702925700003002952700002002982700002003002700002603022700001903048700001703067700002403084700002403108700001803132700001903150700002403169700002003193700002403213700001803237700003003255700002403285700001803309700002803327700002203355700001803377700002403395700002003419700002303439700002203462700002303484856003603507 2013 eng d a1938-320700aCommon genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.0 aCommon genetic loci influencing plasma homocysteine concentratio c2013 Sep a668-760 v983 aBACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD.
OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.
DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls.
RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49).
CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.
10aCoronary Artery Disease10aGenes10aGenetic Loci10aGenetic Predisposition to Disease10aGenotype10aHomocysteine10aHumans10aPolymorphism, Genetic10aRisk Factors1 avan Meurs, Joyce, B J1 aParé, Guillaume1 aSchwartz, Stephen, M1 aHazra, Aditi1 aTanaka, Toshiko1 aVermeulen, Sita, H1 aCotlarciuc, Ioana1 aYuan, Xin1 aMälarstig, Anders1 aBandinelli, Stefania1 aBis, Joshua, C1 aBlom, Henk1 aBrown, Morris, J1 aChen, Constance1 aDer Chen, Yii-1 aClarke, Robert, J1 aDehghan, Abbas1 aErdmann, Jeanette1 aFerrucci, Luigi1 aHamsten, Anders1 aHofman, Albert1 aHunter, David, J1 aGoel, Anuj1 aJohnson, Andrew, D1 aKathiresan, Sekar1 aKampman, Ellen1 aKiel, Douglas, P1 aKiemeney, Lambertus, A L M1 aChambers, John, C1 aKraft, Peter1 aLindemans, Jan1 aMcKnight, Barbara1 aNelson, Christopher, P1 aO'Donnell, Christopher, J1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRose, Lynda, M1 aSeedorf, Udo1 aSiscovick, David, S1 aSchunkert, Heribert1 aSelhub, Jacob1 aUeland, Per, M1 aVollenweider, Peter1 aWaeber, Gérard1 aWaterworth, Dawn, M1 aWatkins, Hugh1 aWitteman, Jacqueline, C M1 aHeijer, Martin, den1 aJacques, Paul1 aUitterlinden, André, G1 aKooner, Jaspal, S1 aRader, Dan, J1 aReilly, Muredach, P1 aMooser, Vincent1 aChasman, Daniel, I1 aSamani, Nilesh, J1 aAhmadi, Kourosh, R uhttps://chs-nhlbi.org/node/628409406nas a2203037 4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520104700257653002501304653004001329653001901369653001701388653003401405653001201439653000901451653001101460653001301471653003601484653002401520653001401544100001901558700001801577700002201595700002201617700001801639700002501657700002001682700002201702700002601724700001901750700001601769700002001785700002301805700002101828700002101849700001501870700002301885700002601908700002101934700002101955700002001976700001201996700002202008700002202030700002202052700001602074700001902090700001902109700002102128700001402149700002202163700002002185700001502205700001702220700002202237700002102259700001902280700001902299700002102318700001902339700002502358700001902383700001902402700002202421700001902443700002002462700001702482700002102499700001902520700002202539700002202561700002002583700001802603700002302621700002702644700001802671700002002689700001702709700002002726700002202746700002102768700002902789700002202818700002202840700002102862700002302883700002102906700001802927700002002945700002302965700002402988700002503012700001903037700002103056700002203077700002403099700002203123700002103145700001503166700001703181700001803198700002203216700002003238700002403258700002003282700002003302700002103322700001703343700001803360700002103378700002103399700002203420700001603442700002103458700001903479700002403498700002503522700001803547700001603565700001903581700002103600700002103621700002703642700001403669700002103683700002503704700002303729700001803752700002503770700002103795700002003816700001603836700002403852700001803876700002603894700002203920700001703942700001703959700002403976700002104000700002204021700001804043700002804061700002304089700001904112700002304131700002204154700001704176700001904193700002204212700001804234700001904252700001704271700002104288700002404309700001904333700001504352700001704367700001904384700002604403700002804429700001904457700002804476700002104504700002204525700002504547700002004572700002304592700001904615700001904634700002504653700002404678700002104702700002204723700001604745700001904761700002004780700001804800700002004818700001704838700002004855700002004875700001904895700002804914700002704942700002204969700002204991700001905013700002505032700002205057700001805079700002005097700001605117700001605133700001805149700002105167700002005188700001505208700001905223700001705242700002905259700001905288700002405307700001805331700002205349700002305371700002005394700002105414700002405435700001905459700002005478700001605498700002505514700002105539700002005560700002305580700002305603700002005626700002205646700001805668700003005686700002205716700002005738700002605758700002005784700002005804700002005824700001805844700001805862700003005880700001805910700001905928700002305947700001805970700002005988700002006008700002106028700002306049700002006072700002006092700001906112700002106131700002006152700002106172700002206193710002706215710002606242710002306268710002006291710002106311856003606332 2013 eng d a1546-171800aGenome-wide association analyses identify 18 new loci associated with serum urate concentrations.0 aGenomewide association analyses identify 18 new loci associated c2013 Feb a145-540 v453 aElevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
10aAnalysis of Variance10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aGlucose10aGout10aHumans10aInhibins10aPolymorphism, Single Nucleotide10aSignal Transduction10aUric Acid1 aKöttgen, Anna1 aAlbrecht, Eva1 aTeumer, Alexander1 aVitart, Veronique1 aKrumsiek, Jan1 aHundertmark, Claudia1 aPistis, Giorgio1 aRuggiero, Daniela1 aO'Seaghdha, Conall, M1 aHaller, Toomas1 aYang, Qiong1 aTanaka, Toshiko1 aJohnson, Andrew, D1 aKutalik, Zoltán1 aSmith, Albert, V1 aShi, Julia1 aStruchalin, Maksim1 aMiddelberg, Rita, P S1 aBrown, Morris, J1 aGaffo, Angelo, L1 aPirastu, Nicola1 aLi, Guo1 aHayward, Caroline1 aZemunik, Tatijana1 aHuffman, Jennifer1 aYengo, Loic1 aZhao, Jing Hua1 aDemirkan, Ayse1 aFeitosa, Mary, F1 aLiu, Xuan1 aMalerba, Giovanni1 aLopez, Lorna, M1 aHarst, Pim1 aLi, Xinzhong1 aKleber, Marcus, E1 aHicks, Andrew, A1 aNolte, Ilja, M1 aJohansson, Asa1 aMurgia, Federico1 aWild, Sarah, H1 aBakker, Stephan, J L1 aPeden, John, F1 aDehghan, Abbas1 aSteri, Maristella1 aTenesa, Albert1 aLagou, Vasiliki1 aSalo, Perttu1 aMangino, Massimo1 aRose, Lynda, M1 aLehtimäki, Terho1 aWoodward, Owen, M1 aOkada, Yukinori1 aTin, Adrienne1 aMüller, Christian1 aOldmeadow, Christopher1 aPutku, Margus1 aCzamara, Darina1 aKraft, Peter1 aFrogheri, Laura1 aThun, Gian, Andri1 aGrotevendt, Anne1 aGislason, Gauti, Kjartan1 aHarris, Tamara, B1 aLauner, Lenore, J1 aMcArdle, Patrick1 aShuldiner, Alan, R1 aBoerwinkle, Eric1 aCoresh, Josef1 aSchmidt, Helena1 aSchallert, Michael1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aKubo, Michiaki1 aNakamura, Yusuke1 aTanaka, Toshihiro1 aMunroe, Patricia, B1 aSamani, Nilesh, J1 aJacobs, David, R1 aLiu, Kiang1 aD'Adamo, Pio1 aUlivi, Sheila1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aVollenweider, Peter1 aWaeber, Gérard1 aCampbell, Susan1 aDevuyst, Olivier1 aNavarro, Pau1 aKolcic, Ivana1 aHastie, Nicholas1 aBalkau, Beverley1 aFroguel, Philippe1 aEsko, Tõnu1 aSalumets, Andres1 aKhaw, Kay, Tee1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aIsaacs, Aaron1 aKraja, Aldi1 aZhang, Qunyuan1 aWild, Philipp, S1 aScott, Rodney, J1 aHolliday, Elizabeth, G1 aOrg, Elin1 aViigimaa, Margus1 aBandinelli, Stefania1 aMetter, Jeffrey, E1 aLupo, Antonio1 aTrabetti, Elisabetta1 aSorice, Rossella1 aDöring, Angela1 aLattka, Eva1 aStrauch, Konstantin1 aTheis, Fabian1 aWaldenberger, Melanie1 aWichmann, H-Erich1 aDavies, Gail1 aGow, Alan, J1 aBruinenberg, Marcel1 aStolk, Ronald, P1 aKooner, Jaspal, S1 aZhang, Weihua1 aWinkelmann, Bernhard, R1 aBoehm, Bernhard, O1 aLucae, Susanne1 aPenninx, Brenda, W1 aSmit, Johannes, H1 aCurhan, Gary1 aMudgal, Poorva1 aPlenge, Robert, M1 aPortas, Laura1 aPersico, Ivana1 aKirin, Mirna1 aWilson, James, F1 aLeach, Irene, Mateo1 aGilst, Wiek, H1 aGoel, Anuj1 aOngen, Halit1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aImboden, Medea1 avon Eckardstein, Arnold1 aCucca, Francesco1 aNagaraja, Ramaiah1 aPiras, Maria, Grazia1 aNauck, Matthias1 aSchurmann, Claudia1 aBudde, Kathrin1 aErnst, Florian1 aFarrington, Susan, M1 aTheodoratou, Evropi1 aProkopenko, Inga1 aStumvoll, Michael1 aJula, Antti1 aPerola, Markus1 aSalomaa, Veikko1 aShin, So-Youn1 aSpector, Tim, D1 aSala, Cinzia1 aRidker, Paul, M1 aKähönen, Mika1 aViikari, Jorma1 aHengstenberg, Christian1 aNelson, Christopher, P1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aSingleton, Andrew, B1 aKamatani, Naoyuki1 aZeller, Tanja1 aBurnier, Michel1 aAttia, John1 aLaan, Maris1 aKlopp, Norman1 aHillege, Hans, L1 aKloiber, Stefan1 aChoi, Hyon1 aPirastu, Mario1 aTore, Silvia1 aProbst-Hensch, Nicole, M1 aVölzke, Henry1 aGudnason, Vilmundur1 aParsa, Afshin1 aSchmidt, Reinhold1 aWhitfield, John, B1 aFornage, Myriam1 aGasparini, Paolo1 aSiscovick, David, S1 aPolasek, Ozren1 aCampbell, Harry1 aRudan, Igor1 aBouatia-Naji, Nabila1 aMetspalu, Andres1 aLoos, Ruth, J F1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aFerrucci, Luigi1 aGambaro, Giovanni1 aDeary, Ian, J1 aWolffenbuttel, Bruce, H R1 aChambers, John, C1 aMärz, Winfried1 aPramstaller, Peter, P1 aSnieder, Harold1 aGyllensten, Ulf1 aWright, Alan, F1 aNavis, Gerjan1 aWatkins, Hugh1 aWitteman, Jacqueline, C M1 aSanna, Serena1 aSchipf, Sabine1 aDunlop, Malcolm, G1 aTönjes, Anke1 aRipatti, Samuli1 aSoranzo, Nicole1 aToniolo, Daniela1 aChasman, Daniel, I1 aRaitakari, Olli1 aKao, Linda, W H1 aCiullo, Marina1 aFox, Caroline, S1 aCaulfield, Mark1 aBochud, Murielle1 aGieger, Christian1 aLifeLines Cohort Study1 aCARDIoGRAM consortium1 aDIAGRAM Consortium1 aICBP Consortium1 aMAGIC Consortium uhttps://chs-nhlbi.org/node/607512626nas 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/615208187nas a2202209 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2013 eng d a1524-453900aMultiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.0 aMultiethnic metaanalysis of genomewide association studies in 10 c2013 Sep 17 a1310-240 v1283 aBACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.
METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.
CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aCardiovascular Diseases10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHispanic Americans10aHumans10aMale10aMiddle Aged10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke10aVenous Thromboembolism10aYoung Adult1 aSabater-Lleal, Maria1 aHuang, Jie1 aChasman, Daniel1 aNaitza, Silvia1 aDehghan, Abbas1 aJohnson, Andrew, D1 aTeumer, Alexander1 aReiner, Alex, P1 aFolkersen, Lasse1 aBasu, Saonli1 aRudnicka, Alicja, R1 aTrompet, Stella1 aMälarstig, Anders1 aBaumert, Jens1 aBis, Joshua, C1 aGuo, Xiuqing1 aHottenga, Jouke, J1 aShin, So-Youn1 aLopez, Lorna, M1 aLahti, Jari1 aTanaka, Toshiko1 aYanek, Lisa, R1 aOudot-Mellakh, Tiphaine1 aWilson, James, F1 aNavarro, Pau1 aHuffman, Jennifer, E1 aZemunik, Tatijana1 aRedline, Susan1 aMehra, Reena1 aPulanic, Drazen1 aRudan, Igor1 aWright, Alan, F1 aKolcic, Ivana1 aPolasek, Ozren1 aWild, Sarah, H1 aCampbell, Harry1 aCurb, David1 aWallace, Robert1 aLiu, Simin1 aEaton, Charles, B1 aBecker, Diane, M1 aBecker, Lewis, C1 aBandinelli, Stefania1 aRäikkönen, Katri1 aWiden, Elisabeth1 aPalotie, Aarno1 aFornage, Myriam1 aGreen, David1 aGross, Myron1 aDavies, Gail1 aHarris, Sarah, E1 aLiewald, David, C1 aStarr, John, M1 aWilliams, Frances, M K1 aGrant, Peter, J1 aSpector, Timothy, D1 aStrawbridge, Rona, J1 aSilveira, Angela1 aSennblad, Bengt1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aFranco, Oscar, H1 aHofman, Albert1 avan Dongen, Jenny1 aWillemsen, Gonneke1 aBoomsma, Dorret, I1 aYao, Jie1 aJenny, Nancy, Swords1 aHaritunians, Talin1 aMcKnight, Barbara1 aLumley, Thomas1 aTaylor, Kent, D1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aPeters, Annette1 aGieger, Christian1 aIllig, Thomas1 aGrotevendt, Anne1 aHomuth, Georg1 aVölzke, Henry1 aKocher, Thomas1 aGoel, Anuj1 aFranzosi, Maria Grazia1 aSeedorf, Udo1 aClarke, Robert1 aSteri, Maristella1 aTarasov, Kirill, V1 aSanna, Serena1 aSchlessinger, David1 aStott, David, J1 aSattar, Naveed1 aBuckley, Brendan, M1 aRumley, Ann1 aLowe, Gordon, D1 aMcArdle, Wendy, L1 aChen, Ming-Huei1 aTofler, Geoffrey, H1 aSong, Jaejoon1 aBoerwinkle, Eric1 aFolsom, Aaron, R1 aRose, Lynda, M1 aFranco-Cereceda, Anders1 aTeichert, Martina1 aIkram, Arfan, M1 aMosley, Thomas, H1 aBevan, Steve1 aDichgans, Martin1 aRothwell, Peter, M1 aSudlow, Cathie, L M1 aHopewell, Jemma, C1 aChambers, John, C1 aSaleheen, Danish1 aKooner, Jaspal, S1 aDanesh, John1 aNelson, Christopher, P1 aErdmann, Jeanette1 aReilly, Muredach, P1 aKathiresan, Sekar1 aSchunkert, Heribert1 aMorange, Pierre-Emmanuel1 aFerrucci, Luigi1 aEriksson, Johan, G1 aJacobs, David1 aDeary, Ian, J1 aSoranzo, Nicole1 aWitteman, Jacqueline, C M1 aGeus, Eco, J C1 aTracy, Russell, P1 aHayward, Caroline1 aKoenig, Wolfgang1 aCucca, Francesco1 aJukema, Wouter1 aEriksson, Per1 aSeshadri, Sudha1 aMarkus, Hugh, S1 aWatkins, Hugh1 aSamani, Nilesh, J1 aWallaschofski, Henri1 aSmith, Nicholas, L1 aTregouet, David1 aRidker, Paul, M1 aTang, Weihong1 aStrachan, David, P1 aHamsten, Anders1 aO'Donnell, Christopher, J1 aVTE Consortium1 aSTROKE Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2)1 aC4D Consortium1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/615511004nas 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/602805943nas a2201657 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2014 eng d a1537-660500aAssociation of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.0 aAssociation of lowfrequency and rare codingsequence variants wit c2014 Feb 06 a223-320 v943 aLow-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAdult10aAfrican Continental Ancestry Group10aAged10aAlleles10aAnimals10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Association Studies10aGenetic Code10aGenetic Variation10aHumans10aLinear Models10aMale10aMice10aMice, Inbred C57BL10aMicrotubule-Associated Proteins10aMiddle Aged10aPhenotype10aSequence Analysis, DNA10aSubtilisins10aTriglycerides1 aPeloso, Gina, M1 aAuer, Paul, L1 aBis, Joshua, C1 aVoorman, Arend1 aMorrison, Alanna, C1 aStitziel, Nathan, O1 aBrody, Jennifer, A1 aKhetarpal, Sumeet, A1 aCrosby, Jacy, R1 aFornage, Myriam1 aIsaacs, Aaron1 aJakobsdottir, Johanna1 aFeitosa, Mary, F1 aDavies, Gail1 aHuffman, Jennifer, E1 aManichaikul, Ani1 aDavis, Brian1 aLohman, Kurt1 aJoon, Aron, Y1 aSmith, Albert, V1 aGrove, Megan, L1 aZanoni, Paolo1 aRedon, Valeska1 aDemissie, Serkalem1 aLawson, Kim1 aPeters, Ulrike1 aCarlson, Christopher1 aJackson, Rebecca, D1 aRyckman, Kelli, K1 aMackey, Rachel, H1 aRobinson, Jennifer, G1 aSiscovick, David, S1 aSchreiner, Pamela, J1 aMychaleckyj, Josyf, C1 aPankow, James, S1 aHofman, Albert1 aUitterlinden, André, G1 aHarris, Tamara, B1 aTaylor, Kent, D1 aStafford, Jeanette, M1 aReynolds, Lindsay, M1 aMarioni, Riccardo, E1 aDehghan, Abbas1 aFranco, Oscar, H1 aPatel, Aniruddh, P1 aLu, Yingchang1 aHindy, George1 aGottesman, Omri1 aBottinger, Erwin, P1 aMelander, Olle1 aOrho-Melander, Marju1 aLoos, Ruth, J F1 aDuga, Stefano1 aMerlini, Piera, Angelica1 aFarrall, Martin1 aGoel, Anuj1 aAsselta, Rosanna1 aGirelli, Domenico1 aMartinelli, Nicola1 aShah, Svati, H1 aKraus, William, E1 aLi, Mingyao1 aRader, Daniel, J1 aReilly, Muredach, P1 aMcPherson, Ruth1 aWatkins, Hugh1 aArdissino, Diego1 aZhang, Qunyuan1 aWang, Judy1 aTsai, Michael, Y1 aTaylor, Herman, A1 aCorrea, Adolfo1 aGriswold, Michael, E1 aLange, Leslie, A1 aStarr, John, M1 aRudan, Igor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aOrdovas, Jose, M1 aLevy, Daniel1 aChen, Y-D, Ida1 aReiner, Alexander, P1 aHayward, Caroline1 aPolasek, Ozren1 aDeary, Ian, J1 aBorecki, Ingrid, B1 aLiu, Yongmei1 aGudnason, Vilmundur1 aWilson, James, G1 aDuijn, Cornelia, M1 aKooperberg, Charles1 aRich, Stephen, S1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aO'Donnell, Christopher, J1 aRice, Kenneth1 aBoerwinkle, Eric1 aKathiresan, Sekar1 aCupples, Adrienne, L1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659005870nas a2201489 4500008004100000022001400041245013500055210006900190260001600259300001000275490000700285520175700292653001502049653001002064653001602074653000902090653001902099653001902118653001102137653001602148653001602164100002202180700001402202700001902216700002302235700002002258700001702278700001702295700002002312700002002332700002102352700002602373700003102399700001702430700001502447700002002462700001802482700002302500700001502523700001802538700002202556700002602578700001802604700002802622700001902650700001702669700001702686700002702703700001802730700001902748700001602767700002102783700002102804700001902825700002402844700002002868700002102888700002202909700002202931700002002953700001902973700001902992700002303011700002003034700001803054700002103072700002203093700002203115700001203137700001703149700001503166700002403181700001803205700002303223700002703246700002303273700002003296700002203316700002303338700001803361700002603379700001903405700001803424700002103442700002403463700002103487700002803508700002203536700003003558700002703588700003203615700001703647700001903664700001803683700002003701700001403721700002103735700002003756700002603776700001603802700002303818700002203841700002003863700001703883700002003900700002003920700001903940700002003959700001903979700001803998700001504016700002504031700002004056700002004076700002004096700002404116700001704140700001904157700002004176700002204196700002304218700003004241700002604271700002004297710002704317856003604344 2014 eng d a1537-660500aGene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.0 aGeneage interactions in blood pressure regulation a largescale i c2014 Jul 03 a24-380 v953 aAlthough age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.
10aAdolescent10aAdult10aAge Factors10aAged10aBlood Pressure10aCohort Studies10aHumans10aMiddle Aged10aYoung Adult1 aSimino, Jeannette1 aShi, Gang1 aBis, Joshua, C1 aChasman, Daniel, I1 aEhret, Georg, B1 aGu, Xiangjun1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aSijbrands, Eric1 aSmith, Albert, V1 aVerwoert, Germaine, C1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aChen, Peng1 aCheng, Ching-Yu1 aCorre, Tanguy1 ade Boer, Rudolf, A1 aGoel, Anuj1 aJohnson, Toby1 aKhor, Chiea-Chuen1 aLluís-Ganella, Carla1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aSim, Xueling1 aSõber, Siim1 avan der Most, Peter, J1 aVerweij, Niek1 aZhao, Jing Hua1 aAmin, Najaf1 aBoerwinkle, Eric1 aBouchard, Claude1 aDehghan, Abbas1 aEiriksdottir, Gudny1 aElosua, Roberto1 aFranco, Oscar, H1 aGieger, Christian1 aHarris, Tamara, B1 aHercberg, Serge1 aHofman, Albert1 aJames, Alan, L1 aJohnson, Andrew, D1 aKähönen, Mika1 aKhaw, Kay-Tee1 aKutalik, Zoltán1 aLarson, Martin, G1 aLauner, Lenore, J1 aLi, Guo1 aLiu, Jianjun1 aLiu, Kiang1 aMorrison, Alanna, C1 aNavis, Gerjan1 aOng, Rick Twee-Hee1 aPapanicolau, George, J1 aPenninx, Brenda, W1 aPsaty, Bruce, M1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRice, Kenneth1 aRivadeneira, Fernando1 aRose, Lynda, M1 aSanna, Serena1 aScott, Robert, A1 aSiscovick, David, S1 aStolk, Ronald, P1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Klauw, Melanie, M1 aVasan, Ramachandran, S1 aVithana, Eranga, Nishanthie1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Hugh1 aYoung, Terri, L1 aAung, Tin1 aBochud, Murielle1 aFarrall, Martin1 aHartman, Catharina, A1 aLaan, Maris1 aLakatta, Edward, G1 aLehtimäki, Terho1 aLoos, Ruth, J F1 aLucas, Gavin1 aMeneton, Pierre1 aPalmer, Lyle, J1 aRettig, Rainer1 aSnieder, Harold1 aTai, Shyong, E1 aTeo, Yik-Ying1 aHarst, Pim1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aWong, Tien, Yin1 aFornage, Myriam1 aGudnason, Vilmundur1 aLevy, Daniel1 aPalmas, Walter1 aRidker, Paul, M1 aRotter, Jerome, I1 aDuijn, Cornelia, M1 aWitteman, Jacqueline, C M1 aChakravarti, Aravinda1 aRao, Dabeeru, C1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/659905734nas a2201333 4500008004100000022001400041245007800055210006900133260001500202300001000217490000800227520196900235653003902204653002502243653002102268653004002289653001002329653001302339653001702352653001102369653001002380653001302390653001702403653002702420653001802447110010402465700001702569700002002586700001802606700002302624700002402647700002102671700001802692700002202710700001402732700001802746700002002764700002302784700002202807700001202829700001302841700001402854700002002868700001602888700001502904700002002919700001802939700002802957700002102985700002203006700002303028700002303051700001203074700001903086700002503105700002103130700002003151700002303171700001803194700002303212700002903235700002303264700002303287700001903310700002003329700001903349700001903368700002203387700002403409700002403433700002303457700002203480700001703502700002203519700002003541700001903561700001903580700002003599700001903619700002603638700002003664700002403684700003003708700002003738700002803758700002203786700002103808700001903829700001803848700002503866700002103891700002003912700002003932700002303952700002203975700002203997700002204019700002004041700002404061700002104085700002404106700002104130700002204151700001604173700002104189700002004210700002604230700002004256700002504276700002004301700002104321700002204342856003604364 2014 eng d a1533-440600aLoss-of-function mutations in APOC3, triglycerides, and coronary disease.0 aLossoffunction mutations in APOC3 triglycerides and coronary dis c2014 Jul 3 a22-310 v3713 aBACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.
METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.
RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).
CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).
10aAfrican Continental Ancestry Group10aApolipoprotein C-III10aCoronary Disease10aEuropean Continental Ancestry Group10aExome10aGenotype10aHeterozygote10aHumans10aLiver10aMutation10aRisk Factors10aSequence Analysis, DNA10aTriglycerides1 aTG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute1 aCrosby, Jacy1 aPeloso, Gina, M1 aAuer, Paul, L1 aCrosslin, David, R1 aStitziel, Nathan, O1 aLange, Leslie, A1 aLu, Yingchang1 aTang, Zheng-Zheng1 aZhang, He1 aHindy, George1 aMasca, Nicholas1 aStirrups, Kathleen1 aKanoni, Stavroula1 aDo, Ron1 aJun, Goo1 aHu, Youna1 aKang, Hyun, Min1 aXue, Chenyi1 aGoel, Anuj1 aFarrall, Martin1 aDuga, Stefano1 aMerlini, Pier, Angelica1 aAsselta, Rosanna1 aGirelli, Domenico1 aOlivieri, Oliviero1 aMartinelli, Nicola1 aYin, Wu1 aReilly, Dermot1 aSpeliotes, Elizabeth1 aFox, Caroline, S1 aHveem, Kristian1 aHolmen, Oddgeir, L1 aNikpay, Majid1 aFarlow, Deborah, N1 aAssimes, Themistocles, L1 aFranceschini, Nora1 aRobinson, Jennifer1 aNorth, Kari, E1 aMartin, Lisa, W1 aDePristo, Mark1 aGupta, Namrata1 aEscher, Stefan, A1 aJansson, Jan-Håkan1 aVan Zuydam, Natalie1 aPalmer, Colin, N A1 aWareham, Nicholas1 aKoch, Werner1 aMeitinger, Thomas1 aPeters, Annette1 aLieb, Wolfgang1 aErbel, Raimund1 aKönig, Inke, R1 aKruppa, Jochen1 aDegenhardt, Franziska1 aGottesman, Omri1 aBottinger, Erwin, P1 aO'Donnell, Christopher, J1 aPsaty, Bruce, M1 aBallantyne, Christie, M1 aAbecasis, Goncalo1 aOrdovas, Jose, M1 aMelander, Olle1 aWatkins, Hugh1 aOrho-Melander, Marju1 aArdissino, Diego1 aLoos, Ruth, J F1 aMcPherson, Ruth1 aWiller, Cristen, J1 aErdmann, Jeanette1 aHall, Alistair, S1 aSamani, Nilesh, J1 aDeloukas, Panos1 aSchunkert, Heribert1 aWilson, James, G1 aKooperberg, Charles1 aRich, Stephen, S1 aTracy, Russell, P1 aLin, Dan-Yu1 aAltshuler, David1 aGabriel, Stacey1 aNickerson, Deborah, A1 aJarvik, Gail, P1 aCupples, Adrienne, L1 aReiner, Alex, P1 aBoerwinkle, Eric1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/660505936nas a2201453 4500008004100000022001400041245016600055210006900221260000900290300001200299490000600311520182200317653002102139653002002160653001502180653003302195653001302228653001102241653001202252100001802264700001502282700002202297700002502319700002202344700001902366700002002385700002002405700002002425700002202445700001802467700002402485700002302509700002402532700002002556700001602576700002002592700002202612700002502634700002902659700001902688700001702707700001602724700002002740700002402760700002502784700001802809700001802827700001902845700001802864700002102882700002002903700001502923700001802938700003002956700002102986700001703007700002003024700001903044700001903063700003003082700002503112700001903137700001703156700002403173700001803197700001903215700001803234700002203252700001403274700001903288700002403307700002103331700002703352700001803379700002603397700001903423700002403442700002303466700002803489700002603517700002303543700002303566700002103589700002003610700002603630700002003656700002103676700002503697700002503722700001703747700002103764700001903785700002403804700002203828700002103850700002103871700001903892700001503911700002003926700001903946700002103965700002803986700002004014700001704034700002504051700002004076700002304096700001904119700001904138700002004157700002104177700001904198700001904217700002004236700001904256700001804275700002504293700003204318700003004350700002304380700002004403700002304423856003604446 2014 eng d a1932-620300aNo evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.0 aNo evidence for genomewide interactions on plasma fibrinogen by c2014 ae1111560 v93 aPlasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
10aAlcohol Drinking10aBody Mass Index10aFibrinogen10aGene-Environment Interaction10aGenomics10aHumans10aSmoking1 aBaumert, Jens1 aHuang, Jie1 aMcKnight, Barbara1 aSabater-Lleal, Maria1 aSteri, Maristella1 aChu, Audrey, Y1 aTrompet, Stella1 aLopez, Lorna, M1 aFornage, Myriam1 aTeumer, Alexander1 aTang, Weihong1 aRudnicka, Alicja, R1 aMälarstig, Anders1 aHottenga, Jouke-Jan1 aKavousi, Maryam1 aLahti, Jari1 aTanaka, Toshiko1 aHayward, Caroline1 aHuffman, Jennifer, E1 aMorange, Pierre-Emmanuel1 aRose, Lynda, M1 aBasu, Saonli1 aRumley, Ann1 aStott, David, J1 aBuckley, Brendan, M1 ade Craen, Anton, J M1 aSanna, Serena1 aMasala, Marco1 aBiffar, Reiner1 aHomuth, Georg1 aSilveira, Angela1 aSennblad, Bengt1 aGoel, Anuj1 aWatkins, Hugh1 aMüller-Nurasyid, Martina1 aRückerl, Regina1 aTaylor, Kent1 aChen, Ming-Huei1 aGeus, Eco, J C1 aHofman, Albert1 aWitteman, Jacqueline, C M1 ade Maat, Moniek, P M1 aPalotie, Aarno1 aDavies, Gail1 aSiscovick, David, S1 aKolcic, Ivana1 aWild, Sarah, H1 aSong, Jaejoon1 aMcArdle, Wendy, L1 aFord, Ian1 aSattar, Naveed1 aSchlessinger, David1 aGrotevendt, Anne1 aFranzosi, Maria Grazia1 aIllig, Thomas1 aWaldenberger, Melanie1 aLumley, Thomas1 aTofler, Geoffrey, H1 aWillemsen, Gonneke1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aRäikkönen, Katri1 aChasman, Daniel, I1 aFolsom, Aaron, R1 aLowe, Gordon, D1 aWestendorp, Rudi, G J1 aSlagboom, Eline1 aCucca, Francesco1 aWallaschofski, Henri1 aStrawbridge, Rona, J1 aSeedorf, Udo1 aKoenig, Wolfgang1 aBis, Joshua, C1 aMukamal, Kenneth, J1 avan Dongen, Jenny1 aWiden, Elisabeth1 aFranco, Oscar, H1 aStarr, John, M1 aLiu, Kiang1 aFerrucci, Luigi1 aPolasek, Ozren1 aWilson, James, F1 aOudot-Mellakh, Tiphaine1 aCampbell, Harry1 aNavarro, Pau1 aBandinelli, Stefania1 aEriksson, Johan1 aBoomsma, Dorret, I1 aDehghan, Abbas1 aClarke, Robert1 aHamsten, Anders1 aBoerwinkle, Eric1 aJukema, Wouter1 aNaitza, Silvia1 aRidker, Paul, M1 aVölzke, Henry1 aDeary, Ian, J1 aReiner, Alexander, P1 aTrégouët, David-Alexandre1 aO'Donnell, Christopher, J1 aStrachan, David, P1 aPeters, Annette1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/666706191nas a2201513 4500008004100000022001400041245010300055210006900158260001500227300001000242490000800252520194100260653001602201653001702217653001202234653002202246653002502268653002102293653002802314653001002342653001102352653003802363653002502401653001702426653001102443653000902454653001602463653001302479653002602492653005302518653001902571653001802590653001802608100001202626700002402638700001802662700002902680700001802709700002802727700001702755700002002772700001502792700001202807700002002819700002102839700002102860700002002881700001802901700002202919700002302941700002302964700002202987700002003009700002803029700002103057700001703078700002403095700002803119700001803147700002303165700002203188700002403210700002203234700001903256700002203275700001903297700001803316700002903334700001503363700002203378700002003400700002003420700002203440700001503462700002303477700001603500700001903516700001703535700001703552700002903569700001903598700002003617700002103637700002203658700002303680700002003703700001903723700002203742700001203764700002103776700002003797700002403817700002003841700002503861700002103886700002103907700002403928700002203952700002503974700002103999700002404020700002104044700001904065700002004084700002204104700002204126700002004148700002004168700002804188700002404216700002404240700002104264700002004285700002504305700002404330700002004354700002604374700002504400700001804425700002604443700002104469700002304490700003004513700002104543700002004564700002204584710003504606856003604641 2015 eng d a1476-468700aExome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.0 aExome sequencing identifies rare LDLR and APOA5 alleles conferri c2015 Feb 5 a102-60 v5183 aMyocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
10aAge Factors10aAge of Onset10aAlleles10aApolipoproteins A10aCase-Control Studies10aCholesterol, LDL10aCoronary Artery Disease10aExome10aFemale10aGenetic Predisposition to Disease10aGenetics, Population10aHeterozygote10aHumans10aMale10aMiddle Aged10aMutation10aMyocardial Infarction10aNational Heart, Lung, and Blood Institute (U.S.)10aReceptors, LDL10aTriglycerides10aUnited States1 aDo, Ron1 aStitziel, Nathan, O1 aWon, Hong-Hee1 aJørgensen, Anders, Berg1 aDuga, Stefano1 aMerlini, Pier, Angelica1 aKiezun, Adam1 aFarrall, Martin1 aGoel, Anuj1 aZuk, Or1 aGuella, Illaria1 aAsselta, Rosanna1 aLange, Leslie, A1 aPeloso, Gina, M1 aAuer, Paul, L1 aGirelli, Domenico1 aMartinelli, Nicola1 aFarlow, Deborah, N1 aDePristo, Mark, A1 aRoberts, Robert1 aStewart, Alexander, F R1 aSaleheen, Danish1 aDanesh, John1 aEpstein, Stephen, E1 aSivapalaratnam, Suthesh1 aHovingh, Kees1 aKastelein, John, J1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aShah, Svati, H1 aKraus, William, E1 aDavies, Robert1 aNikpay, Majid1 aJohansen, Christopher, T1 aWang, Jian1 aHegele, Robert, A1 aHechter, Eliana1 aMärz, Winfried1 aKleber, Marcus, E1 aHuang, Jie1 aJohnson, Andrew, D1 aLi, Mingyao1 aBurke, Greg, L1 aGross, Myron1 aLiu, Yongmei1 aAssimes, Themistocles, L1 aHeiss, Gerardo1 aLange, Ethan, M1 aFolsom, Aaron, R1 aTaylor, Herman, A1 aOlivieri, Oliviero1 aHamsten, Anders1 aClarke, Robert1 aReilly, Dermot, F1 aYin, Wu1 aRivas, Manuel, A1 aDonnelly, Peter1 aRossouw, Jacques, E1 aPsaty, Bruce, M1 aHerrington, David, M1 aWilson, James, G1 aRich, Stephen, S1 aBamshad, Michael, J1 aTracy, Russell, P1 aCupples, Adrienne, L1 aRader, Daniel, J1 aReilly, Muredach, P1 aSpertus, John, A1 aCresci, Sharon1 aHartiala, Jaana1 aTang, W, H Wilson1 aHazen, Stanley, L1 aAllayee, Hooman1 aReiner, Alex, P1 aCarlson, Christopher, S1 aKooperberg, Charles1 aJackson, Rebecca, D1 aBoerwinkle, Eric1 aLander, Eric, S1 aSchwartz, Stephen, M1 aSiscovick, David, S1 aMcPherson, Ruth1 aTybjaerg-Hansen, Anne1 aAbecasis, Goncalo, R1 aWatkins, Hugh1 aNickerson, Deborah, A1 aArdissino, Diego1 aSunyaev, Shamil, R1 aO'Donnell, Christopher, J1 aAltshuler, David1 aGabriel, Stacey1 aKathiresan, Sekar1 aNHLBI Exome Sequencing Project uhttps://chs-nhlbi.org/node/669109013nas a2202797 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2015 eng d a2041-172300aLow-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.0 aLowfrequency and rare exome chip variants associate with fasting c2015 a58970 v63 aFasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
10aAfrican Continental Ancestry Group10aBlood Glucose10aDiabetes Mellitus, Type 210aEuropean Continental Ancestry Group10aExome10aFasting10aGenetic Association Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGlucagon-Like Peptide-1 Receptor10aGlucose-6-Phosphatase10aHumans10aInsulin10aMutation Rate10aOligonucleotide Array Sequence Analysis10aPolymorphism, Single Nucleotide1 aWessel, Jennifer1 aChu, Audrey, Y1 aWillems, Sara, M1 aWang, Shuai1 aYaghootkar, Hanieh1 aBrody, Jennifer, A1 aDauriz, Marco1 aHivert, Marie-France1 aRaghavan, Sridharan1 aLipovich, Leonard1 aHidalgo, Bertha1 aFox, Keolu1 aHuffman, Jennifer, E1 aAn, Ping1 aLu, Yingchang1 aRasmussen-Torvik, Laura, J1 aGrarup, Niels1 aEhm, Margaret, G1 aLi, Li1 aBaldridge, Abigail, S1 aStančáková, Alena1 aAbrol, Ravinder1 aBesse, Céline1 aBoland, Anne1 aBork-Jensen, Jette1 aFornage, Myriam1 aFreitag, Daniel, F1 aGarcia, Melissa, E1 aGuo, Xiuqing1 aHara, Kazuo1 aIsaacs, Aaron1 aJakobsdottir, Johanna1 aLange, Leslie, A1 aLayton, Jill, C1 aLi, Man1 aZhao, Jing, Hua1 aMeidtner, Karina1 aMorrison, Alanna, C1 aNalls, Mike, A1 aPeters, Marjolein, J1 aSabater-Lleal, Maria1 aSchurmann, Claudia1 aSilveira, Angela1 aSmith, Albert, V1 aSoutham, Lorraine1 aStoiber, Marcus, H1 aStrawbridge, Rona, J1 aTaylor, Kent, D1 aVarga, Tibor, V1 aAllin, Kristine, H1 aAmin, Najaf1 aAponte, Jennifer, L1 aAung, Tin1 aBarbieri, Caterina1 aBihlmeyer, Nathan, A1 aBoehnke, Michael1 aBombieri, Cristina1 aBowden, Donald, W1 aBurns, Sean, M1 aChen, Yuning1 aChen, Yii-DerI1 aCheng, Ching-Yu1 aCorrea, Adolfo1 aCzajkowski, Jacek1 aDehghan, Abbas1 aEhret, Georg, B1 aEiriksdottir, Gudny1 aEscher, Stefan, A1 aFarmaki, Aliki-Eleni1 aFrånberg, Mattias1 aGambaro, Giovanni1 aGiulianini, Franco1 aGoddard, William, A1 aGoel, Anuj1 aGottesman, Omri1 aGrove, Megan, L1 aGustafsson, Stefan1 aHai, Yang1 aHallmans, Göran1 aHeo, Jiyoung1 aHoffmann, Per1 aIkram, Mohammad, K1 aJensen, Richard, A1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKaraleftheri, Maria1 aKhor, Chiea, C1 aKirkpatrick, Andrea1 aKraja, Aldi, T1 aKuusisto, Johanna1 aLange, Ethan, M1 aLee, I, T1 aLee, Wen-Jane1 aLeong, Aaron1 aLiao, Jiemin1 aLiu, Chunyu1 aLiu, Yongmei1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aMalerba, Giovanni1 aMamakou, Vasiliki1 aMarouli, Eirini1 aMaruthur, Nisa, M1 aMatchan, Angela1 aMcKean-Cowdin, Roberta1 aMcLeod, Olga1 aMetcalf, Ginger, A1 aMohlke, Karen, L1 aMuzny, Donna, M1 aNtalla, Ioanna1 aPalmer, Nicholette, D1 aPasko, Dorota1 aPeter, Andreas1 aRayner, Nigel, W1 aRenstrom, Frida1 aRice, Ken1 aSala, Cinzia, F1 aSennblad, Bengt1 aSerafetinidis, Ioannis1 aSmith, Jennifer, A1 aSoranzo, Nicole1 aSpeliotes, Elizabeth, K1 aStahl, Eli, A1 aStirrups, Kathleen1 aTentolouris, Nikos1 aThanopoulou, Anastasia1 aTorres, Mina1 aTraglia, Michela1 aTsafantakis, Emmanouil1 aJavad, Sundas1 aYanek, Lisa, R1 aZengini, Eleni1 aBecker, Diane, M1 aBis, Joshua, C1 aBrown, James, B1 aCupples, Adrienne, L1 aHansen, Torben1 aIngelsson, Erik1 aKarter, Andrew, J1 aLorenzo, Carlos1 aMathias, Rasika, A1 aNorris, Jill, M1 aPeloso, Gina, M1 aSheu, Wayne, H-H1 aToniolo, Daniela1 aVaidya, Dhananjay1 aVarma, Rohit1 aWagenknecht, Lynne, E1 aBoeing, Heiner1 aBottinger, Erwin, P1 aDedoussis, George1 aDeloukas, Panos1 aFerrannini, Ele1 aFranco, Oscar, H1 aFranks, Paul, W1 aGibbs, Richard, A1 aGudnason, Vilmundur1 aHamsten, Anders1 aHarris, Tamara, B1 aHattersley, Andrew, T1 aHayward, Caroline1 aHofman, Albert1 aJansson, Jan-Håkan1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLevy, Daniel1 aOostra, Ben, A1 aO'Donnell, Christopher, J1 aO'Rahilly, Stephen1 aPadmanabhan, Sandosh1 aPankow, James, S1 aPolasek, Ozren1 aProvince, Michael, A1 aRich, Stephen, S1 aRidker, Paul, M1 aRudan, Igor1 aSchulze, Matthias, B1 aSmith, Blair, H1 aUitterlinden, André, G1 aWalker, Mark1 aWatkins, Hugh1 aWong, Tien, Y1 aZeggini, Eleftheria1 aLaakso, Markku1 aBorecki, Ingrid, B1 aChasman, Daniel, I1 aPedersen, Oluf1 aPsaty, Bruce, M1 aTai, Shyong, E1 aDuijn, Cornelia, M1 aWareham, Nicholas, J1 aWaterworth, Dawn, M1 aBoerwinkle, Eric1 aKao, Linda, W H1 aFlorez, Jose, C1 aLoos, Ruth, J F1 aWilson, James, G1 aFrayling, Timothy, M1 aSiscovick, David, S1 aDupuis, Josée1 aRotter, Jerome, I1 aMeigs, James, B1 aScott, Robert, A1 aGoodarzi, Mark, O1 aEPIC-InterAct Consortium uhttps://chs-nhlbi.org/node/668604476nas a2201081 4500008004100000022001400041245011400055210006900169260001600238300001100254490000800265520141200273653001901685653001501704653001601719653001501735653001901750653003201769653002201801653001101823653002601834653003601860653002301896653002601919100002501945700002201970700002401992700002502016700002002041700001802061700002302079700002302102700002002125700001702145700001502162700002502177700003002202700001902232700002102251700002002272700002502292700001802317700002202335700001502357700002002372700002102392700001902413700001802432700002602450700001902476700001502495700002002510700002202530700002802552700002202580700001302602700001802615700001702633700002602650700002102676700002102697700002302718700002402741700001902765700002402784700002402808700002102832700001902853700002402872700002502896700002002921700002202941700002102963700001602984700002303000700002003023700002003043700002403063700001703087700001803104700002003122700002003142700001803162700002103180700002103201700002203222700002203244700001903266700002003285700003003305700002303335856003603358 2015 eng d a1528-002000aRare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.0 aRare and lowfrequency variants and their association with plasma c2015 Sep 10 ae19-290 v1263 aFibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.
10aCohort Studies10aFactor VII10aFactor VIII10aFibrinogen10aGene Frequency10aGenetic Association Studies10aGenetic Variation10aHumans10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels10avon Willebrand Factor1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMorrison, Alanna, C1 aSabater-Lleal, Maria1 aKacprowski, Tim1 aAuer, Paul, L1 aBrody, Jennifer, A1 aChasman, Daniel, I1 aChen, Ming-Huei1 aGuo, Xiuqing1 aLin, Li-An1 aMarioni, Riccardo, E1 aMüller-Nurasyid, Martina1 aYanek, Lisa, R1 aPankratz, Nathan1 aGrove, Megan, L1 ade Maat, Moniek, P M1 aCushman, Mary1 aWiggins, Kerri, L1 aQi, Lihong1 aSennblad, Bengt1 aHarris, Sarah, E1 aPolasek, Ozren1 aRiess, Helene1 aRivadeneira, Fernando1 aRose, Lynda, M1 aGoel, Anuj1 aTaylor, Kent, D1 aTeumer, Alexander1 aUitterlinden, André, G1 aVaidya, Dhananjay1 aYao, Jie1 aTang, Weihong1 aLevy, Daniel1 aWaldenberger, Melanie1 aBecker, Diane, M1 aFolsom, Aaron, R1 aGiulianini, Franco1 aGreinacher, Andreas1 aHofman, Albert1 aHuang, Chiang-Ching1 aKooperberg, Charles1 aSilveira, Angela1 aStarr, John, M1 aStrauch, Konstantin1 aStrawbridge, Rona, J1 aWright, Alan, F1 aMcKnight, Barbara1 aFranco, Oscar, H1 aZakai, Neil1 aMathias, Rasika, A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aTofler, Geoffrey, H1 aVölker, Uwe1 aWatkins, Hugh1 aFornage, Myriam1 aHamsten, Anders1 aDeary, Ian, J1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aRotter, Jerome, I1 aHayward, Caroline1 aDehghan, Abbas1 aReiner, Alex, P1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/678805818nas a2201705 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520107200254100002201326700002301348700002501371700002001396700002501416700002201441700001801463700002201481700002501503700002001528700002301548700002001571700003001591700001901621700002301640700002201663700001701685700001901702700001801721700001901739700001901758700002801777700001601805700002401821700002001845700002401865700002001889700002301909700001801932700001701950700001901967700002701986700001802013700001902031700001702050700001502067700001602082700002102098700002302119700001602142700002202158700002502180700002102205700001802226700002002244700002502264700001302289700002002302700002402322700001802346700002002364700002302384700002302407700002102430700002502451700002402476700001602500700003202516700002002548700002102568700002202589700002402611700002002635700002102655700002502676700001902701700002002720700002802740700001902768700001902787700001702806700002602823700001802849700002202867700001502889700002002904700002702924700001502951700002002966700002102986700001903007700002303026700001903049700002303068700001703091700002003108700002003128700002603148700002203174700002003196700001803216700002103234700002003255700002303275700001703298700001903315700002803334700002003362700001903382700002103401700001903422700001603441700002903457700002103486700002403507700002003531700002003551700002303571700001903594700001803613700002103631700002103652700001903673700002003692700002103712700002003733700002403753700002103777700001903798700002303817700002203840700002103862700001903883700001803902700002003920700002103940700002003961700003003981700002304011700002304034700001904057856003604076 2016 eng d a1460-208300aA meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.0 ametaanalysis of 120 246 individuals identifies 18 new loci for f c2016 Jan 15 a358-700 v253 aGenome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
1 ade Vries, Paul, S1 aChasman, Daniel, I1 aSabater-Lleal, Maria1 aChen, Ming-Huei1 aHuffman, Jennifer, E1 aSteri, Maristella1 aTang, Weihong1 aTeumer, Alexander1 aMarioni, Riccardo, E1 aGrossmann, Vera1 aHottenga, Jouke, J1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aZhao, Jing Hua1 aBrody, Jennifer, A1 aKleber, Marcus, E1 aGuo, Xiuqing1 aWang, Jie, Jin1 aAuer, Paul, L1 aAttia, John, R1 aYanek, Lisa, R1 aAhluwalia, Tarunveer, S1 aLahti, Jari1 aVenturini, Cristina1 aTanaka, Toshiko1 aBielak, Lawrence, F1 aJoshi, Peter, K1 aRocanin-Arjo, Ares1 aKolcic, Ivana1 aNavarro, Pau1 aRose, Lynda, M1 aOldmeadow, Christopher1 aRiess, Helene1 aMazur, Johanna1 aBasu, Saonli1 aGoel, Anuj1 aYang, Qiong1 aGhanbari, Mohsen1 aWillemsen, Gonneke1 aRumley, Ann1 aFiorillo, Edoardo1 ade Craen, Anton, J M1 aGrotevendt, Anne1 aScott, Robert1 aTaylor, Kent, D1 aDelgado, Graciela, E1 aYao, Jie1 aKifley, Annette1 aKooperberg, Charles1 aQayyum, Rehan1 aLopez, Lorna, M1 aBerentzen, Tina, L1 aRäikkönen, Katri1 aMangino, Massimo1 aBandinelli, Stefania1 aPeyser, Patricia, A1 aWild, Sarah1 aTrégouët, David-Alexandre1 aWright, Alan, F1 aMarten, Jonathan1 aZemunik, Tatijana1 aMorrison, Alanna, C1 aSennblad, Bengt1 aTofler, Geoffrey1 ade Maat, Moniek, P M1 aGeus, Eco, J C1 aLowe, Gordon, D1 aZoledziewska, Magdalena1 aSattar, Naveed1 aBinder, Harald1 aVölker, Uwe1 aWaldenberger, Melanie1 aKhaw, Kay-Tee1 aMcKnight, Barbara1 aHuang, Jie1 aJenny, Nancy, S1 aHolliday, Elizabeth, G1 aQi, Lihong1 aMcevoy, Mark, G1 aBecker, Diane, M1 aStarr, John, M1 aSarin, Antti-Pekka1 aHysi, Pirro, G1 aHernandez, Dena, G1 aJhun, Min, A1 aCampbell, Harry1 aHamsten, Anders1 aRivadeneira, Fernando1 aMcArdle, Wendy, L1 aSlagboom, Eline1 aZeller, Tanja1 aKoenig, Wolfgang1 aPsaty, Bruce, M1 aHaritunians, Talin1 aLiu, Jingmin1 aPalotie, Aarno1 aUitterlinden, André, G1 aStott, David, J1 aHofman, Albert1 aFranco, Oscar, H1 aPolasek, Ozren1 aRudan, Igor1 aMorange, Pierre-Emmanuel1 aWilson, James, F1 aKardia, Sharon, L R1 aFerrucci, Luigi1 aSpector, Tim, D1 aEriksson, Johan, G1 aHansen, Torben1 aDeary, Ian, J1 aBecker, Lewis, C1 aScott, Rodney, J1 aMitchell, Paul1 aMärz, Winfried1 aWareham, Nick, J1 aPeters, Annette1 aGreinacher, Andreas1 aWild, Philipp, S1 aJukema, Wouter1 aBoomsma, Dorret, I1 aHayward, Caroline1 aCucca, Francesco1 aTracy, Russell1 aWatkins, Hugh1 aReiner, Alex, P1 aFolsom, Aaron, R1 aRidker, Paul, M1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aStrachan, David, P1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/693610963nas a2203529 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2016 eng d a2041-172300aA principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.0 aprincipal component metaanalysis on multiple anthropometric trai c2016 11 23 a133570 v73 aLarge consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
10aAnthropometry10aBody Size10aGenome-Wide Association Study10aGenotype10aHumans10aModels, Genetic10aPrincipal Component Analysis1 aRied, Janina, S1 aM, Janina, Jeff1 aChu, Audrey, Y1 aBragg-Gresham, Jennifer, L1 avan Dongen, Jenny1 aHuffman, Jennifer, E1 aAhluwalia, Tarunveer, S1 aCadby, Gemma1 aEklund, Niina1 aEriksson, Joel1 aEsko, Tõnu1 aFeitosa, Mary, F1 aGoel, Anuj1 aGorski, Mathias1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aJackson, Anne, U1 aJokinen, Eero1 aKanoni, Stavroula1 aKristiansson, Kati1 aKutalik, Zoltán1 aLahti, Jari1 aLuan, Jian'an1 aMägi, Reedik1 aMahajan, Anubha1 aMangino, Massimo1 aMedina-Gómez, Carolina1 aMonda, Keri, L1 aNolte, Ilja, M1 aPerusse, Louis1 aProkopenko, Inga1 aQi, Lu1 aRose, Lynda, M1 aSalvi, Erika1 aSmith, Megan, T1 aSnieder, Harold1 aStančáková, Alena1 aSung, Yun, Ju1 aTachmazidou, Ioanna1 aTeumer, Alexander1 aThorleifsson, Gudmar1 aHarst, Pim1 aWalker, Ryan, W1 aWang, Sophie, R1 aWild, Sarah, H1 aWillems, Sara, M1 aWong, Andrew1 aZhang, Weihua1 aAlbrecht, Eva1 aAlves, Alexessander, Couto1 aBakker, Stephan, J L1 aBarlassina, Cristina1 aBartz, Traci, M1 aBeilby, John1 aBellis, Claire1 aBergman, Richard, N1 aBergmann, Sven1 aBlangero, John1 aBlüher, Matthias1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBruinenberg, Marcel1 aCampbell, Harry1 aChen, Yii-Der Ida1 aChiang, Charleston, W K1 aChines, Peter, S1 aCollins, Francis, S1 aCucca, Fracensco1 aCupples, Adrienne, L1 aD'Avila, Francesca1 aGeus, Eco, J C1 aDedoussis, George1 aDimitriou, Maria1 aDöring, Angela1 aEriksson, Johan, G1 aFarmaki, Aliki-Eleni1 aFarrall, Martin1 aFerreira, Teresa1 aFischer, Krista1 aForouhi, Nita, G1 aFriedrich, Nele1 aGjesing, Anette, Prior1 aGlorioso, Nicola1 aGraff, Mariaelisa1 aGrallert, Harald1 aGrarup, Niels1 aGräßler, Jürgen1 aGrewal, Jagvir1 aHamsten, Anders1 aHarder, Marie, Neergaard1 aHartman, Catharina, A1 aHassinen, Maija1 aHastie, Nicholas1 aHattersley, Andrew, Tym1 aHavulinna, Aki, S1 aHeliövaara, Markku1 aHillege, Hans1 aHofman, Albert1 aHolmen, Oddgeir1 aHomuth, Georg1 aHottenga, Jouke-Jan1 aHui, Jennie1 aHusemoen, Lise, Lotte1 aHysi, Pirro, G1 aIsaacs, Aaron1 aIttermann, Till1 aJalilzadeh, Shapour1 aJames, Alan, L1 aJørgensen, Torben1 aJousilahti, Pekka1 aJula, Antti1 aJustesen, Johanne, Marie1 aJustice, Anne, E1 aKähönen, Mika1 aKaraleftheri, Maria1 aKhaw, Kay, Tee1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKinnunen, Leena1 aKnekt, Paul, B1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooner, Ishminder, K1 aKoskinen, Seppo1 aKovacs, Peter1 aKyriakou, Theodosios1 aLaitinen, Tomi1 aLangenberg, Claudia1 aLewin, Alexandra, M1 aLichtner, Peter1 aLindgren, Cecilia, M1 aLindström, Jaana1 aLinneberg, Allan1 aLorbeer, Roberto1 aLorentzon, Mattias1 aLuben, Robert1 aLyssenko, Valeriya1 aMännistö, Satu1 aManunta, Paolo1 aLeach, Irene, Mateo1 aMcArdle, Wendy, L1 aMcKnight, Barbara1 aMohlke, Karen, L1 aMihailov, Evelin1 aMilani, Lili1 aMills, Rebecca1 aMontasser, May, E1 aMorris, Andrew, P1 aMüller, Gabriele1 aMusk, Arthur, W1 aNarisu, Narisu1 aOng, Ken, K1 aOostra, Ben, A1 aOsmond, Clive1 aPalotie, Aarno1 aPankow, James, S1 aPaternoster, Lavinia1 aPenninx, Brenda, W1 aPichler, Irene1 aPilia, Maria, G1 aPolasek, Ozren1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRankinen, Tuomo1 aRao, D, C1 aRayner, Nigel, W1 aRibel-Madsen, Rasmus1 aRice, Treva, K1 aRichards, Marcus1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRyan, Kathy, A1 aSanna, Serena1 aSarzynski, Mark, A1 aScholtens, Salome1 aScott, Robert, A1 aSebert, Sylvain1 aSoutham, Lorraine1 aSparsø, Thomas, Hempel1 aSteinthorsdottir, Valgerdur1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStrauch, Konstantin1 aStringham, Heather, M1 aSwertz, Morris, A1 aSwift, Amy, J1 aTönjes, Anke1 aTsafantakis, Emmanouil1 avan der Most, Peter, J1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aVartiainen, Erkki1 aVenturini, Cristina1 aVerweij, Niek1 aViikari, Jorma, S1 aVitart, Veronique1 aVohl, Marie-Claude1 aVonk, Judith, M1 aWaeber, Gérard1 aWiden, Elisabeth1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWinkler, Thomas, W1 aWright, Alan, F1 aYerges-Armstrong, Laura, M1 aZhao, Jing, Hua1 aZillikens, Carola, M1 aBoomsma, Dorret, I1 aBouchard, Claude1 aChambers, John, C1 aChasman, Daniel, I1 aCusi, Daniele1 aGansevoort, Ron, T1 aGieger, Christian1 aHansen, Torben1 aHicks, Andrew, A1 aHu, Frank1 aHveem, Kristian1 aJarvelin, Marjo-Riitta1 aKajantie, Eero1 aKooner, Jaspal, S1 aKuh, Diana1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMetspalu, Andres1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aPalmer, Lyle, J1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPsaty, Bruce, M1 aPuolijoki, Hannu1 aRauramaa, Rainer1 aRudan, Igor1 aSalomaa, Veikko1 aSchwarz, Peter, E H1 aShudiner, Alan, R1 aSmit, Jan, H1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aStumvoll, Michael1 aTremblay, Angelo1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aVölker, Uwe1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWilson, James, F1 aZeggini, Eleftheria1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aDuijn, Cornelia, M1 aFox, Caroline1 aGroop, Leif, C1 aHeid, Iris, M1 aHunter, David, J1 aKaplan, Robert, C1 aMcCarthy, Mark, I1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aSchlessinger, David1 aThorsteinsdottir, Unnur1 aStrachan, David, P1 aFrayling, Timothy1 aHirschhorn, Joel, N1 aMüller-Nurasyid, Martina1 aLoos, Ruth, J F uhttps://chs-nhlbi.org/node/857011080nas a2202833 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2017 eng d a1549-167600aImpact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.0 aImpact of common genetic determinants of Hemoglobin A1c on type c2017 Sep ae10023830 v143 aBACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.
METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.
CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
10aDiabetes Mellitus, Type 210aGenetic Variation10aGenome-Wide Association Study10aGlycated Hemoglobin A10aHumans10aPhenotype10aRisk1 aWheeler, Eleanor1 aLeong, Aaron1 aLiu, Ching-Ti1 aHivert, Marie-France1 aStrawbridge, Rona, J1 aPodmore, Clara1 aLi, Man1 aYao, Jie1 aSim, Xueling1 aHong, Jaeyoung1 aChu, Audrey, Y1 aZhang, Weihua1 aWang, Xu1 aChen, Peng1 aMaruthur, Nisa, M1 aPorneala, Bianca, C1 aSharp, Stephen, J1 aJia, Yucheng1 aKabagambe, Edmond, K1 aChang, Li-Ching1 aChen, Wei-Min1 aElks, Cathy, E1 aEvans, Daniel, S1 aFan, Qiao1 aGiulianini, Franco1 aGo, Min Jin1 aHottenga, Jouke-Jan1 aHu, Yao1 aJackson, Anne, U1 aKanoni, Stavroula1 aKim, Young, Jin1 aKleber, Marcus, E1 aLadenvall, Claes1 aLecoeur, Cécile1 aLim, Sing-Hui1 aLu, Yingchang1 aMahajan, Anubha1 aMarzi, Carola1 aNalls, Mike, A1 aNavarro, Pau1 aNolte, Ilja, M1 aRose, Lynda, M1 aRybin, Denis, V1 aSanna, Serena1 aShi, Yuan1 aStram, Daniel, O1 aTakeuchi, Fumihiko1 aTan, Shu, Pei1 avan der Most, Peter, J1 avan Vliet-Ostaptchouk, Jana, V1 aWong, Andrew1 aYengo, Loic1 aZhao, Wanting1 aGoel, Anuj1 aLarrad, Maria, Teresa Mar1 aRadke, Dörte1 aSalo, Perttu1 aTanaka, Toshiko1 avan Iperen, Erik, P A1 aAbecasis, Goncalo1 aAfaq, Saima1 aAlizadeh, Behrooz, Z1 aBertoni, Alain, G1 aBonnefond, Amélie1 aBöttcher, Yvonne1 aBottinger, Erwin, P1 aCampbell, Harry1 aCarlson, Olga, D1 aChen, Chien-Hsiun1 aCho, Yoon Shin1 aGarvey, Timothy1 aGieger, Christian1 aGoodarzi, Mark, O1 aGrallert, Harald1 aHamsten, Anders1 aHartman, Catharina, A1 aHerder, Christian1 aHsiung, Chao, Agnes1 aHuang, Jie1 aIgase, Michiya1 aIsono, Masato1 aKatsuya, Tomohiro1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKohara, Katsuhiko1 aKovacs, Peter1 aLee, Juyoung1 aLee, Wen-Jane1 aLehne, Benjamin1 aLi, Huaixing1 aLiu, Jianjun1 aLobbens, Stephane1 aLuan, Jian'an1 aLyssenko, Valeriya1 aMeitinger, Thomas1 aMiki, Tetsuro1 aMiljkovic, Iva1 aMoon, Sanghoon1 aMulas, Antonella1 aMüller, Gabriele1 aMüller-Nurasyid, Martina1 aNagaraja, Ramaiah1 aNauck, Matthias1 aPankow, James, S1 aPolasek, Ozren1 aProkopenko, Inga1 aRamos, Paula, S1 aRasmussen-Torvik, Laura1 aRathmann, Wolfgang1 aRich, Stephen, S1 aRobertson, Neil, R1 aRoden, Michael1 aRoussel, Ronan1 aRudan, Igor1 aScott, Robert, A1 aScott, William, R1 aSennblad, Bengt1 aSiscovick, David, S1 aStrauch, Konstantin1 aSun, Liang1 aSwertz, Morris1 aTajuddin, Salman, M1 aTaylor, Kent, D1 aTeo, Yik-Ying1 aTham, Yih, Chung1 aTönjes, Anke1 aWareham, Nicholas, J1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aHingorani, Aroon, D1 aEgan, Josephine1 aFerrucci, Luigi1 aHovingh, Kees1 aJula, Antti1 aKivimaki, Mika1 aKumari, Meena1 aNjølstad, Inger1 aPalmer, Colin, N A1 aRíos, Manuel, Serrano1 aStumvoll, Michael1 aWatkins, Hugh1 aAung, Tin1 aBlüher, Matthias1 aBoehnke, Michael1 aBoomsma, Dorret, I1 aBornstein, Stefan, R1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aChen, Yduan-Tsong1 aCheng, Ching-Yu1 aCucca, Francesco1 aGeus, Eco, J C1 aDeloukas, Panos1 aEvans, Michele, K1 aFornage, Myriam1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGroop, Leif1 aGross, Myron, D1 aHarris, Tamara, B1 aHayward, Caroline1 aHeng, Chew-Kiat1 aIngelsson, Erik1 aKato, Norihiro1 aKim, Bong-Jo1 aKoh, Woon-Puay1 aKooner, Jaspal, S1 aKörner, Antje1 aKuh, Diana1 aKuusisto, Johanna1 aLaakso, Markku1 aLin, Xu1 aLiu, Yongmei1 aLoos, Ruth, J F1 aMagnusson, Patrik, K E1 aMärz, Winfried1 aMcCarthy, Mark, I1 aOldehinkel, Albertine, J1 aOng, Ken, K1 aPedersen, Nancy, L1 aPereira, Mark, A1 aPeters, Annette1 aRidker, Paul, M1 aSabanayagam, Charumathi1 aSale, Michele1 aSaleheen, Danish1 aSaltevo, Juha1 aSchwarz, Peter, Eh1 aSheu, Wayne, H H1 aSnieder, Harold1 aSpector, Timothy, D1 aTabara, Yasuharu1 aTuomilehto, Jaakko1 avan Dam, Rob, M1 aWilson, James, G1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWong, Tien, Yin1 aWu, Jer-Yuarn1 aYuan, Jian-Min1 aZonderman, Alan, B1 aSoranzo, Nicole1 aGuo, Xiuqing1 aRoberts, David, J1 aFlorez, Jose, C1 aSladek, Robert1 aDupuis, Josée1 aMorris, Andrew, P1 aTai, E-Shyong1 aSelvin, Elizabeth1 aRotter, Jerome, I1 aLangenberg, Claudia1 aBarroso, Inês1 aMeigs, James, B1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/759609467nas a2203025 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2017 eng d a1524-456300aNovel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.0 aNovel Blood Pressure Locus and Gene Discovery Using GenomeWide A c2017 Jul 243 aElevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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aZemunik, Tatijana1 aLu, Yingchang1 aEvangelou, Evangelos1 aShah, Nabi1 ade Borst, Martin, H1 aMangino, Massimo1 aPrins, Bram, P1 aCampbell, Archie1 aLi-Gao, Ruifang1 aChauhan, Ganesh1 aOldmeadow, Christopher1 aAbecasis, Goncalo1 aAbedi, Maryam1 aBarbieri, Caterina, M1 aBarnes, Michael, R1 aBatini, Chiara1 aBeilby, John1 aBlake, Tineka1 aBoehnke, Michael1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrown, Morris1 aBrumat, Marco1 aCampbell, Harry1 aChambers, John, C1 aCocca, Massimiliano1 aCollins, Francis1 aConnell, John1 aCordell, Heather, J1 aDamman, Jeffrey, J1 aDavies, Gail1 ade Geus, Eco, J1 ade Mutsert, Renée1 aDeelen, Joris1 aDemirkale, Yusuf1 aDoney, Alex, S F1 aDörr, Marcus1 aFarrall, Martin1 aFerreira, Teresa1 aFrånberg, Mattias1 aGao, He1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGiulianini, Franco1 aGow, Alan, J1 aHamsten, Anders1 aHarris, Tamara, B1 aHofman, Albert1 aHolliday, Elizabeth, G1 aHui, Jennie1 aJarvelin, Marjo-Riitta1 aJohansson, Asa1 aJohnson, Andrew, D1 aJousilahti, Pekka1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKhaw, Kay-Tee1 aKolcic, Ivana1 aKoskinen, Seppo1 aLangenberg, Claudia1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aMach, François1 aMamasoula, Chrysovalanto1 aMenni, Cristina1 aMifsud, Borbala1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNandakumar, Priyanka1 aNguyen, Quang, Tri1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalotie, Aarno1 aParé, Guillaume1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPoulter, Neil1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRen, Meixia1 aRice, Kenneth1 aRidker, Paul, M1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRotter, Jerome, I1 aRudan, Igor1 aSaba, Yasaman1 aPierre, Aude, Saint1 aSala, Cinzia, F1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aScott, Rodney1 aSeelen, Marc, A1 aShields, Denis, C1 aSiscovick, David1 aSorice, Rossella1 aStanton, Alice1 aStott, David, J1 aSundström, Johan1 aSwertz, Morris1 aTaylor, Kent, D1 aThom, Simon1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, André, G1 aVölker, Uwe1 aVollenweider, Peter1 aWild, Sarah1 aWillemsen, Gonneke1 aWright, Alan, F1 aYao, Jie1 aThériault, Sébastien1 aConen, David1 aAttia, John1 aSever, Peter1 aDebette, Stephanie1 aMook-Kanamori, Dennis, O1 aZeggini, Eleftheria1 aSpector, Tim, D1 aHarst, Pim1 aPalmer, Colin, N A1 aVergnaud, Anne-Claire1 aLoos, Ruth, J F1 aPolasek, Ozren1 aStarr, John, M1 aGirotto, Giorgia1 aHayward, Caroline1 aKooner, Jaspal, S1 aLindgren, Cecila, M1 aVitart, Veronique1 aSamani, Nilesh, J1 aTuomilehto, Jaakko1 aGyllensten, Ulf1 aKnekt, Paul1 aDeary, Ian, J1 aCiullo, Marina1 aElosua, Roberto1 aKeavney, Bernard, D1 aHicks, Andrew, A1 aScott, Robert, A1 aGasparini, Paolo1 aLaan, Maris1 aLiu, Yongmei1 aWatkins, Hugh1 aHartman, Catharina, A1 aSalomaa, Veikko1 aToniolo, Daniela1 aPerola, Markus1 aWilson, James, F1 aSchmidt, Helena1 aZhao, Jing Hua1 aLehtimäki, Terho1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aPeters, Annette1 aRettig, Rainer1 aJames, Alan1 aJukema, Wouter1 aStrachan, David, P1 aPalmas, Walter1 aMetspalu, Andres1 aIngelsson, Erik1 aBoomsma, Dorret, I1 aFranco, Oscar, H1 aBochud, Murielle1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aElliott, Paul1 aChasman, Daniel, I1 aChakravarti, Aravinda1 aKnight, Joanne1 aMorris, Andrew, P1 aLevy, Daniel1 aTobin, Martin, D1 aSnieder, Harold1 aCaulfield, Mark, J1 aEhret, Georg, B uhttps://chs-nhlbi.org/node/749210328nas a2203505 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2018 eng d a1546-171800aGenetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.0 aGenetic analysis of over 1 million people identifies 535 new loc c2018 Oct a1412-14250 v503 aHigh blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
1 aEvangelou, Evangelos1 aWarren, Helen, R1 aMosen-Ansorena, David1 aMifsud, Borbala1 aPazoki, Raha1 aGao, He1 aNtritsos, Georgios1 aDimou, Niki1 aCabrera, Claudia, P1 aKaraman, Ibrahim1 aNg, Fu, Liang1 aEvangelou, Marina1 aWitkowska, Katarzyna1 aTzanis, Evan1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aEdwards, Digna, R Velez1 aSun, Yan, V1 aCho, Kelly1 aGaziano, Michael1 aWilson, Peter, W F1 aTsao, Philip, S1 aKovesdy, Csaba, P1 aEsko, Tõnu1 aMägi, Reedik1 aMilani, Lili1 aAlmgren, Peter1 aBoutin, Thibaud1 aDebette, Stephanie1 aDing, Jun1 aGiulianini, Franco1 aHolliday, Elizabeth, G1 aJackson, Anne, U1 aLi-Gao, Ruifang1 aLin, Wei-Yu1 aLuan, Jian'an1 aMangino, Massimo1 aOldmeadow, Christopher1 aPrins, Bram, Peter1 aQian, Yong1 aSargurupremraj, Muralidharan1 aShah, Nabi1 aSurendran, Praveen1 aThériault, Sébastien1 aVerweij, Niek1 aWillems, Sara, M1 aZhao, Jing-Hua1 aAmouyel, Philippe1 aConnell, John1 ade Mutsert, Renée1 aDoney, Alex, S F1 aFarrall, Martin1 aMenni, Cristina1 aMorris, Andrew, D1 aNoordam, Raymond1 aParé, Guillaume1 aPoulter, Neil, R1 aShields, Denis, C1 aStanton, Alice1 aThom, Simon1 aAbecasis, Goncalo1 aAmin, Najaf1 aArking, Dan, E1 aAyers, Kristin, L1 aBarbieri, Caterina, M1 aBatini, Chiara1 aBis, Joshua, C1 aBlake, Tineka1 aBochud, Murielle1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrumat, Marco1 aCampbell, Archie1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChauhan, Ganesh1 aCiullo, Marina1 aCocca, Massimiliano1 aCollins, Francis1 aCordell, Heather, J1 aDavies, Gail1 ade Borst, Martin, H1 ade Geus, Eco, J1 aDeary, Ian, J1 aDeelen, Joris1 aM, Fabiola, del Greco1 aDemirkale, Cumhur, Yusuf1 aDörr, Marcus1 aEhret, Georg, B1 aElosua, Roberto1 aEnroth, Stefan1 aErzurumluoglu, Mesut1 aFerreira, Teresa1 aFrånberg, Mattias1 aFranco, Oscar, H1 aGandin, Ilaria1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGoel, Anuj1 aGow, Alan, J1 aGudnason, 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aMorgan, Anna1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNalls, Mike, A1 aNandakumar, Priyanka1 aNelson, Christopher, P1 aNiiranen, Teemu1 aNolte, Ilja, M1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aO'Reilly, Paul, F1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPalotie, Aarno1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPramstaller, Peter, P1 aNguyen, Quang, Tri1 aRaitakari, Olli, T1 aRen, Meixia1 aRettig, Rainer1 aRice, Kenneth1 aRidker, Paul, M1 aRied, Janina, S1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRose, Lynda, M1 aRotter, Jerome, I1 aRudan, Igor1 aRuggiero, Daniela1 aSaba, Yasaman1 aSala, Cinzia, F1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aSchmidt, Helena1 aShrine, Nick1 aSiscovick, David1 aSmith, Albert, V1 aSnieder, Harold1 aSõber, Siim1 aSorice, Rossella1 aStarr, John, M1 aStott, David, J1 aStrachan, David, P1 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2018 eng d a1537-660500aA Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.0 aLargeScale Multiancestry Genomewide Study Accounting for Smoking c2018 Mar 01 a375-4000 v1023 aGenome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
1 aSung, Yun, J1 aWinkler, Thomas, W1 aFuentes, Lisa, de Las1 aBentley, Amy, R1 aBrown, Michael, R1 aKraja, Aldi, T1 aSchwander, Karen1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aKilpeläinen, Tuomas, O1 aRichard, Melissa, A1 aNoordam, Raymond1 aAslibekyan, Stella1 aAschard, Hugues1 aBartz, Traci, M1 aDorajoo, Rajkumar1 aLiu, Yongmei1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, Vernon1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aWarren, Helen, R1 aZhao, Wei1 aZhou, Yanhua1 aMatoba, Nana1 aSofer, Tamar1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGiulianini, Franco1 aGoel, Anuj1 aHarris, Sarah, E1 aHartwig, Fernando, Pires1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKuhnel, Brigitte1 aLeander, Karin1 aLee, Wen-Jane1 aLin, Keng-Hung1 aLuan, Jian, 'an1 aMcKenzie, Colin, A1 aMeian, He1 aNelson, Christopher, P1 aRauramaa, Rainer1 aSchupf, Nicole1 aScott, Robert, A1 aSheu, Wayne, H H1 aStančáková, Alena1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Heming1 aWang, Yajuan1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAlfred, Tamuno1 aAmin, Najaf1 aArking, Dan1 aAung, Tin1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCabrera, Claudia, P1 aCade, Brian1 aCaizheng, Yu1 aCampbell, Archie1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aChauhan, Ganesh1 aChristensen, Kaare1 aCocca, Massimiliano1 aCollins, Francis, S1 aConnell, John, M1 ade Mutsert, Renée1 ade Silva, Janaka1 aDebette, Stephanie1 aDörr, Marcus1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFisher, Virginia, A1 aForouhi, Nita, G1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGraff, Misa1 aGu, Charles1 aGu, Dongfeng1 aGupta, Preeti1 aHagenaars, Saskia, P1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHofman, Albert1 aHoward, Barbara, V1 aHunt, Steven1 aIrvin, Marguerite, R1 aJia, Yucheng1 aJoehanes, Roby1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKaufman, Joel1 aKerrison, Nicola, D1 aKhor, Chiea, Chuen1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKomulainen, Pirjo1 aKooperberg, Charles1 aKrieger, Jose, E1 aKubo, Michiaki1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLim, Sing, Hui1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Jingmin1 aLiu, Kiang1 aLiu, Yeheng1 aLoh, Marie1 aLohman, Kurt, K1 aLong, Jirong1 aLouie, Tin1 aMägi, Reedik1 aMahajan, Anubha1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilani, Lili1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMosley, Thomas, H1 aMunson, Peter1 aMurray, Alison, D1 aNalls, Mike, A1 aNasri, Ubaydah1 aNorris, Jill, M1 aNorth, Kari1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmas, Walter, R1 aPalmer, Nicholette, D1 aPankow, James, S1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRenstrom, Frida1 aRice, Treva, K1 aRidker, Paul, M1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSandow, Kevin1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSeshadri, Sudha1 aSever, Peter1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, X1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYuan, Jian-Min1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aChen, Yii-Der Ida1 ade Faire, Ulf1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aForrester, Terrence1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, Lessa1 aHung, Yi-Jen1 aJonas, Jost, B1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLehtimäki, Terho1 aLiang, Kae-Woei1 aMagnusson, Patrik, K E1 aNewman, Anne, B1 aOldehinkel, Albertine, J1 aPereira, Alexandre, C1 aRedline, Susan1 aRettig, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aKamatani, Yoichiro1 aLaurie, Cathy, C1 aBouchard, Claude1 aCooper, Richard, S1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aO'Connell, Jeff, R1 aPsaty, Bruce, M1 avan Dam, Rob, M1 aSims, Mario1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aFornage, Myriam1 aRotimi, Charles, N1 aProvince, Michael, A1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aReiner, Alex, P1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aCaulfield, Mark, J1 aElliott, Paul1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aChasman, Daniel, I1 aCHARGE Neurology Working Group1 aCOGENT-Kidney Consortium1 aGIANT Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/768611027nas a2203421 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2018 eng d a1932-620300aNovel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.0 aNovel genetic associations for blood pressure identified via gen c2018 ae01981660 v133 aHeavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1 aFeitosa, Mary, F1 aKraja, Aldi, T1 aChasman, Daniel, I1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aBentley, Amy, R1 aBrown, Michael, R1 aSchwander, Karen1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aWojczynski, Mary, K1 aAlver, Maris1 aBoissel, Mathilde1 aCai, Qiuyin1 aCampbell, Archie1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLuan, Jian'an1 aMatoba, Nana1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRiaz, Muhammad1 aRueedi, Rico1 aRobino, Antonietta1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVitart, Veronique1 aWang, Yajuan1 aWare, Erin, B1 aWarren, Helen, R1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBoerwinkle, Eric1 aBorecki, Ingrid1 aBroeckel, Ulrich1 aBrown, Morris1 aBrumat, Marco1 aBurke, Gregory, L1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aCharumathi, Sabanayagam1 aChen, Yii-Der, Ida1 aConnell, John, M1 aCorrea, Adolfo1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDeng, Xuan1 aDing, Jingzhong1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEppinga, Ruben, N1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFelix, Stephan, B1 aForouhi, Nita, G1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGigante, Bruna1 aGu, Charles1 aGu, Dongfeng1 aHagenaars, Saskia, P1 aHallmans, Göran1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJohn, Ulrich1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLin, Shiow1 aLiu, Jianjun1 aLiu, Jingmin1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aNalls, Mike, A1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aNorris, Jill, M1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPerls, Thomas1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRoll, Kathryn1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRotter, Jerome, I1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aSchupf, Nicole1 aScott, William, R1 aSever, Peter, S1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVollenweider, Peter1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, Xing1 aBin Wei, Wen1 aWilliams, Christine1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLaakso, Markku1 aLaurie, Cathy, C1 aLeander, Karin1 aLehtimäki, Terho1 aStudy, Lifelines, Cohort1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPolasek, Ozren1 aPorteous, David, J1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aBouchard, Claude1 aChristensen, Kaare1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPereira, Alexandre, C1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aGauderman, James1 aZhu, Xiaofeng1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aKooperberg, Charles1 aPalmas, Walter1 aRice, Kenneth1 aMorrison, Alanna, C1 aElliott, Paul1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aRao, Dabeeru, C1 aProvince, Michael, A1 aLevy, Daniel1 aInterAct Consortium uhttps://chs-nhlbi.org/node/779215950nas a2205365 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2019 eng d a2041-172300aAssociations of autozygosity with a broad range of human phenotypes.0 aAssociations of autozygosity with a broad range of human phenoty c2019 Oct 31 a49570 v103 aIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
1 aClark, David, W1 aOkada, Yukinori1 aMoore, Kristjan, H S1 aMason, Dan1 aPirastu, Nicola1 aGandin, Ilaria1 aMattsson, Hannele1 aBarnes, Catriona, L K1 aLin, Kuang1 aZhao, Jing Hua1 aDeelen, Patrick1 aRohde, Rebecca1 aSchurmann, Claudia1 aGuo, Xiuqing1 aGiulianini, Franco1 aZhang, Weihua1 aMedina-Gómez, Carolina1 aKarlsson, Robert1 aBao, Yanchun1 aBartz, Traci, M1 aBaumbach, Clemens1 aBiino, Ginevra1 aBixley, Matthew, J1 aBrumat, Marco1 aChai, Jin-Fang1 aCorre, Tanguy1 aCousminer, Diana, L1 aDekker, Annelot, M1 aEccles, David, A1 avan Eijk, Kristel, R1 aFuchsberger, Christian1 aGao, He1 aGermain, Marine1 aGordon, Scott, D1 ade Haan, Hugoline, G1 aHarris, Sarah, E1 aHofer, Edith1 aHuerta-Chagoya, Alicia1 aIgartua, Catherine1 aJansen, Iris, E1 aJia, Yucheng1 aKacprowski, Tim1 aKarlsson, Torgny1 aKleber, Marcus, E1 aLi, Shengchao, Alfred1 aLi-Gao, Ruifang1 aMahajan, Anubha1 aMatsuda, Koichi1 aMeidtner, Karina1 aMeng, Weihua1 aMontasser, May, E1 avan der Most, Peter, J1 aMunz, Matthias1 aNutile, Teresa1 aPalviainen, Teemu1 aPrasad, Gauri1 aPrasad, Rashmi, B1 aPriyanka, Tallapragada, Divya Sri1 aRizzi, Federica1 aSalvi, Erika1 aSapkota, Bishwa, R1 aShriner, Daniel1 aSkotte, Line1 aSmart, Melissa, C1 aSmith, Albert, Vernon1 avan der Spek, Ashley1 aSpracklen, Cassandra, N1 aStrawbridge, Rona, J1 aTajuddin, Salman, M1 aTrompet, Stella1 aTurman, Constance1 aVerweij, Niek1 aViberti, Clara1 aWang, Lihua1 aWarren, Helen, R1 aWootton, Robyn, E1 aYanek, Lisa, R1 aYao, Jie1 aYousri, Noha, A1 aZhao, Wei1 aAdeyemo, Adebowale, A1 aAfaq, Saima1 aAguilar-Salinas, Carlos, Alberto1 aAkiyama, Masato1 aAlbert, Matthew, L1 aAllison, Matthew, A1 aAlver, Maris1 aAung, Tin1 aAzizi, Fereidoun1 aBentley, Amy, R1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBorja, Judith, B1 ade Borst, Gert, J1 aBottinger, Erwin, P1 aBroer, Linda1 aCampbell, Harry1 aChanock, Stephen1 aChee, Miao-Li1 aChen, Guanjie1 aChen, Yii-der, I1 aChen, Zhengming1 aChiu, Yen-Feng1 aCocca, Massimiliano1 aCollins, Francis, S1 aConcas, Maria, Pina1 aCorley, Janie1 aCugliari, Giovanni1 avan Dam, Rob, M1 aDamulina, Anna1 aDaneshpour, Maryam, S1 aDay, Felix, R1 aDelgado, Graciela, E1 aDhana, Klodian1 aDoney, Alexander, S F1 aDörr, Marcus1 aDoumatey, Ayo, P1 aDzimiri, Nduna1 aEbenesersdóttir, Sunna1 aElliott, Joshua1 aElliott, Paul1 aEwert, Ralf1 aFelix, Janine, F1 aFischer, Krista1 aFreedman, Barry, I1 aGirotto, Giorgia1 aGoel, Anuj1 aGögele, Martin1 aGoodarzi, Mark, O1 aGraff, Mariaelisa1 aGranot-Hershkovitz, Einat1 aGrodstein, Francine1 aGuarrera, Simonetta1 aGudbjartsson, Daniel, F1 aGuity, Kamran1 aGunnarsson, Bjarni1 aGuo, Yu1 aHagenaars, Saskia, P1 aHaiman, Christopher, A1 aHalevy, Avner1 aHarris, Tamara, B1 aHedayati, Mehdi1 avan Heel, David, A1 aHirata, Makoto1 aHöfer, Imo1 aHsiung, Chao, Agnes1 aHuang, Jinyan1 aHung, Yi-Jen1 aIkram, Arfan, M1 aJagadeesan, Anuradha1 aJousilahti, Pekka1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerrison, Nicola, D1 aKessler, Thorsten1 aKhaw, Kay-Tee1 aKhor, Chiea, Chuen1 ade Kleijn, Dominique, P V1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKraft, Peter1 aKrämer, Bernhard, K1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLawlor, Deborah, A1 aLee, I-Te1 aLee, Wen-Jane1 aLerch, Markus, M1 aLi, Liming1 aLiu, Jianjun1 aLoh, Marie1 aLondon, Stephanie, J1 aLoomis, Stephanie1 aLu, Yingchang1 aLuan, Jian'an1 aMägi, Reedik1 aManichaikul, Ani, W1 aManunta, Paolo1 aMásson, Gísli1 aMatoba, Nana1 aMei, Xue, W1 aMeisinger, Christa1 aMeitinger, Thomas1 aMezzavilla, Massimo1 aMilani, Lili1 aMillwood, Iona, Y1 aMomozawa, Yukihide1 aMoore, Amy1 aMorange, Pierre-Emmanuel1 aMoreno-Macias, Hortensia1 aMori, Trevor, A1 aMorrison, Alanna, C1 aMuka, Taulant1 aMurakami, Yoshinori1 aMurray, Alison, D1 ade Mutsert, Renée1 aMychaleckyj, Josyf, C1 aNalls, Mike, A1 aNauck, Matthias1 aNeville, Matt, J1 aNolte, Ilja, M1 aOng, Ken, K1 aOrozco, Lorena1 aPadmanabhan, Sandosh1 aPálsson, Gunnar1 aPankow, James, S1 aPattaro, Cristian1 aPattie, Alison1 aPolasek, Ozren1 aPoulter, Neil1 aPramstaller, Peter, P1 aQuintana-Murci, Lluis1 aRäikkönen, Katri1 aRalhan, Sarju1 aRao, Dabeeru, C1 avan Rheenen, Wouter1 aRich, Stephen, S1 aRidker, Paul, M1 aRietveld, Cornelius, A1 aRobino, Antonietta1 avan Rooij, Frank, J A1 aRuggiero, Daniela1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSabater-Lleal, Maria1 aSala, Cinzia, Felicita1 aSalomaa, Veikko1 aSandow, Kevin1 aSchmidt, Helena1 aScott, Laura, J1 aScott, William, R1 aSedaghati-Khayat, Bahareh1 aSennblad, Bengt1 avan Setten, Jessica1 aSever, Peter, J1 aSheu, Wayne, H-H1 aShi, Yuan1 aShrestha, Smeeta1 aShukla, Sharvari, Rahul1 aSigurdsson, Jon, K1 aSikka, Timo, Tonis1 aSingh, Jai, Rup1 aSmith, Blair, H1 aStančáková, Alena1 aStanton, Alice1 aStarr, John, M1 aStefansdottir, Lilja1 aStraker, Leon1 aSulem, Patrick1 aSveinbjornsson, Gardar1 aSwertz, Morris, A1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTerzikhan, Natalie1 aTham, Yih-Chung1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTillander, Annika1 aTracy, Russell, P1 aTusié-Luna, Teresa1 aTzoulaki, Ioanna1 aVaccargiu, Simona1 aVangipurapu, Jagadish1 aVeldink, Jan, H1 aVitart, Veronique1 aVölker, Uwe1 aVuoksimaa, Eero1 aWakil, Salma, M1 aWaldenberger, Melanie1 aWander, Gurpreet, S1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWild, Sarah1 aYajnik, Chittaranjan, S1 aYuan, Jian-Min1 aZeng, Lingyao1 aZhang, Liang1 aZhou, Jie1 aAmin, Najaf1 aAsselbergs, Folkert, W1 aBakker, Stephan, J L1 aBecker, Diane, M1 aLehne, Benjamin1 aBennett, David, A1 avan den Berg, Leonard, H1 aBerndt, Sonja, I1 aBharadwaj, Dwaipayan1 aBielak, Lawrence, F1 aBochud, Murielle1 aBoehnke, Mike1 aBouchard, Claude1 aBradfield, Jonathan, P1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarmi, Shai1 aCaulfield, Mark, J1 aCesarini, David1 aChambers, John, C1 aChandak, Giriraj, Ratan1 aCheng, Ching-Yu1 aCiullo, Marina1 aCornelis, Marilyn1 aCusi, Daniele1 aSmith, George Davey1 aDeary, Ian, J1 aDorajoo, Rajkumar1 aDuijn, Cornelia, M1 aEllinghaus, David1 aErdmann, Jeanette1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aEvans, Michele, K1 aFaul, Jessica, D1 aFeenstra, Bjarke1 aFeitosa, Mary1 aFoisy, Sylvain1 aFranke, Andre1 aFriedlander, Yechiel1 aGasparini, Paolo1 aGieger, Christian1 aGonzalez, Clicerio1 aGoyette, Philippe1 aGrant, Struan, F A1 aGriffiths, Lyn, R1 aGroop, Leif1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHakonarson, Hakon1 aHamsten, Anders1 aHarst, Pim1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHochner, Hagit1 aHuikuri, Heikki1 aHunt, Steven, C1 aJaddoe, Vincent, W V1 aDe Jager, Philip, L1 aJohannesson, Magnus1 aJohansson, Asa1 aJonas, Jost, B1 aJukema, Wouter1 aJunttila, Juhani1 aKaprio, Jaakko1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKumari, Meena1 aLaakso, Markku1 avan der Laan, Sander, W1 aLahti, Jari1 aLaudes, Matthias1 aLea, Rodney, A1 aLieb, Wolfgang1 aLumley, Thomas1 aMartin, Nicholas, G1 aMärz, Winfried1 aMatullo, Giuseppe1 aMcCarthy, Mark, I1 aMedland, Sarah, E1 aMerriman, Tony, R1 aMetspalu, Andres1 aMeyer, Brian, F1 aMohlke, Karen, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis1 aMunroe, Patricia, B1 aNorth, Kari, E1 aNyholt, Dale, R1 aO'Connell, Jeffery, R1 aOber, Carole1 aOldehinkel, Albertine, J1 aPalmas, Walter1 aPalmer, Colin1 aPasterkamp, Gerard, G1 aPatin, Etienne1 aPennell, Craig, E1 aPerusse, Louis1 aPeyser, Patricia, A1 aPirastu, Mario1 aPolderman, Tinca, J C1 aPorteous, David, J1 aPosthuma, Danielle1 aPsaty, Bruce, M1 aRioux, John, D1 aRivadeneira, Fernando1 aRotimi, Charles1 aRotter, Jerome, I1 aRudan, Igor1 aRuijter, Hester, M den1 aSanghera, Dharambir, K1 aSattar, Naveed1 aSchmidt, Reinhold1 aSchulze, Matthias, B1 aSchunkert, Heribert1 aScott, Robert, A1 aShuldiner, Alan, R1 aSim, Xueling1 aSmall, Neil1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aTai, E-Shyong1 aTeumer, Alexander1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTrégouët, David-Alexandre1 aTuomi, Tiinamaija1 aVollenweider, Peter1 aWang, Carol, A1 aWeir, David, R1 aWhitfield, John, B1 aWijmenga, Cisca1 aWong, Tien-Yin1 aWright, John1 aYang, Jingyun1 aYu, Lei1 aZemel, Babette, S1 aZonderman, Alan, B1 aPerola, Markus1 aMagnusson, Patrik, K E1 aUitterlinden, André, G1 aKooner, Jaspal, S1 aChasman, Daniel, I1 aLoos, Ruth, J F1 aFranceschini, Nora1 aFranke, Lude1 aHaley, Chris, S1 aHayward, Caroline1 aWalters, Robin, G1 aPerry, John, R B1 aEsko, Tõnu1 aHelgason, Agnar1 aStefansson, Kari1 aJoshi, Peter, K1 aKubo, Michiaki1 aWilson, James, F uhttps://chs-nhlbi.org/node/819810550nas a2203325 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2019 eng d a1476-625600aMulti-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.0 aMultiAncestry GenomeWide Association Study of Lipid Levels Incor c2019 Jan 293 aAn individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
1 ade Vries, Paul, S1 aBrown, Michael, R1 aBentley, Amy, R1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aSchwander, Karen1 aKraja, Aldi, T1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDeng, Xuan1 aDorajoo, Rajkumar1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aEvangelou, Evangelos1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLee, Joseph, H1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aRiaz, Muhammad1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aConnell, John, M1 ade Faire, Ulf1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDing, Jingzhong1 aDominiczak, Anna, F1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGrabe, Hans, J1 aGrove, Megan, L1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJacobs, David, R1 aJohnson, Craig1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Steve, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLemaitre, Rozenn, N1 aLi, Yize1 aLiang, Jingjing1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMukamal, Kenneth, J1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRice, Treva, K1 aRich, Stephen, S1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTan, Nicholas1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 avan Heemst, Diana1 aVuckovic, Dragana1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Yujie1 aWang, Zhe1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aPenninx, Brenda1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aZheng, Wei1 aElliott, Paul1 aNorth, Kari, E1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aLiu, Ching-Ti1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aKardia, Sharon, L R1 aZhu, Xiaofeng1 aRotimi, Charles, N1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLiu, Jingmin1 aRotter, Jerome, I1 aGauderman, James1 aProvince, Michael, A1 aMunroe, Patricia, B1 aRice, Kenneth1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aMorrison, Alanna, C1 aInterAct Consortium1 aLifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study) uhttps://chs-nhlbi.org/node/797011178nas a2203793 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2019 eng d a1546-171800aMulti-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.0 aMultiancestry genomewide genesmoking interaction study of 387272 c2019 Apr a636-6480 v513 aThe concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
1 aBentley, Amy, R1 aSung, Yun, J1 aBrown, Michael, R1 aWinkler, Thomas, W1 aKraja, Aldi, T1 aNtalla, Ioanna1 aSchwander, Karen1 aChasman, Daniel, I1 aLim, Elise1 aDeng, Xuan1 aGuo, Xiuqing1 aLiu, Jingmin1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aBaker, Jenna1 aChen, Guanjie1 aAschard, Hugues1 aBartz, Traci, M1 aDing, Jingzhong1 aDorajoo, Rajkumar1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aZhao, Wei1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aHung, Yi-Jen1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLeander, Karin1 aLin, Keng-Hung1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aPrins, Bram1 aRiaz, Muhammad1 aRobino, Antonietta1 aSaid, Abdullah1 aSchupf, Nicole1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Tzung-Dau1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aXiang, Yong-Bing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAdeyemo, Adebowale1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aArzumanyan, Zorayr1 aAung, Tin1 aBallantyne, Christie1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBroeckel, Ulrich1 aBrown, Morris1 aCade, Brian, E1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aChristensen, Kaare1 aConcas, Maria, Pina1 aConnell, John, M1 aFuentes, Lisa, de Las1 ade Silva, Janaka1 ade Vries, Paul, S1 aDoumatey, Ayo1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFloyd, James, S1 aForouhi, Nita, G1 aForrester, Terrence1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGharib, Sina, A1 aGigante, Bruna1 aGiulianini, Franco1 aGrabe, Hans, J1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aIkram, Arfan, M1 aJia, Yucheng1 aJoehanes, Roby1 aJohnson, Craig1 aJonas, Jost, Bruno1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLiang, Jingjing1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLohman, Kurt, K1 aLouie, Tin1 aLuzzi, Anna1 aMägi, Reedik1 aMahajan, Anubha1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMurray, Alison, D1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRenstrom, Frida1 aRice, Treva, K1 aRich, Stephen, S1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTiemeier, Henning1 aTurner, Stephen, T1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Heming1 aWang, Lan1 aWang, Lihua1 aBin Wei, Wen1 aWilliams, Christine, A1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYoung, Kristin1 aYu, Caizheng1 aYuan, Jian-Min1 aZhou, Jie1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aCooper, Richard, S1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aJuang, Jyh-Ming, Jimmy1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLaurie, Cathy, C1 aLee, I-Te1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aRedline, Susan1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Jun-Sing1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZeggini, Eleftheria1 aZheng, Wei1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aProvince, Michael, A1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aFranceschini, Nora1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aCOGENT-Kidney Consortium1 aEPIC-InterAct Consortium1 aUnderstanding Society Scientific Group1 aLifelines Cohort uhttps://chs-nhlbi.org/node/800505138nas a2201357 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2023 eng d a2041-172300aGenetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.0 aGenetic architecture of spatial electrical biomarkers for cardia c2023 Mar 14 a14110 v143 aThe 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
10aArrhythmias, Cardiac10aAtrioventricular Block10aBiomarkers10aCardiovascular Diseases10aElectrocardiography10aGenome-Wide Association Study10aHumans10aRisk Factors1 aYoung, William, J1 aHaessler, Jeffrey1 aBenjamins, Jan-Walter1 aRepetto, Linda1 aYao, Jie1 aIsaacs, Aaron1 aHarper, Andrew, R1 aRamirez, Julia1 aGarnier, Sophie1 aVan Duijvenboden, Stefan1 aBaldassari, Antoine, R1 aConcas, Maria, Pina1 aDuong, ThuyVy1 aFoco, Luisa1 aIsaksen, Jonas, L1 aMei, Hao1 aNoordam, Raymond1 aNursyifa, Casia1 aRichmond, Anne1 aSantolalla, Meddly, L1 aSitlani, Colleen, M1 aSoroush, Negin1 aThériault, Sébastien1 aTrompet, Stella1 aAeschbacher, Stefanie1 aAhmadizar, Fariba1 aAlonso, Alvaro1 aBrody, Jennifer, A1 aCampbell, Archie1 aCorrea, Adolfo1 aDarbar, Dawood1 aDe Luca, Antonio1 aDeleuze, Jean-Francois1 aEllervik, Christina1 aFuchsberger, Christian1 aGoel, Anuj1 aGrace, Christopher1 aGuo, Xiuqing1 aHansen, Torben1 aHeckbert, Susan, R1 aJackson, Rebecca, D1 aKors, Jan, A1 aLima-Costa, Maria, Fernanda1 aLinneberg, Allan1 aMacfarlane, Peter, W1 aMorrison, Alanna, C1 aNavarro, Pau1 aPorteous, David, J1 aPramstaller, Peter, P1 aReiner, Alexander, P1 aRisch, Lorenz1 aSchotten, Ulrich1 aShen, Xia1 aSinagra, Gianfranco1 aSoliman, Elsayed, Z1 aStoll, Monika1 aTarazona-Santos, Eduardo1 aTinker, Andrew1 aTrajanoska, Katerina1 aVillard, Eric1 aWarren, Helen, R1 aWhitsel, Eric, A1 aWiggins, Kerri, L1 aArking, Dan, E1 aAvery, Christy, L1 aConen, David1 aGirotto, Giorgia1 aGrarup, Niels1 aHayward, Caroline1 aJukema, Wouter1 aMook-Kanamori, Dennis, O1 aOlesen, Morten, Salling1 aPadmanabhan, Sandosh1 aPsaty, Bruce, M1 aPattaro, Cristian1 aRibeiro, Antonio, Luiz P1 aRotter, Jerome, I1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aWilson, James, G1 aOrini, Michele1 aCharron, Philippe1 aWatkins, Hugh1 aKooperberg, Charles1 aLin, Henry, J1 aWilson, James, F1 aKanters, Jørgen, K1 aSotoodehnia, Nona1 aMifsud, Borbala1 aLambiase, Pier, D1 aTereshchenko, Larisa, G1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/9322