03838nas a2200829 4500008004100000022001400041245013700055210006900192260001300261300001100274490000600285520145100291653001001742653000901752653002201761653002801783653001901811653004001830653001101870653001501881653001701896653003401913653001101947653000901958653001601967653001301983653003601996653001602032100001902048700001602067700002002083700001702103700001902120700002402139700002002163700002002183700001802203700002202221700002202243700001802265700002002283700002202303700002302325700002202348700001902370700002102389700001902410700002302429700002602452700001802478700002002496700002302516700002202539700001802561700002402579700002102603700002302624700002802647700002402675700002202699700002002721700002102741700002102762700002102783700003002804700002802834700002302862700002302885700002102908710004302929856003602972 2009 eng d a1942-326800aAssociation of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.0 aAssociation of novel genetic Loci with circulating fibrinogen le c2009 Apr a125-330 v23 a
BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.
METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).
CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPedigree10aPolymorphism, Single Nucleotide10aYoung Adult1 aDehghan, Abbas1 aYang, Qiong1 aPeters, Annette1 aBasu, Saonli1 aBis, Joshua, C1 aRudnicka, Alicja, R1 aKavousi, Maryam1 aChen, Ming-Huei1 aBaumert, Jens1 aLowe, Gordon, D O1 aMcKnight, Barbara1 aTang, Weihong1 ade Maat, Moniek1 aLarson, Martin, G1 aEyhermendy, Susana1 aMcArdle, Wendy, L1 aLumley, Thomas1 aPankow, James, S1 aHofman, Albert1 aMassaro, Joseph, M1 aRivadeneira, Fernando1 aKolz, Melanie1 aTaylor, Kent, D1 aDuijn, Cornelia, M1 aKathiresan, Sekar1 aIllig, Thomas1 aAulchenko, Yurii, S1 aVolcik, Kelly, A1 aJohnson, Andrew, D1 aUitterlinden, André, G1 aTofler, Geoffrey, H1 aGieger, Christian1 aPsaty, Bruce, M1 aCouper, David, J1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aO'Donnell, Christopher, J1 aWitteman, Jacqueline, C1 aStrachan, David, P1 aSmith, Nicholas, L1 aFolsom, Aaron, R1 aWellcome Trust Case Control Consortium uhttps://chs-nhlbi.org/node/115305728nas a2201213 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520227000293653001002563653000902573653002202582653001002604653002802614653002102642653004002663653001102703653003402714653001302748653001602761653002102777653001102798653000902809653001602818653001502834653001402849653003602863653001702899653003402916653003102950100002702981700002203008700002103030700001903051700002103070700002203091700002303113700002203136700002303158700001903181700002303200700002003223700002203243700002203265700002203287700001903309700002403328700002003352700001803372700001803390700002303408700002103431700001903452700002603471700002203497700002403519700001803543700002003561700001503581700002703596700002703623700001703650700002303667700002103690700001803711700002103729700001703750700002003767700002003787700002303807700003003830700002303860700002303883700002103906700002503927700002603952700001703978700002203995700001804017700002104035700001904056700002404075700002804099700002204127700002004149700002004169700002004189700002004209700002304229700002204252700002204274700002104296700002404317700002204341700002804363700002404391700002004415700001904435700002404454856003604478 2009 eng d a1538-359800aGenetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.0 aGenetic variants associated with cardiac structure and function c2009 Jul 08 a168-780 v3023 aCONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.
OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.
DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.
MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.
RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).
CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
10aAdult10aAged10aAged, 80 and over10aAorta10aCardiovascular Diseases10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart Atria10aHeart Ventricles10aHumans10aMale10aMiddle Aged10aOrgan Size10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aVentricular Dysfunction, Left10aVentricular Function, Left1 aVasan, Ramachandran, S1 aGlazer, Nicole, L1 aFelix, Janine, F1 aLieb, Wolfgang1 aWild, Philipp, S1 aFelix, Stephan, B1 aWatzinger, Norbert1 aLarson, Martin, G1 aSmith, Nicholas, L1 aDehghan, Abbas1 aGrosshennig, Anika1 aSchillert, Arne1 aTeumer, Alexander1 aSchmidt, Reinhold1 aKathiresan, Sekar1 aLumley, Thomas1 aAulchenko, Yurii, S1 aKönig, Inke, R1 aZeller, Tanja1 aHomuth, Georg1 aStruchalin, Maksim1 aAragam, Jayashri1 aBis, Joshua, C1 aRivadeneira, Fernando1 aErdmann, Jeanette1 aSchnabel, Renate, B1 aDörr, Marcus1 aZweiker, Robert1 aLind, Lars1 aRodeheffer, Richard, J1 aGreiser, Karin, Halina1 aLevy, Daniel1 aHaritunians, Talin1 aDeckers, Jaap, W1 aStritzke, Jan1 aLackner, Karl, J1 aVölker, Uwe1 aIngelsson, Erik1 aKullo, Iftikhar1 aHaerting, Johannes1 aO'Donnell, Christopher, J1 aHeckbert, Susan, R1 aStricker, Bruno, H1 aZiegler, Andreas1 aReffelmann, Thorsten1 aRedfield, Margaret, M1 aWerdan, Karl1 aMitchell, Gary, F1 aRice, Kenneth1 aArnett, Donna, K1 aHofman, Albert1 aGottdiener, John, S1 aUitterlinden, André, G1 aMeitinger, Thomas1 aBlettner, Maria1 aFriedrich, Nele1 aWang, Thomas, J1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aMunzel, Thomas, F1 aKroemer, Heyo, K1 aBenjamin, Emelia, J1 aRotter, Jerome, I1 aWitteman, Jacqueline, C1 aSchunkert, Heribert1 aSchmidt, Helena1 aVölzke, Henry1 aBlankenberg, Stefan uhttps://chs-nhlbi.org/node/110814196nas a2204789 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2010 eng d a1546-171800aAssociation analyses of 249,796 individuals reveal 18 new loci associated with body mass index.0 aAssociation analyses of 249796 individuals reveal 18 new loci as c2010 Nov a937-480 v423 aObesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
10aBody Height10aBody Mass Index10aBody Size10aBody Weight10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aObesity10aPolymorphism, Single Nucleotide1 aSpeliotes, Elizabeth, K1 aWiller, Cristen, J1 aBerndt, Sonja, I1 aMonda, Keri, L1 aThorleifsson, Gudmar1 aJackson, Anne, U1 aAllen, Hana, Lango1 aLindgren, Cecilia, M1 aLuan, Jian'an1 aMägi, Reedik1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWinkler, Thomas, W1 aQi, Lu1 aWorkalemahu, Tsegaselassie1 aHeid, Iris, M1 aSteinthorsdottir, Valgerdur1 aStringham, Heather, M1 aWeedon, Michael, N1 aWheeler, Eleanor1 aWood, Andrew, R1 aFerreira, Teresa1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aEstrada, Karol1 aLiang, Liming1 aNemesh, James1 aPark, Ju-Hyun1 aGustafsson, Stefan1 aKilpeläinen, Tuomas, O1 aYang, Jian1 aBouatia-Naji, Nabila1 aEsko, Tõnu1 aFeitosa, Mary, F1 aKutalik, Zoltán1 aMangino, Massimo1 aRaychaudhuri, Soumya1 aScherag, Andre1 aSmith, Albert, Vernon1 aWelch, Ryan1 aZhao, Jing Hua1 aAben, Katja, K1 aAbsher, Devin, M1 aAmin, Najaf1 aDixon, Anna, L1 aFisher, Eva1 aGlazer, Nicole, L1 aGoddard, Michael, E1 aHeard-Costa, Nancy, L1 aHoesel, Volker1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJohnson, Toby1 aKetkar, Shamika1 aLamina, Claudia1 aLi, Shengxu1 aMoffatt, Miriam, F1 aMyers, Richard, H1 aNarisu, Narisu1 aPerry, John, R B1 aPeters, Marjolein, J1 aPreuss, Michael1 aRipatti, Samuli1 aRivadeneira, Fernando1 aSandholt, Camilla1 aScott, Laura, J1 aTimpson, Nicholas, J1 aTyrer, Jonathan, P1 avan Wingerden, Sophie1 aWatanabe, Richard, M1 aWhite, Charles, C1 aWiklund, Fredrik1 aBarlassina, Christina1 aChasman, Daniel, I1 aCooper, Matthew, N1 aJansson, John-Olov1 aLawrence, Robert, W1 aPellikka, Niina1 aProkopenko, Inga1 aShi, Jianxin1 aThiering, Elisabeth1 aAlavere, Helene1 aAlibrandi, Maria, T S1 aAlmgren, Peter1 aArnold, Alice, M1 aAspelund, Thor1 aAtwood, Larry, D1 aBalkau, Beverley1 aBalmforth, Anthony, J1 aBennett, Amanda, J1 aBen-Shlomo, Yoav1 aBergman, Richard, N1 aBergmann, Sven1 aBiebermann, Heike1 aBlakemore, Alexandra, I F1 aBoes, Tanja1 aBonnycastle, Lori, L1 aBornstein, Stefan, R1 aBrown, Morris, J1 aBuchanan, Thomas, A1 aBusonero, Fabio1 aCampbell, Harry1 aCappuccio, Francesco, P1 aCavalcanti-Proença, Christine1 aChen, Yii-Der Ida1 aChen, Chih-Mei1 aChines, Peter, S1 aClarke, Robert1 aCoin, Lachlan1 aConnell, John1 aDay, Ian, N M1 aHeijer, Martin, den1 aDuan, Jubao1 aEbrahim, Shah1 aElliott, Paul1 aElosua, Roberto1 aEiriksdottir, Gudny1 aErdos, Michael, R1 aEriksson, Johan, G1 aFacheris, Maurizio, F1 aFelix, Stephan, B1 aFischer-Posovszky, Pamela1 aFolsom, Aaron, R1 aFriedrich, Nele1 aFreimer, Nelson, B1 aFu, Mao1 aGaget, Stefan1 aGejman, Pablo, V1 aGeus, Eco, J C1 aGieger, Christian1 aGjesing, Anette, P1 aGoel, Anuj1 aGoyette, Philippe1 aGrallert, Harald1 aGrässler, Jürgen1 aGreenawalt, Danielle, M1 aGroves, Christopher, J1 aGudnason, Vilmundur1 aGuiducci, Candace1 aHartikainen, Anna-Liisa1 aHassanali, Neelam1 aHall, Alistair, S1 aHavulinna, Aki, S1 aHayward, Caroline1 aHeath, Andrew, C1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHinney, Anke1 aHofman, Albert1 aHomuth, Georg1 aHui, Jennie1 aIgl, Wilmar1 aIribarren, Carlos1 aIsomaa, Bo1 aJacobs, Kevin, B1 aJarick, Ivonne1 aJewell, Elizabeth1 aJohn, Ulrich1 aJørgensen, Torben1 aJousilahti, Pekka1 aJula, Antti1 aKaakinen, Marika1 aKajantie, Eero1 aKaplan, Lee, M1 aKathiresan, Sekar1 aKettunen, Johannes1 aKinnunen, Leena1 aKnowles, Joshua, W1 aKolcic, Ivana1 aKönig, Inke, R1 aKoskinen, Seppo1 aKovacs, Peter1 aKuusisto, Johanna1 aKraft, Peter1 aKvaløy, Kirsti1 aLaitinen, Jaana1 aLantieri, Olivier1 aLanzani, Chiara1 aLauner, Lenore, J1 aLecoeur, Cécile1 aLehtimäki, Terho1 aLettre, Guillaume1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aLuben, Robert, N1 aLudwig, Barbara1 aManunta, Paolo1 aMarek, Diana1 aMarre, Michel1 aMartin, Nicholas, G1 aMcArdle, Wendy, L1 aMcCarthy, Anne1 aMcKnight, Barbara1 aMeitinger, Thomas1 aMelander, Olle1 aMeyre, David1 aMidthjell, Kristian1 aMontgomery, Grant, W1 aMorken, Mario, A1 aMorris, Andrew, P1 aMulic, Rosanda1 aNgwa, Julius, S1 aNelis, Mari1 aNeville, Matt, J1 aNyholt, Dale, R1 aO'Donnell, Christopher, J1 aO'Rahilly, Stephen1 aOng, Ken, K1 aOostra, Ben1 aParé, Guillaume1 aParker, Alex, N1 aPerola, Markus1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPlatou, Carl, G P1 aPolasek, Ozren1 aPouta, Anneli1 aRafelt, Suzanne1 aRaitakari, Olli1 aRayner, Nigel, W1 aRidderstråle, Martin1 aRief, Winfried1 aRuokonen, Aimo1 aRobertson, Neil, R1 aRzehak, Peter1 aSalomaa, Veikko1 aSanders, Alan, R1 aSandhu, Manjinder, S1 aSanna, Serena1 aSaramies, Jouko1 aSavolainen, Markku, J1 aScherag, Susann1 aSchipf, Sabine1 aSchreiber, Stefan1 aSchunkert, Heribert1 aSilander, Kaisa1 aSinisalo, Juha1 aSiscovick, David, S1 aSmit, Jan, H1 aSoranzo, Nicole1 aSovio, Ulla1 aStephens, Jonathan1 aSurakka, Ida1 aSwift, Amy, J1 aTammesoo, Mari-Liis1 aTardif, Jean-Claude1 aTeder-Laving, Maris1 aTeslovich, Tanya, M1 aThompson, John, R1 aThomson, Brian1 aTönjes, Anke1 aTuomi, Tiinamaija1 avan Meurs, Joyce, B J1 avan Ommen, Gert-Jan1 aVatin, Vincent1 aViikari, Jorma1 aVisvikis-Siest, Sophie1 aVitart, Veronique1 aVogel, Carla, I G1 aVoight, Benjamin, F1 aWaite, Lindsay, L1 aWallaschofski, Henri1 aWalters, Bragi, G1 aWiden, Elisabeth1 aWiegand, Susanna1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWitte, Daniel, R1 aWitteman, Jacqueline, C1 aXu, Jianfeng1 aZhang, Qunyuan1 aZgaga, Lina1 aZiegler, Andreas1 aZitting, Paavo1 aBeilby, John, P1 aFarooqi, Sadaf1 aHebebrand, Johannes1 aHuikuri, Heikki, V1 aJames, Alan, L1 aKähönen, Mika1 aLevinson, Douglas, F1 aMacciardi, Fabio1 aNieminen, Markku, S1 aOhlsson, Claes1 aPalmer, Lyle, J1 aRidker, Paul, M1 aStumvoll, Michael1 aBeckmann, Jacques, S1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCollins, Francis, S1 aCupples, Adrienne, L1 aSmith, George Davey1 aErdmann, Jeanette1 aFroguel, Philippe1 aGrönberg, Henrik1 aGyllensten, Ulf1 aHall, Per1 aHansen, Torben1 aHarris, Tamara, B1 aHattersley, Andrew, T1 aHayes, Richard, B1 aHeinrich, Joachim1 aHu, Frank, B1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aKaprio, Jaakko1 aKarpe, Fredrik1 aKhaw, Kay-Tee1 aKiemeney, Lambertus, A1 aKrude, Heiko1 aLaakso, Markku1 aLawlor, Debbie, A1 aMetspalu, Andres1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPedersen, Oluf1 aPenninx, Brenda, W1 aPeters, Annette1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aReinehr, Thomas1 aRissanen, Aila1 aRudan, Igor1 aSamani, Nilesh, J1 aSchwarz, Peter, E H1 aShuldiner, Alan, R1 aSpector, Timothy, D1 aTuomilehto, Jaakko1 aUda, Manuela1 aUitterlinden, Andre1 aValle, Timo, T1 aWabitsch, Martin1 aWaeber, Gérard1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWilson, James, F1 aWright, Alan, F1 aZillikens, Carola, M1 aChatterjee, Nilanjan1 aMcCarroll, Steven, A1 aPurcell, Shaun1 aSchadt, Eric, E1 aVisscher, Peter, M1 aAssimes, Themistocles, L1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aGroop, Leif, C1 aHaritunians, Talin1 aHunter, David, J1 aKaplan, Robert, C1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPeltonen, Leena1 aSchlessinger, David1 aStrachan, David, P1 aDuijn, Cornelia, M1 aWichmann, H-Erich1 aFrayling, Timothy, M1 aThorsteinsdottir, Unnur1 aAbecasis, Goncalo, R1 aBarroso, Inês1 aBoehnke, Michael1 aStefansson, Kari1 aNorth, Kari, E1 aMcCarthy, Mark, I1 aHirschhorn, Joel, N1 aIngelsson, Erik1 aLoos, Ruth, J F1 aMAGIC1 aProcardis Consortium uhttps://chs-nhlbi.org/node/123709616nas a2202929 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2010 eng d a1476-468700aBiological, clinical and population relevance of 95 loci for blood lipids.0 aBiological clinical and population relevance of 95 loci for bloo c2010 Aug 05 a707-130 v4663 aPlasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
10aAfrican Americans10aAnimals10aAsian Continental Ancestry Group10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aLipid Metabolism10aLipids10aLiver10aMale10aMice10aN-Acetylgalactosaminyltransferases10aPhenotype10aPolymorphism, Single Nucleotide10aProtein Phosphatase 110aReproducibility of Results10aTriglycerides1 aTeslovich, Tanya, M1 aMusunuru, Kiran1 aSmith, Albert, V1 aEdmondson, Andrew, C1 aStylianou, Ioannis, M1 aKoseki, Masahiro1 aPirruccello, James, P1 aRipatti, Samuli1 aChasman, Daniel, I1 aWiller, Cristen, J1 aJohansen, Christopher, T1 aFouchier, Sigrid, W1 aIsaacs, Aaron1 aPeloso, Gina, M1 aBarbalic, Maja1 aRicketts, Sally, L1 aBis, Joshua, C1 aAulchenko, Yurii, S1 aThorleifsson, Gudmar1 aFeitosa, Mary, F1 aChambers, John1 aOrho-Melander, Marju1 aMelander, Olle1 aJohnson, Toby1 aLi, Xiaohui1 aGuo, Xiuqing1 aLi, Mingyao1 aCho, Yoon, Shin1 aGo, Min, Jin1 aKim, Young, Jin1 aLee, Jong-Young1 aPark, Taesung1 aKim, Kyunga1 aSim, Xueling1 aOng, Rick, Twee-Hee1 aCroteau-Chonka, Damien, C1 aLange, Leslie, A1 aSmith, Joshua, D1 aSong, Kijoung1 aZhao, Jing, Hua1 aYuan, Xin1 aLuan, Jian'an1 aLamina, Claudia1 aZiegler, Andreas1 aZhang, Weihua1 aZee, Robert, Y L1 aWright, Alan, F1 aWitteman, Jacqueline, C M1 aWilson, James, F1 aWillemsen, Gonneke1 aWichmann, H-Erich1 aWhitfield, John, B1 aWaterworth, Dawn, M1 aWareham, Nicholas, J1 aWaeber, Gérard1 aVollenweider, Peter1 aVoight, Benjamin, F1 aVitart, Veronique1 aUitterlinden, André, G1 aUda, Manuela1 aTuomilehto, Jaakko1 aThompson, John, R1 aTanaka, Toshiko1 aSurakka, Ida1 aStringham, Heather, M1 aSpector, Tim, D1 aSoranzo, Nicole1 aSmit, Johannes, H1 aSinisalo, Juha1 aSilander, Kaisa1 aSijbrands, Eric, J G1 aScuteri, Angelo1 aScott, James1 aSchlessinger, David1 aSanna, Serena1 aSalomaa, Veikko1 aSaharinen, Juha1 aSabatti, Chiara1 aRuokonen, Aimo1 aRudan, Igor1 aRose, Lynda, M1 aRoberts, Robert1 aRieder, Mark1 aPsaty, Bruce, M1 aPramstaller, Peter, P1 aPichler, Irene1 aPerola, Markus1 aPenninx, Brenda, W J H1 aPedersen, Nancy, L1 aPattaro, Cristian1 aParker, Alex, N1 aParé, Guillaume1 aOostra, Ben, A1 aO'Donnell, Christopher, J1 aNieminen, Markku, S1 aNickerson, Deborah, A1 aMontgomery, Grant, W1 aMeitinger, Thomas1 aMcPherson, Ruth1 aMcCarthy, Mark, I1 aMcArdle, Wendy1 aMasson, David1 aMartin, Nicholas, G1 aMarroni, Fabio1 aMangino, Massimo1 aMagnusson, Patrik, K E1 aLucas, Gavin1 aLuben, Robert1 aLoos, Ruth, J F1 aLokki, Marja-Liisa1 aLettre, Guillaume1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLakatta, Edward, G1 aLaaksonen, Reijo1 aKyvik, Kirsten, O1 aKronenberg, Florian1 aKönig, Inke, R1 aKhaw, Kay-Tee1 aKaprio, Jaakko1 aKaplan, Lee, M1 aJohansson, Asa1 aJarvelin, Marjo-Riitta1 aJanssens, Cecile, J W1 aIngelsson, Erik1 aIgl, Wilmar1 aHovingh, Kees1 aHottenga, Jouke-Jan1 aHofman, Albert1 aHicks, Andrew, A1 aHengstenberg, Christian1 aHeid, Iris, M1 aHayward, Caroline1 aHavulinna, Aki, S1 aHastie, Nicholas, D1 aHarris, Tamara, B1 aHaritunians, Talin1 aHall, Alistair, S1 aGyllensten, Ulf1 aGuiducci, Candace1 aGroop, Leif, C1 aGonzalez, Elena1 aGieger, Christian1 aFreimer, Nelson, B1 aFerrucci, Luigi1 aErdmann, Jeanette1 aElliott, Paul1 aEjebe, Kenechi, G1 aDöring, Angela1 aDominiczak, Anna, F1 aDemissie, Serkalem1 aDeloukas, Panagiotis1 aGeus, Eco, J C1 ade Faire, Ulf1 aCrawford, Gabriel1 aCollins, Francis, S1 aChen, Yii-der, I1 aCaulfield, Mark, J1 aCampbell, Harry1 aBurtt, Noel, P1 aBonnycastle, Lori, L1 aBoomsma, Dorret, I1 aBoekholdt, Matthijs1 aBergman, Richard, N1 aBarroso, Inês1 aBandinelli, Stefania1 aBallantyne, Christie, M1 aAssimes, Themistocles, L1 aQuertermous, Thomas1 aAltshuler, David1 aSeielstad, Mark1 aWong, Tien, Y1 aTai, E-Shyong1 aFeranil, Alan, B1 aKuzawa, Christopher, W1 aAdair, Linda, S1 aTaylor, Herman, A1 aBorecki, Ingrid, B1 aGabriel, Stacey, B1 aWilson, James, G1 aHolm, Hilma1 aThorsteinsdottir, Unnur1 aGudnason, Vilmundur1 aKrauss, Ronald, M1 aMohlke, Karen, L1 aOrdovas, Jose, M1 aMunroe, Patricia, B1 aKooner, Jaspal, S1 aTall, Alan, R1 aHegele, Robert, A1 aKastelein, John, J P1 aSchadt, Eric, E1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aStrachan, David, P1 aMooser, Vincent1 aStefansson, Kari1 aReilly, Muredach, P1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRidker, Paul, M1 aRader, Daniel, J1 aDuijn, Cornelia, M1 aPeltonen, Leena1 aAbecasis, Goncalo, R1 aBoehnke, Michael1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/122104142nas a2200757 4500008004100000022001400041245008700055210006900142260001300211300001100224490000600235520194100241653002202182653002102204653002102225653001902246653002302265653004002288653003202328653001302360653001102373653001402384653001902398653003602417653002002453653001802473100002002491700002202511700001802533700002302551700002602574700002202600700002402622700001602646700002002662700001802682700002102700700001902721700002202740700002402762700002502786700002002811700001802831700002302849700002402872700002902896700002302925700002002948700002802968700002102996700002003017700002103037700001903058700002103077700002203098700002203120700002203142700002703164700002103191700002203212700002403234700002103258700002303279710004603302856003603348 2010 eng d a1942-326800aCandidate gene association resource (CARe): design, methods, and proof of concept.0 aCandidate gene association resource CARe design methods and proo c2010 Jun a267-750 v33 aBACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.
METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.
CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.
10aAfrican Americans10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenotype10aHumans10aPhenotype10aPilot Projects10aPolymorphism, Single Nucleotide10aResearch Design10aTriglycerides1 aMusunuru, Kiran1 aLettre, Guillaume1 aYoung, Taylor1 aFarlow, Deborah, N1 aPirruccello, James, P1 aEjebe, Kenechi, G1 aKeating, Brendan, J1 aYang, Qiong1 aChen, Ming-Huei1 aLapchyk, Nina1 aCrenshaw, Andrew1 aZiaugra, Liuda1 aRachupka, Anthony1 aBenjamin, Emelia, J1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, R1 aHeckbert, Susan, R1 aHirschhorn, Joel, N1 aNewton-Cheh, Christopher1 aNizzari, Marcia, M1 aPaltoo, Dina, N1 aPapanicolaou, George, J1 aPatel, Sanjay, R1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aTaylor, Herman, A1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aWilson, James, G1 aKathiresan, Sekar1 aFabsitz, Richard, R1 aBoerwinkle, Eric1 aGabriel, Stacey, B1 aNHLBI Candidate Gene Association Resource uhttps://chs-nhlbi.org/node/118812698nas a2203781 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2010 eng d a1476-468700aHundreds of variants clustered in genomic loci and biological pathways affect human height.0 aHundreds of variants clustered in genomic loci and biological pa c2010 Oct 14 a832-80 v4673 aMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
10aBody Height10aChromosomes, Human, Pair 310aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aMetabolic Networks and Pathways10aMultifactorial Inheritance10aPhenotype10aPolymorphism, Single Nucleotide1 aAllen, Hana, Lango1 aEstrada, Karol1 aLettre, Guillaume1 aBerndt, Sonja, I1 aWeedon, Michael, N1 aRivadeneira, Fernando1 aWiller, Cristen, J1 aJackson, Anne, U1 aVedantam, Sailaja1 aRaychaudhuri, Soumya1 aFerreira, Teresa1 aWood, Andrew, R1 aWeyant, Robert, J1 aSegrè, Ayellet, V1 aSpeliotes, Elizabeth, K1 aWheeler, Eleanor1 aSoranzo, Nicole1 aPark, Ju-Hyun1 aYang, Jian1 aGudbjartsson, Daniel1 aHeard-Costa, Nancy, L1 aRandall, Joshua, C1 aQi, Lu1 aSmith, Albert, Vernon1 aMägi, Reedik1 aPastinen, Tomi1 aLiang, Liming1 aHeid, Iris, M1 aLuan, Jian'an1 aThorleifsson, Gudmar1 aWinkler, Thomas, W1 aGoddard, Michael, E1 aLo, Ken, Sin1 aPalmer, Cameron1 aWorkalemahu, Tsegaselassie1 aAulchenko, Yurii, S1 aJohansson, Asa1 aZillikens, Carola, M1 aFeitosa, Mary, F1 aEsko, Tõnu1 aJohnson, Toby1 aKetkar, Shamika1 aKraft, Peter1 aMangino, Massimo1 aProkopenko, Inga1 aAbsher, Devin1 aAlbrecht, Eva1 aErnst, Florian1 aGlazer, Nicole, L1 aHayward, Caroline1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aKnowles, Joshua, W1 aKutalik, Zoltán1 aMonda, Keri, L1 aPolasek, Ozren1 aPreuss, Michael1 aRayner, Nigel, W1 aRobertson, Neil, R1 aSteinthorsdottir, Valgerdur1 aTyrer, Jonathan, P1 aVoight, Benjamin, F1 aWiklund, Fredrik1 aXu, Jianfeng1 aZhao, Jing Hua1 aNyholt, Dale, R1 aPellikka, Niina1 aPerola, Markus1 aPerry, John, R B1 aSurakka, Ida1 aTammesoo, Mari-Liis1 aAltmaier, Elizabeth, L1 aAmin, Najaf1 aAspelund, Thor1 aBhangale, Tushar1 aBoucher, Gabrielle1 aChasman, Daniel, I1 aChen, Constance1 aCoin, Lachlan1 aCooper, Matthew, N1 aDixon, Anna, L1 aGibson, Quince1 aGrundberg, Elin1 aHao, Ke1 aJunttila, Juhani1 aKaplan, Lee, M1 aKettunen, Johannes1 aKönig, Inke, R1 aKwan, Tony1 aLawrence, Robert, W1 aLevinson, Douglas, F1 aLorentzon, Mattias1 aMcKnight, Barbara1 aMorris, Andrew, P1 aMüller, Martina1 aNgwa, Julius, Suh1 aPurcell, Shaun1 aRafelt, Suzanne1 aSalem, Rany, M1 aSalvi, Erika1 aSanna, Serena1 aShi, Jianxin1 aSovio, Ulla1 aThompson, John, R1 aTurchin, Michael, C1 aVandenput, Liesbeth1 aVerlaan, Dominique, J1 aVitart, Veronique1 aWhite, Charles, C1 aZiegler, Andreas1 aAlmgren, Peter1 aBalmforth, Anthony, J1 aCampbell, Harry1 aCitterio, Lorena1 aDe Grandi, Alessandro1 aDominiczak, Anna1 aDuan, Jubao1 aElliott, Paul1 aElosua, Roberto1 aEriksson, Johan, G1 aFreimer, Nelson, B1 aGeus, Eco, J C1 aGlorioso, Nicola1 aHaiqing, Shen1 aHartikainen, Anna-Liisa1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHui, Jennie1 aIgl, Wilmar1 aIllig, Thomas1 aJula, Antti1 aKajantie, Eero1 aKilpeläinen, Tuomas, O1 aKoiranen, Markku1 aKolcic, Ivana1 aKoskinen, Seppo1 aKovacs, Peter1 aLaitinen, Jaana1 aLiu, Jianjun1 aLokki, Marja-Liisa1 aMarusic, Ana1 aMaschio, Andrea1 aMeitinger, Thomas1 aMulas, Antonella1 aParé, Guillaume1 aParker, Alex, N1 aPeden, John, F1 aPetersmann, Astrid1 aPichler, Irene1 aPietiläinen, Kirsi, H1 aPouta, Anneli1 aRidderstråle, Martin1 aRotter, Jerome, I1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSchmidt, Carsten, Oliver1 aSinisalo, Juha1 aSmit, Jan, H1 aStringham, Heather, M1 aWalters, Bragi1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aZagato, Laura1 aZgaga, Lina1 aZitting, Paavo1 aAlavere, Helene1 aFarrall, Martin1 aMcArdle, Wendy, L1 aNelis, Mari1 aPeters, Marjolein, J1 aRipatti, Samuli1 avan Meurs, Joyce, B J1 aAben, Katja, K1 aArdlie, Kristin, G1 aBeckmann, Jacques, S1 aBeilby, John, P1 aBergman, Richard, N1 aBergmann, Sven1 aCollins, Francis, S1 aCusi, Daniele1 aHeijer, Martin, den1 aEiriksdottir, Gudny1 aGejman, Pablo, V1 aHall, Alistair, S1 aHamsten, Anders1 aHuikuri, Heikki, V1 aIribarren, Carlos1 aKähönen, Mika1 aKaprio, Jaakko1 aKathiresan, Sekar1 aKiemeney, Lambertus1 aKocher, Thomas1 aLauner, Lenore, J1 aLehtimäki, Terho1 aMelander, Olle1 aMosley, Tom, H1 aMusk, Arthur, W1 aNieminen, Markku, S1 aO'Donnell, Christopher, J1 aOhlsson, Claes1 aOostra, Ben1 aPalmer, Lyle, J1 aRaitakari, Olli1 aRidker, Paul, M1 aRioux, John, D1 aRissanen, Aila1 aRivolta, Carlo1 aSchunkert, Heribert1 aShuldiner, Alan, R1 aSiscovick, David, S1 aStumvoll, Michael1 aTönjes, Anke1 aTuomilehto, Jaakko1 avan Ommen, Gert-Jan1 aViikari, Jorma1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aProvince, Michael, A1 aKayser, Manfred1 aArnold, Alice, M1 aAtwood, Larry, D1 aBoerwinkle, Eric1 aChanock, Stephen, J1 aDeloukas, Panos1 aGieger, Christian1 aGrönberg, Henrik1 aHall, Per1 aHattersley, Andrew, T1 aHengstenberg, Christian1 aHoffman, Wolfgang1 aLathrop, Mark, G1 aSalomaa, Veikko1 aSchreiber, Stefan1 aUda, Manuela1 aWaterworth, Dawn1 aWright, Alan, F1 aAssimes, Themistocles, L1 aBarroso, Inês1 aHofman, Albert1 aMohlke, Karen, L1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aCupples, Adrienne, L1 aErdmann, Jeanette1 aFox, Caroline, S1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHarris, Tamara, B1 aHayes, Richard, B1 aJarvelin, Marjo-Riitta1 aMooser, Vincent1 aMunroe, Patricia, B1 aOuwehand, Willem, H1 aPenninx, Brenda, W1 aPramstaller, Peter, P1 aQuertermous, Thomas1 aRudan, Igor1 aSamani, Nilesh, J1 aSpector, Timothy, D1 aVölzke, Henry1 aWatkins, Hugh1 aWilson, James, F1 aGroop, Leif, C1 aHaritunians, Talin1 aHu, Frank, B1 aKaplan, Robert, C1 aMetspalu, Andres1 aNorth, Kari, E1 aSchlessinger, David1 aWareham, Nicholas, J1 aHunter, David, J1 aO'Connell, Jeffrey, R1 aStrachan, David, P1 aWichmann, H-Erich1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aSchadt, Eric, E1 aThorsteinsdottir, Unnur1 aPeltonen, Leena1 aUitterlinden, André, G1 aVisscher, Peter, M1 aChatterjee, Nilanjan1 aLoos, Ruth, J F1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aIngelsson, Erik1 aLindgren, Cecilia, M1 aAbecasis, Goncalo, R1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N uhttps://chs-nhlbi.org/node/123404638nas a2200901 4500008004100000022001400041245020700055210006900262260001600331300001200347490000800359520199800367653001002365653001502375653001602390653001102406653003402417653001502451653001102466653000902477653001602486653001402502653003602516653001502552653002602567100002302593700002002616700001902636700002302655700001702678700002002695700002202715700001602737700002502753700001902778700002502797700001602822700001902838700001602857700002702873700002202900700002002922700002302942700002202965700002302987700002203010700002103032700002303053700002103076700002203097700002803119700001803147700002003165700002003185700002103205700001803226700002203244700002203266700002103288700001903309700002103328700002403349700001903373700002003392700001903412700002103431700002203452700002403474700002003498700002103518700002003539700001903559700003003578700001803608700003003626710004403656856003603700 2010 eng d a1524-453900aNovel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.0 aNovel associations of multiple genetic loci with plasma levels o c2010 Mar 30 a1382-920 v1213 aBACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.
METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.
CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.
10aAdult10aFactor VII10aFactor VIII10aFemale10aGenome-Wide Association Study10aHemostasis10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aThrombosis10avon Willebrand Factor1 aSmith, Nicholas, L1 aChen, Ming-Huei1 aDehghan, Abbas1 aStrachan, David, P1 aBasu, Saonli1 aSoranzo, Nicole1 aHayward, Caroline1 aRudan, Igor1 aSabater-Lleal, Maria1 aBis, Joshua, C1 ade Maat, Moniek, P M1 aRumley, Ann1 aKong, Xiaoxiao1 aYang, Qiong1 aWilliams, Frances, M K1 aVitart, Veronique1 aCampbell, Harry1 aMälarstig, Anders1 aWiggins, Kerri, L1 aDuijn, Cornelia, M1 aMcArdle, Wendy, L1 aPankow, James, S1 aJohnson, Andrew, D1 aSilveira, Angela1 aMcKnight, Barbara1 aUitterlinden, André, G1 aAleksic, Nena1 aMeigs, James, B1 aPeters, Annette1 aKoenig, Wolfgang1 aCushman, Mary1 aKathiresan, Sekar1 aRotter, Jerome, I1 aBovill, Edwin, G1 aHofman, Albert1 aBoerwinkle, Eric1 aTofler, Geoffrey, H1 aPeden, John, F1 aPsaty, Bruce, M1 aLeebeek, Frank1 aFolsom, Aaron, R1 aLarson, Martin, G1 aSpector, Timothy, D1 aWright, Alan, F1 aWilson, James, F1 aHamsten, Anders1 aLumley, Thomas1 aWitteman, Jacqueline, C M1 aTang, Weihong1 aO'Donnell, Christopher, J1 aWellcome Trust Case Control Consortium; uhttps://chs-nhlbi.org/node/117613785nas a2204513 4500008004100000022001400041245009700055210006900152260001600221300001000237490000800247520127300255653001101528653000901539653001901548653002801567653002801595653001101623653003801634653003401672653001101706653001701717653002001734653003601754653001101790110008001801700002001881700002401901700002101925700002101946700002301967700002301990700002102013700002102034700002602055700002002081700001702101700002402118700002202142700001602164700003102180700002202211700002202233700001902255700001902274700002102293700001702314700001702331700001802348700001802366700001802384700001902402700001602421700001702437700002102454700002102475700001902496700002002515700001902535700001602554700001602570700002102586700002002607700002002627700002202647700001802669700001802687700001602705700001502721700002402736700002202760700001502782700002202797700002102819700002202840700002202862700001702884700001402901700002202915700001902937700002002956700001702976700002902993700002203022700002203044700001303066700001803079700003103097700002303128700002203151700001403173700001903187700002003206700001803226700002203244700002103266700002403287700002703311700002303338700001903361700002003380700002003400700002403420700002103444700002603465700001903491700002003510700002203530700002603552700002403578700002603602700001903628700002203647700002403669700002003693700001803713700002203731700001803753700002103771700002103792700002403813700001803837700002203855700002003877700002403897700001903921700002303940700001703963700002503980700001304005700002104018700001904039700002004058700001904078700002004097700002004117700002004137700002004157700002204177700003004199700001904229700001904248700002004267700002104287700002504308700002004333700002104353700002204374700002304396700002504419700002304444700001604467700002404483700002304507700001904530700001904549700002404568700002004592700002004612700001804632700001904650700001804669700001904687700002004706700001604726700002404742700002404766700002504790700002004815700002604835700002004861700001904881700002204900700002504922700002104947700002004968700002004988700002605008700001705034700002005051700001905071700001705090700002005107700002105127700002305148700002305171700002205194700001805216700002005234700001905254700002105273700001805294700002605312700002005338700002305358700002205381700001905403700002205422700002205444700002405466700001705490700002305507700001805530700001805548700002005566700002005586700002205606700002205628700002305650700002105673700002405694700002205718700002205740700001905762700001905781700002005800700001705820700002005837700001805857700001605875700001905891700002405910700001705934700001905951700002505970700002205995700001306017700002206030700003006052700002506082700002006107700002006127700002206147700002006169700002206189700002006211700002106231700001806252700002006270700002106290700001906311700002206330700002406352700001706376700001806393700001506411700002006426700001806446700002506464700001906489700002606508700001906534700002806553700001906581700003306600700001906633700001906652700001806671700002606689700002306715700001706738700002006755700002206775700002106797700002806818700001906846700002006865700001806885700002306903700001806926700002106944700001706965700001906982700001707001700002007018700001807038700002007056700002007076700002107096700002007117700001807137700002207155700002207177700001907199700001807218700002407236700002107260700003107281700002607312700002407338700002207362700002407384700002207408700001707430700002007447700002107467700001507488700002207503700001907525700002407544700002007568700001507588700001607603700002007619700002007639700002207659700001907681700002107700700001807721700002007739700002207759700001807781700001907799700002307818700001907841700002007860700002207880700002307902700002407925700001907949700002307968700001807991700002108009700002408030700001808054700001808072700002008090700001808110700001808128700002208146700001908168700002008187700002508207700002308232700002008255700002108275700002008296700002008316700002308336700002608359700002008385700002008405700002508425700002108450700002008471700002308491700002208514700002008536700002808556700002508584700002408609700002208633700001908655700001708674700002308691700003008714700002808744700002508772700002108797700002708818700002108845700002208866700002708888700002008915700002508935700002608960700001808986700002309004700002909027700001709056700002309073700001809096710002609114710002209140710002509162710002309187710002509210856003609235 2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium uhttps://chs-nhlbi.org/node/132505459nas a2201501 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2011 eng d a1546-171800aMeta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.0 aMetaanalysis of genomewide association studies from the CHARGE c c2011 Sep 11 a940-70 v433 aCarotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
10aAdult10aAged10aAging10aAtherosclerosis10aCarotid Intima-Media Thickness10aCohort Studies10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMiddle Aged10aPhenotype10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aRisk Factors1 aBis, Joshua, C1 aKavousi, Maryam1 aFranceschini, Nora1 aIsaacs, Aaron1 aAbecasis, Goncalo, R1 aSchminke, Ulf1 aPost, Wendy, S1 aSmith, Albert, V1 aCupples, Adrienne, L1 aMarkus, Hugh, S1 aSchmidt, Reinhold1 aHuffman, Jennifer, E1 aLehtimäki, Terho1 aBaumert, Jens1 aMünzel, Thomas1 aHeckbert, Susan, R1 aDehghan, Abbas1 aNorth, Kari1 aOostra, Ben1 aBevan, Steve1 aStoegerer, Eva-Maria1 aHayward, Caroline1 aRaitakari, Olli1 aMeisinger, Christa1 aSchillert, Arne1 aSanna, Serena1 aVölzke, Henry1 aCheng, Yu-Ching1 aThorsson, Bolli1 aFox, Caroline, S1 aRice, Kenneth1 aRivadeneira, Fernando1 aNambi, Vijay1 aHalperin, Eran1 aPetrovic, Katja, E1 aPeltonen, Leena1 aWichmann, Erich, H1 aSchnabel, Renate, B1 aDörr, Marcus1 aParsa, Afshin1 aAspelund, Thor1 aDemissie, Serkalem1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTaylor, Kent1 aUitterlinden, Andre1 aCouper, David, J1 aSitzer, Matthias1 aKähönen, Mika1 aIllig, Thomas1 aWild, Philipp, S1 aOrrù, Marco1 aLüdemann, Jan1 aShuldiner, Alan, R1 aEiriksdottir, Gudny1 aWhite, Charles, C1 aRotter, Jerome, I1 aHofman, Albert1 aSeissler, Jochen1 aZeller, Tanja1 aUsala, Gianluca1 aErnst, Florian1 aLauner, Lenore, J1 aD'Agostino, Ralph, B1 aO'Leary, Daniel, H1 aBallantyne, Christie1 aThiery, Joachim1 aZiegler, Andreas1 aLakatta, Edward, G1 aChilukoti, Ravi, Kumar1 aHarris, Tamara, B1 aWolf, Philip, A1 aPsaty, Bruce, M1 aPolak, Joseph, F1 aLi, Xia1 aRathmann, Wolfgang1 aUda, Manuela1 aBoerwinkle, Eric1 aKlopp, Norman1 aSchmidt, Helena1 aWilson, James, F1 aViikari, Jorma1 aKoenig, Wolfgang1 aBlankenberg, Stefan1 aNewman, Anne, B1 aWitteman, Jacqueline1 aHeiss, Gerardo1 avan Duijn, Cornelia1 aScuteri, Angelo1 aHomuth, Georg1 aMitchell, Braxton, D1 aGudnason, Vilmundur1 aO'Donnell, Christopher, J1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/132308598nas a2202365 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520193500238653005002173653001602223653002002239653002602259653001102285653002202296653003402318653001102352653000902363653002602372653001402398653003602412653001302448653002302461100001502484700002002499700002202519700002202541700002802563700002302591700001902614700002502633700003202658700001802690700001902708700002602727700003102753700001902784700001802803700002002821700001202841700001702853700002202870700002502892700002002917700002002937700001602957700002002973700001902993700001903012700001803031700002103049700001803070700002603088700001903114700002103133700002003154700002103174700001903195700002103214700002003235700001903255700003503274700002403309700002103333700001803354700001503372700002803387700001903415700003403434700001803468700001803486700002003504700002203524700002103546700002103567700002503588700002903613700002303642700001603665700002003681700002203701700001403723700002303737700001603760700001803776700001903794700002203813700001903835700002103854700002203875700002203897700002003919700002103939700002303960700002003983700002004003700001804023700002104041700002304062700002404085700001904109700001804128700002704146700001804173700001704191700002204208700001904230700001904249700002404268700002604292700002104318700001704339700002004356700001904376700002004395700002004415700002004435700002504455700002004480700002404500700002204524700002004546700001604566700001904582700002104601700001904622700002304641700002304664700002504687700002504712700002404737700002304761700002504784700002104809700002104830700002104851700002404872700002104896700002204917700002404939700002804963700001704991700002305008700001905031700001805050700002105068700003005089700002605119700002205145700002405167700002005191700002705211700001905238700002305257700002005280700002105300700002005321700002405341700001505365700002005380700001805400700001905418700002805437700002505465700002805490700002605518700002505544700002705569700002305596700002505619700002405644700001905668700002205687700001805709700002005727700001905747700002205766700002205788700002105810700002105831700002405852700002005876700002505896700002405921700002205945700002305967700002105990700002006011700002006031700002806051700002106079700002506100700002406125700002406149700002306173856003606196 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, Hugh1 aSpector, Timothy, D1 aBecker, Lewis, C1 aTracy, Russell, P1 aMärz, Winfried1 aUitterlinden, André, G1 aEriksson, Per1 aCambien, Francois1 aMorange, Pierre-Emmanuel1 aKoenig, Wolfgang1 aSoranzo, Nicole1 aHarst, Pim1 aLiu, Yongmei1 aO'Donnell, Christopher, J1 aHamsten, Anders1 aDIAGRAM Consortium1 aCARDIoGRAM consortium1 aC4D Consortium1 aCardiogenics consortium uhttps://chs-nhlbi.org/node/608904917nas a2201453 4500008004100000022001400041245008200055210006900137260001600206300001000222490000700232520088500239653001501124653001001139653000901149653002201158653003701180653002401217653001001241653002101251653004001272653001101312653001701323653003801340653003401378653001101412653001101423653002001434653000901454653001601463653003601479653001701515653001601532100002401548700002401572700002501596700002201621700002401643700002101667700001901688700003001707700002201737700002201759700001901781700001901800700001801819700001901837700002201856700001801878700001801896700002201914700001701936700002001953700002301973700002301996700002202019700002102041700002602062700002202088700001702110700002202127700002202149700002302171700002202194700002202216700002302238700002202261700001902283700001702302700001902319700002002338700001902358700002102377700001702398700002402415700002402439700001202463700002602475700001902501700002002520700001902540700002002559700001702579700002302596700002302619700002202642700001402664700002202678700001702700700002102717700001802738700001902756700002002775700002102795700002102816700002002837700002202857700002002879700002202899700003002921700002002951700002202971700001802993700002803011700002603039700002203065700002203087700002003109700001703129700002303146700001903169700002203188700002603210700002203236700001903258700001903277700001803296700002303314700002303337700002403360700002403384700001903408856003603427 2012 eng d a1546-171800aMeta-analysis identifies six new susceptibility loci for atrial fibrillation.0 aMetaanalysis identifies six new susceptibility loci for atrial f c2012 Apr 29 a670-50 v443 aAtrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChild10aChild, Preschool10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aAlbert, Christine, M1 aGlazer, Nicole, L1 aRitchie, Marylyn, D1 aSmith, Albert, V1 aArking, Dan, E1 aMüller-Nurasyid, Martina1 aKrijthe, Bouwe, P1 aLubitz, Steven, A1 aBis, Joshua, C1 aChung, Mina, K1 aDörr, Marcus1 aOzaki, Kouichi1 aRoberts, Jason, D1 aSmith, Gustav1 aPfeufer, Arne1 aSinner, Moritz, F1 aLohman, Kurt1 aDing, Jingzhong1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aRienstra, Michiel1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aMagnani, Jared, W1 aWakili, Reza1 aClauss, Sebastian1 aRotter, Jerome, I1 aSteinbeck, Gerhard1 aLauner, Lenore, J1 aDavies, Robert, W1 aBorkovich, Matthew1 aHarris, Tamara, B1 aLin, Honghuang1 aVölker, Uwe1 aVölzke, Henry1 aMilan, David, J1 aHofman, Albert1 aBoerwinkle, Eric1 aChen, Lin, Y1 aSoliman, Elsayed, Z1 aVoight, Benjamin, F1 aLi, Guo1 aChakravarti, Aravinda1 aKubo, Michiaki1 aTedrow, Usha, B1 aRose, Lynda, M1 aRidker, Paul, M1 aConen, David1 aTsunoda, Tatsuhiko1 aFurukawa, Tetsushi1 aSotoodehnia, Nona1 aXu, Siyan1 aKamatani, Naoyuki1 aLevy, Daniel1 aNakamura, Yusuke1 aParvez, Babar1 aMahida, Saagar1 aFurie, Karen, L1 aRosand, Jonathan1 aMuhammad, Raafia1 aPsaty, Bruce, M1 aMeitinger, Thomas1 aPerz, Siegfried1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aKao, Linda, W H1 aKathiresan, Sekar1 aRoden, Dan, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aMcKnight, Barbara1 aSjögren, Marketa1 aNewman, Anne, B1 aLiu, Yongmei1 aGollob, Michael, H1 aMelander, Olle1 aTanaka, Toshihiro1 aStricker, Bruno, H Ch1 aFelix, Stephan, B1 aAlonso, Alvaro1 aDarbar, Dawood1 aBarnard, John1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aKääb, Stefan uhttps://chs-nhlbi.org/node/138303041nas a2200541 4500008004100000022001400041245007600055210006900131260000900200300001100209490000600220520147100226653002201697653002101719653002101740653004001761653003201801653001701833653001101850653003601861653001801897100002001915700002401935700002201959700002101981700002102002700002102023700002202044700002502066700002202091700002102113700001902134700002002153700002802173700002102201700001502222700002202237700002202259700002302281700002002304700002502324700002202349700002102371700002802392700002202420700002102442856003602463 2012 eng d a1932-620300aMulti-ethnic analysis of lipid-associated loci: the NHLBI CARe project.0 aMultiethnic analysis of lipidassociated loci the NHLBI CARe proj c2012 ae364730 v73 aBACKGROUND: Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.
METHODOLOGY/PRINCIPAL FINDINGS: We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed.
CONCLUSIONS/SIGNIFICANCE: We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.
10aAfrican Americans10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenetic Loci10aHumans10aPolymorphism, Single Nucleotide10aTriglycerides1 aMusunuru, Kiran1 aRomaine, Simon, P R1 aLettre, Guillaume1 aWilson, James, G1 aVolcik, Kelly, A1 aTsai, Michael, Y1 aTaylor, Herman, A1 aSchreiner, Pamela, J1 aRotter, Jerome, I1 aRich, Stephen, S1 aRedline, Susan1 aPsaty, Bruce, M1 aPapanicolaou, George, J1 aOrdovas, Jose, M1 aLiu, Kiang1 aKrauss, Ronald, M1 aGlazer, Nicole, L1 aGabriel, Stacey, B1 aFornage, Myriam1 aCupples, Adrienne, L1 aBuxbaum, Sarah, G1 aBoerwinkle, Eric1 aBallantyne, Christie, M1 aKathiresan, Sekar1 aRader, Daniel, J uhttps://chs-nhlbi.org/node/138821848nas a2207177 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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/137803504nas a2200505 4500008004100000022001400041245021500055210006900270260001300339300000900352490000600361520189100367653003902258653002002297653004002317653001102357653003402368653001102402653000902413653001602422653003502438653003602473653002402509653003002533653001702563653001502580100001302595700001902608700002002627700001702647700002202664700001802686700002202704700002202726700003002748700003002778700002202808700001402830700002302844700002802867700002002895700002102915710002602936856003602962 2013 eng d a1942-326800aAssociation of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies.0 aAssociation of genomewide variation with highly sensitive cardia c2013 Feb a82-80 v63 aBACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.
METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).
CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.
10aAfrican Continental Ancestry Group10aAtherosclerosis10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNuclear Receptor Coactivator 210aPolymorphism, Single Nucleotide10aProspective Studies10aResidence Characteristics10aRisk Factors10aTroponin T1 aYu, Bing1 aBarbalic, Maja1 aBrautbar, Ariel1 aNambi, Vijay1 aHoogeveen, Ron, C1 aTang, Weihong1 aMosley, Thomas, H1 aRotter, Jerome, I1 adeFilippi, Christopher, R1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aRice, Ken1 aHeckbert, Susan, R1 aBallantyne, Christie, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/585703560nas a2200709 4500008004100000022001400041245008800055210006900143260000900212300001100221490000600232520160600238653001001844653001201854653002101866653001901887653003401906653001001940653001101950653001901961653001301980653001301993653001002006653001102016653000902027653004402036653003602080653001602116653001602132653002702148100002002175700001302195700002402208700002302232700001902255700002002274700001702294700002302311700002502334700002002359700002402379700002202403700002202425700001902447700002202466700001702488700001702505700001902522700002002541700002002561700002102581700002602602700002402628700002102652700002402673700002302697700002102720700003002741700002202771700002102793856003602814 2013 eng d a1932-620300aBest practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium.0 aBest practices and joint calling of the HumanExome BeadChip the c2013 ae680950 v83 aGenotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.
10aAging10aAlleles10aCluster Analysis10aCohort Studies10aContinental Population Groups10aExome10aFemale10aGene Frequency10aGenomics10aGenotype10aHeart10aHumans10aMale10aOligonucleotide Array Sequence Analysis10aPolymorphism, Single Nucleotide10aSample Size10aSelf Report10aSequence Analysis, DNA1 aGrove, Megan, L1 aYu, Bing1 aCochran, Barbara, J1 aHaritunians, Talin1 aBis, Joshua, C1 aTaylor, Kent, D1 aHansen, Mark1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aFornage, Myriam1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aKathiresan, Sekar1 aKraaij, Robert1 aLauner, Lenore, J1 aLevy, Daniel1 aLiu, Yongmei1 aMosley, Thomas1 aPeloso, Gina, M1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRivadeneira, Fernando1 aSiscovick, David, S1 aSmith, Albert, V1 aUitterlinden, Andre1 aDuijn, Cornelia, M1 aWilson, James, G1 aO'Donnell, Christopher, J1 aRotter, Jerome, I1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/606704481nas 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/628410597nas a2203385 4500008004100000022001400041245009500055210006900150260001300219300001200232490000700244520112400251653002501375653002101400653002101421653002801442653001101470653003601481653001701517653001801534100001201552700002301564700002201587700002201609700001301631700002001644700002301664700002201687700001801709700001401727700002601741700001601767700002501783700003101808700002001839700001901859700002601878700002401904700002001928700001601948700002101964700002101985700002002006700002402026700002002050700002302070700002202093700002102115700002102136700001802157700002102175700001902196700001802215700002102233700002302254700002202277700001602299700001802315700002802333700002702361700002102388700002102409700002202430700003002452700001902482700002602501700002302527700001902550700002602569700001802595700001802613700002202631700001602653700002002669700001802689700001302707700002502720700001702745700002002762700002402782700002502806700002802831700002402859700002102883700002202904700001702926700001302943700001802956700001802974700001902992700001903011700002103030700002403051700002503075700002103100700002103121700002203142700002103164700002103185700002003206700001803226700002403244700003203268700001903300700002203319700002103341700002303362700002703385700002103412700002803433700002203461700002003483700002103503700001603524700001703540700001803557700002303575700002203598700002503620700001803645700001403663700001803677700002203695700001803717700002403735700002203759700001703781700002203798700002003820700002003840700002203860700002303882700002503905700002303930700002203953700001903975700002503994700002404019700002304043700001604066700001904082700002504101700002204126700001804148700002104166700002404187700002004211700002604231700001604257700001904273700001904292700002204311700001804333700002004351700002504371700002304396700001804419700002004437700002804457700002004485700002204505700002504527700002004552700001904572700002304591700001904614700002104633700002404654700001904678700002004697700002404717700002904741700002504770700002204795700002104817700002304838700002304861700002304884700002504907700001804932700002004950700002004970700002604990700002205016700002205038700002405060700002305084700001705107700002205124700001805146700002105164700002005185700002005205700002305225700002205248700001905270700002405289700002005313700002005333700002205353700002105375700002405396700001905420700001805439700002405457700002405481700002005505700002005525700002205545700002705567700001605594700002005610700001905630700002305649700001905672700002205691700002405713700002205737700001505759700002205774700002205796700001905818700001905837700001505856700002505871700002405896700002005920700002205940700002305962700002005985700002106005700002006026700002206046700002406068700002106092700002306113700001706136700002606153700002106179700002006200700002406220700002106244700002106265700002006286700002706306700002006333700002406353700002106377700002306398700002106421700002006442700002106462700002306483700002206506700001906528700002306547700002006570700002306590700002406613700002006637700002506657700002306682700003006705700002106735700002106756700002106777700002306798700002806821700002306849700002206872700002006894700002006914700002506934700002506959700002106984700002107005700002007026700002107046700002007067700002507087700001807112700002307130700002207153856003607175 2013 eng d a1546-171800aCommon variants associated with plasma triglycerides and risk for coronary artery disease.0 aCommon variants associated with plasma triglycerides and risk fo c2013 Nov a1345-520 v453 aTriglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
10aBiological Transport10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors10aTriglycerides1 aDo, Ron1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aGao, Chi1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 aKesäniemi, Antero1 aKivimaki, Mika1 aKooner, Jaspal, S1 aKoudstaal, Peter, J1 aKrauss, Ronald, M1 aKuh, Diana1 aKuusisto, Johanna1 aKyvik, Kirsten, O1 aLaakso, Markku1 aLakka, Timo, A1 aLind, Lars1 aLindgren, Cecilia, M1 aMartin, Nicholas, G1 aMärz, Winfried1 aMcCarthy, Mark, I1 aMcKenzie, Colin, A1 aMeneton, Pierre1 aMetspalu, Andres1 aMoilanen, Leena1 aMorris, Andrew, D1 aMunroe, Patricia, B1 aNjølstad, Inger1 aPedersen, Nancy, L1 aPower, Chris1 aPramstaller, Peter, P1 aPrice, Jackie, F1 aPsaty, Bruce, M1 aQuertermous, Thomas1 aRauramaa, Rainer1 aSaleheen, Danish1 aSalomaa, Veikko1 aSanghera, Dharambir, K1 aSaramies, Jouko1 aSchwarz, Peter, E H1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aSiegbahn, Agneta1 aSpector, Tim, D1 aStefansson, Kari1 aStrachan, David, P1 aTayo, Bamidele, O1 aTremoli, Elena1 aTuomilehto, Jaakko1 aUusitupa, Matti1 aDuijn, Cornelia, M1 aVollenweider, Peter1 aWallentin, Lars1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWolffenbuttel, Bruce, H R1 aAltshuler, David1 aOrdovas, Jose, M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aDaly, Mark, J1 aNeale, Benjamin, M1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/801410661nas a2203397 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2013 eng d a1546-171800aDiscovery and refinement of loci associated with lipid levels.0 aDiscovery and refinement of loci associated with lipid levels c2013 Nov a1274-12830 v453 aLevels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
10aAfrican Continental Ancestry Group10aAsian Continental Ancestry Group10aCholesterol, HDL10aCholesterol, LDL10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLipids10aTriglycerides1 aWiller, Cristen, J1 aSchmidt, Ellen, M1 aSengupta, Sebanti1 aPeloso, Gina, M1 aGustafsson, Stefan1 aKanoni, Stavroula1 aGanna, Andrea1 aChen, Jin1 aBuchkovich, Martin, L1 aMora, Samia1 aBeckmann, Jacques, S1 aBragg-Gresham, Jennifer, L1 aChang, Hsing-Yi1 aDemirkan, Ayse1 aHertog, Heleen, M Den1 aDo, Ron1 aDonnelly, Louise, A1 aEhret, Georg, B1 aEsko, Tõnu1 aFeitosa, Mary, F1 aFerreira, Teresa1 aFischer, Krista1 aFontanillas, Pierre1 aFraser, Ross, M1 aFreitag, Daniel, F1 aGurdasani, Deepti1 aHeikkilä, Kauko1 aHyppönen, Elina1 aIsaacs, Aaron1 aJackson, Anne, U1 aJohansson, Asa1 aJohnson, Toby1 aKaakinen, Marika1 aKettunen, Johannes1 aKleber, Marcus, E1 aLi, Xiaohui1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMihailov, Evelin1 aMontasser, May, E1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aPalmer, Cameron, D1 aPerola, Markus1 aPetersen, Ann-Kristin1 aSanna, Serena1 aSaxena, Richa1 aService, Susan, K1 aShah, Sonia1 aShungin, Dmitry1 aSidore, Carlo1 aSong, Ci1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTanaka, Toshiko1 aTeslovich, Tanya, M1 aThorleifsson, Gudmar1 avan den Herik, Evita, G1 aVoight, Benjamin, F1 aVolcik, Kelly, A1 aWaite, Lindsay, L1 aWong, Andrew1 aWu, Ying1 aZhang, Weihua1 aAbsher, Devin1 aAsiki, Gershim1 aBarroso, Inês1 aBeen, Latonya, F1 aBolton, Jennifer, L1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBurnett, Mary, S1 aCesana, Giancarlo1 aDimitriou, Maria1 aDoney, Alex, S F1 aDöring, Angela1 aElliott, Paul1 aEpstein, Stephen, E1 aEyjolfsson, Gudmundur, Ingi1 aGigante, Bruna1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGravito, Martha, L1 aGroves, Christopher, J1 aHallmans, Göran1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHernandez, Dena1 aHicks, Andrew, A1 aHolm, Hilma1 aHung, Yi-Jen1 aIllig, Thomas1 aJones, Michelle, R1 aKaleebu, Pontiano1 aKastelein, John, J P1 aKhaw, Kay-Tee1 aKim, Eric1 aKlopp, Norman1 aKomulainen, Pirjo1 aKumari, Meena1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLin, Shih-Yi1 aLindström, Jaana1 aLoos, Ruth, J F1 aMach, François1 aMcArdle, Wendy, L1 aMeisinger, Christa1 aMitchell, Braxton, D1 aMüller, Gabrielle1 aNagaraja, Ramaiah1 aNarisu, Narisu1 aNieminen, Tuomo, V M1 aNsubuga, Rebecca, N1 aOlafsson, Isleifur1 aOng, Ken, K1 aPalotie, Aarno1 aPapamarkou, Theodore1 aPomilla, Cristina1 aPouta, Anneli1 aRader, Daniel, J1 aReilly, Muredach, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRudan, Igor1 aRuokonen, Aimo1 aSamani, Nilesh1 aScharnagl, Hubert1 aSeeley, Janet1 aSilander, Kaisa1 aStančáková, Alena1 aStirrups, Kathleen1 aSwift, Amy, J1 aTiret, Laurence1 aUitterlinden, André, G1 avan Pelt, Joost1 aVedantam, Sailaja1 aWainwright, Nicholas1 aWijmenga, Cisca1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aWilson, James, F1 aYoung, Elizabeth, H1 aZhao, Jing Hua1 aAdair, Linda, S1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aBandinelli, Stefania1 aBennett, Franklyn1 aBochud, Murielle1 aBoehm, Bernhard, O1 aBoomsma, Dorret, I1 aBorecki, Ingrid, B1 aBornstein, Stefan, R1 aBovet, Pascal1 aBurnier, Michel1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChen, Yii-Der Ida1 aCollins, Francis, S1 aCooper, Richard, S1 aDanesh, John1 aDedoussis, George1 ade Faire, Ulf1 aFeranil, Alan, B1 aFerrieres, Jean1 aFerrucci, Luigi1 aFreimer, Nelson, B1 aGieger, Christian1 aGroop, Leif, C1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHingorani, Aroon1 aHirschhorn, Joel, N1 aHofman, Albert1 aHovingh, Kees1 aHsiung, Chao, Agnes1 aHumphries, Steve, E1 aHunt, Steven, C1 aHveem, Kristian1 aIribarren, Carlos1 aJarvelin, Marjo-Riitta1 aJula, Antti1 aKähönen, Mika1 aKaprio, Jaakko1 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M1 aBoerwinkle, Eric1 aPalmer, Colin, N A1 aThorsteinsdottir, Unnur1 aChasman, Daniel, I1 aRotter, Jerome, I1 aFranks, Paul, W1 aRipatti, Samuli1 aCupples, Adrienne, L1 aSandhu, Manjinder, S1 aRich, Stephen, S1 aBoehnke, Michael1 aDeloukas, Panos1 aKathiresan, Sekar1 aMohlke, Karen, L1 aIngelsson, Erik1 aAbecasis, Goncalo, R1 aGlobal Lipids Genetics Consortium uhttps://chs-nhlbi.org/node/615412626nas a2204177 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2013 eng d a1546-171800aGenome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.0 aGenomewide metaanalysis identifies 11 new loci for anthropometri c2013 May a501-120 v453 aApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
10aAnthropometry10aBody Height10aBody Mass Index10aCase-Control Studies10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMeta-Analysis as Topic10aObesity10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aWaist-Hip Ratio1 aBerndt, Sonja, I1 aGustafsson, Stefan1 aMägi, Reedik1 aGanna, Andrea1 aWheeler, Eleanor1 aFeitosa, Mary, F1 aJustice, Anne, E1 aMonda, Keri, L1 aCroteau-Chonka, Damien, C1 aDay, Felix, R1 aEsko, Tõnu1 aFall, Tove1 aFerreira, Teresa1 aGentilini, Davide1 aJackson, Anne, U1 aLuan, Jian'an1 aRandall, Joshua, C1 aVedantam, Sailaja1 aWiller, Cristen, J1 aWinkler, Thomas, W1 aWood, Andrew, R1 aWorkalemahu, Tsegaselassie1 aHu, Yi-Juan1 aLee, Sang, Hong1 aLiang, Liming1 aLin, Dan-Yu1 aMin, Josine, L1 aNeale, Benjamin, M1 aThorleifsson, Gudmar1 aYang, Jian1 aAlbrecht, Eva1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aCadby, Gemma1 aHeijer, Martin, den1 aEklund, Niina1 aFischer, Krista1 aGoel, Anuj1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aJarick, Ivonne1 aJohansson, Asa1 aJohnson, Toby1 aKanoni, Stavroula1 aKleber, Marcus, E1 aKönig, Inke, R1 aKristiansson, Kati1 aKutalik, Zoltán1 aLamina, Claudia1 aLecoeur, Cécile1 aLi, Guo1 aMangino, Massimo1 aMcArdle, Wendy, L1 aMedina-Gómez, Carolina1 aMüller-Nurasyid, Martina1 aNgwa, Julius, S1 aNolte, Ilja, M1 aPaternoster, Lavinia1 aPechlivanis, Sonali1 aPerola, Markus1 aPeters, Marjolein, J1 aPreuss, Michael1 aRose, Lynda, M1 aShi, Jianxin1 aShungin, Dmitry1 aSmith, Albert, Vernon1 aStrawbridge, Rona, J1 aSurakka, Ida1 aTeumer, Alexander1 aTrip, Mieke, D1 aTyrer, Jonathan1 avan Vliet-Ostaptchouk, Jana, V1 aVandenput, Liesbeth1 aWaite, Lindsay, L1 aZhao, Jing Hua1 aAbsher, Devin1 aAsselbergs, Folkert, W1 aAtalay, Mustafa1 aAttwood, Antony, P1 aBalmforth, Anthony, J1 aBasart, Hanneke1 aBeilby, John1 aBonnycastle, Lori, L1 aBrambilla, Paolo1 aBruinenberg, Marcel1 aCampbell, Harry1 aChasman, Daniel, I1 aChines, Peter, S1 aCollins, Francis, S1 aConnell, John, M1 aCookson, William, O1 ade Faire, Ulf1 ade Vegt, Femmie1 aDei, Mariano1 aDimitriou, Maria1 aEdkins, Sarah1 aEstrada, Karol1 aEvans, David, M1 aFarrall, Martin1 aFerrario, Marco, M1 aFerrieres, Jean1 aFranke, Lude1 aFrau, Francesca1 aGejman, Pablo, V1 aGrallert, Harald1 aGrönberg, Henrik1 aGudnason, Vilmundur1 aHall, Alistair, S1 aHall, Per1 aHartikainen, Anna-Liisa1 aHayward, Caroline1 aHeard-Costa, Nancy, L1 aHeath, Andrew, C1 aHebebrand, Johannes1 aHomuth, Georg1 aHu, Frank, B1 aHunt, Sarah, E1 aHyppönen, Elina1 aIribarren, Carlos1 aJacobs, Kevin, B1 aJansson, John-Olov1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKee, Frank1 aKhaw, Kay-Tee1 aKivimaki, Mika1 aKoenig, Wolfgang1 aKraja, Aldi, T1 aKumari, Meena1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaitinen, Jaana, H1 aLakka, Timo, A1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLind, Lars1 aLindström, Jaana1 aLiu, Jianjun1 aLiuzzi, Antonio1 aLokki, Marja-Liisa1 aLorentzon, Mattias1 aMadden, Pamela, A1 aMagnusson, Patrik, K1 aManunta, Paolo1 aMarek, Diana1 aMärz, Winfried1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMihailov, Evelin1 aMilani, Lili1 aMontgomery, Grant, W1 aMooser, Vincent1 aMühleisen, Thomas, W1 aMunroe, Patricia, B1 aMusk, Arthur, W1 aNarisu, Narisu1 aNavis, Gerjan1 aNicholson, George1 aNohr, Ellen, A1 aOng, Ken, K1 aOostra, Ben, A1 aPalmer, Colin, N A1 aPalotie, Aarno1 aPeden, John, F1 aPedersen, Nancy1 aPeters, Annette1 aPolasek, Ozren1 aPouta, Anneli1 aPramstaller, Peter, P1 aProkopenko, Inga1 aPütter, Carolin1 aRadhakrishnan, Aparna1 aRaitakari, Olli1 aRendon, Augusto1 aRivadeneira, Fernando1 aRudan, Igor1 aSaaristo, Timo, E1 aSambrook, Jennifer, G1 aSanders, Alan, R1 aSanna, Serena1 aSaramies, Jouko1 aSchipf, Sabine1 aSchreiber, Stefan1 aSchunkert, Heribert1 aShin, So-Youn1 aSignorini, Stefano1 aSinisalo, Juha1 aSkrobek, Boris1 aSoranzo, Nicole1 aStančáková, Alena1 aStark, Klaus1 aStephens, Jonathan, C1 aStirrups, Kathleen1 aStolk, Ronald, P1 aStumvoll, Michael1 aSwift, Amy, J1 aTheodoraki, Eirini, V1 aThorand, Barbara1 aTrégouët, David-Alexandre1 aTremoli, Elena1 avan der Klauw, Melanie, M1 avan Meurs, Joyce, B J1 aVermeulen, Sita, H1 aViikari, Jorma1 aVirtamo, Jarmo1 aVitart, Veronique1 aWaeber, Gérard1 aWang, Zhaoming1 aWiden, Elisabeth1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWinkelmann, Bernhard, R1 aWitteman, Jacqueline, C M1 aWolffenbuttel, Bruce, H R1 aWong, Andrew1 aWright, Alan, F1 aZillikens, Carola, M1 aAmouyel, Philippe1 aBoehm, Bernhard, O1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aCaulfield, Mark, J1 aChanock, Stephen, J1 aCupples, Adrienne, L1 aCusi, Daniele1 aDedoussis, George, V1 aErdmann, Jeanette1 aEriksson, Johan, G1 aFranks, Paul, W1 aFroguel, Philippe1 aGieger, Christian1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHengstenberg, Christian1 aHicks, Andrew, A1 aHingorani, Aroon1 aHinney, Anke1 aHofman, Albert1 aHovingh, Kees, G1 aHveem, Kristian1 aIllig, Thomas1 aJarvelin, Marjo-Riitta1 aJöckel, Karl-Heinz1 aKeinanen-Kiukaanniemi, Sirkka, M1 aKiemeney, Lambertus, A1 aKuh, Diana1 aLaakso, Markku1 aLehtimäki, Terho1 aLevinson, Douglas, F1 aMartin, Nicholas, G1 aMetspalu, Andres1 aMorris, Andrew, D1 aNieminen, Markku, S1 aNjølstad, Inger1 aOhlsson, Claes1 aOldehinkel, Albertine, J1 aOuwehand, Willem, H1 aPalmer, Lyle, J1 aPenninx, Brenda1 aPower, Chris1 aProvince, Michael, A1 aPsaty, Bruce, M1 aQi, Lu1 aRauramaa, Rainer1 aRidker, Paul, M1 aRipatti, Samuli1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSnieder, Harold1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStefansson, Kari1 aTönjes, Anke1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 aUusitupa, Matti1 aHarst, Pim1 aVollenweider, Peter1 aWallaschofski, Henri1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWichmann, H-Erich1 aWilson, James, F1 aAbecasis, Goncalo, R1 aAssimes, Themistocles, L1 aBarroso, Inês1 aBoehnke, Michael1 aBorecki, Ingrid, B1 aDeloukas, Panos1 aFox, Caroline, S1 aFrayling, Timothy1 aGroop, Leif, C1 aHaritunian, Talin1 aHeid, Iris, M1 aHunter, David1 aKaplan, Robert, C1 aKarpe, Fredrik1 aMoffatt, Miriam, F1 aMohlke, Karen, L1 aO'Connell, Jeffrey, R1 aPawitan, Yudi1 aSchadt, Eric, E1 aSchlessinger, David1 aSteinthorsdottir, Valgerdur1 aStrachan, David, P1 aThorsteinsdottir, Unnur1 aDuijn, Cornelia, M1 aVisscher, Peter, M1 aDi Blasio, Anna, Maria1 aHirschhorn, Joel, N1 aLindgren, Cecilia, M1 aMorris, Andrew, P1 aMeyre, David1 aScherag, Andre1 aMcCarthy, Mark, I1 aSpeliotes, Elizabeth, K1 aNorth, Kari, E1 aLoos, Ruth, J F1 aIngelsson, Erik uhttps://chs-nhlbi.org/node/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/659006414nas a2201585 4500008004100000022001400041245015100055210006900206260001300275300001300288490000700301520179000308653000902098653002002107653002802127653002202155653001102177653001102188653003102199653001902230653001702249653003802266653003402304653001102338653000902349653001602358653002602374653001402400653003602414653002102450653001702471653001102488653001502499653003302514653001702547653001802564653001802582100001502600700002502615700002402640700002402664700002002688700002702708700002502735700003202760700001802792700002302810700002202833700001802855700002102873700001802894700001902912700002302931700001702954700002102971700001602992700002803008700002403036700002003060700002703080700002003107700002603127700002203153700001603175700002403191700002103215700002103236700002003257700002003277700002503297700002503322700002403347700001603371700002203387700002003409700001503429700002003444700002103464700002303485700002803508700002203536700001903558700001903577700001903596700002303615700002203638700002203660700002003682700001403702700001703716700002003733700002203753700001803775700002803793700002303821700001903844700002003863700001803883700001903901700003003920700002103950700001703971700002003988700001904008700002104027700002604048700002204074700002404096700002204120700001904142700002804161700002004189700002104209700002204230700002004252700002004272700002404292700002004316700002004336700001804356700002104374700002904395700002004424700002304444700002204467700001504489700002004504700002704524700002304551700003004574710010804604710002604712710005404738856003604792 2014 eng d a1524-463600aGenome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.0 aGenomewide association study for circulating tissue plasminogen c2014 May a1093-1010 v343 aOBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.
APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.
CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
10aAged10aCells, Cultured10aCoronary Artery Disease10aEndothelial Cells10aEurope10aFemale10aGene Expression Regulation10aGene Silencing10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aR-SNARE Proteins10aRisk Factors10aStroke10aSyntaxin 110aTissue Plasminogen Activator10aTransfection10aUnited States10aUp-Regulation1 aHuang, Jie1 aHuffman, Jennifer, E1 aYamakuchi, Munekazu1 aYamkauchi, Munekazu1 aTrompet, Stella1 aAsselbergs, Folkert, W1 aSabater-Lleal, Maria1 aTrégouët, David-Alexandre1 aChen, Wei-Min1 aSmith, Nicholas, L1 aKleber, Marcus, E1 aShin, So-Youn1 aBecker, Diane, M1 aTang, Weihong1 aDehghan, Abbas1 aJohnson, Andrew, D1 aTruong, Vinh1 aFolkersen, Lasse1 aYang, Qiong1 aOudot-Mellkah, Tiphaine1 aBuckley, Brendan, M1 aMoore, Jason, H1 aWilliams, Frances, M K1 aCampbell, Harry1 aSilbernagel, Günther1 aVitart, Veronique1 aRudan, Igor1 aTofler, Geoffrey, H1 aNavis, Gerjan, J1 aDeStefano, Anita1 aWright, Alan, F1 aChen, Ming-Huei1 ade Craen, Anton, J M1 aWorrall, Bradford, B1 aRudnicka, Alicja, R1 aRumley, Ann1 aBookman, Ebony, B1 aPsaty, Bruce, M1 aChen, Fang1 aKeene, Keith, L1 aFranco, Oscar, H1 aBöhm, Bernhard, O1 aUitterlinden, André, G1 aCarter, Angela, M1 aJukema, Wouter1 aSattar, Naveed1 aBis, Joshua, C1 aIkram, Mohammad, A1 aSale, Michèle, M1 aMcKnight, Barbara1 aFornage, Myriam1 aFord, Ian1 aTaylor, Kent1 aSlagboom, Eline1 aMcArdle, Wendy, L1 aHsu, Fang-Chi1 aFranco-Cereceda, Anders1 aGoodall, Alison, H1 aYanek, Lisa, R1 aFurie, Karen, L1 aCushman, Mary1 aHofman, Albert1 aWitteman, Jacqueline, C M1 aFolsom, Aaron, R1 aBasu, Saonli1 aMatijevic, Nena1 aGilst, Wiek, H1 aWilson, James, F1 aWestendorp, Rudi, G J1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTracy, Russell, P1 aPolasek, Ozren1 aWinkelmann, Bernhard, R1 aGrant, Peter, J1 aHillege, Hans, L1 aCambien, Francois1 aStott, David, J1 aLowe, Gordon, D1 aSpector, Timothy, D1 aMeigs, James, B1 aMärz, Winfried1 aEriksson, Per1 aBecker, Lewis, C1 aMorange, Pierre-Emmanuel1 aSoranzo, Nicole1 aWilliams, Scott, M1 aHayward, Caroline1 aHarst, Pim1 aHamsten, Anders1 aLowenstein, Charles, J1 aStrachan, David, P1 aO'Donnell, Christopher, J1 aCohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium Neurology Working Group1 aCARDIoGRAM consortium1 aCHARGE Consortium Hemostatic Factor Working Group uhttps://chs-nhlbi.org/node/636705734nas 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/660504953nas a2201105 4500008004100000022001400041245009300055210006900148260001500217300001200232490000700244520183400251653001002085653000902095653002202104653003702126653002402163653002302187653003102210653001102241653004002252653001102292653002002303653003802323653002502361653001102386653001002397653000902407653001602416653003602432653002602468100002202494700002402516700001902540700001902559700002002578700001202598700002202610700002302632700001802655700002202673700001802695700001902713700002102732700003002753700001902783700002202802700001902824700002302843700001702866700002402883700001402907700002102921700002202942700001902964700001902983700001903002700002203021700001903043700002203062700002503084700002203109700002203131700002203153700002003175700002003195700001903215700002203234700002603256700002303282700002203305700002003327700002003347700002403367700002303391700002803414700002603442700001703468700001903485700002403504700002203528700002403550700002203574700002003596700001603616700002503632700002303657700002203680700002303702700001903725700001903744700002403763700002403787856003603811 2014 eng d a1558-359700aNovel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.0 aNovel genetic markers associate with atrial fibrillation risk in c2014 Apr 1 a1200-100 v633 aOBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factors1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aLin, Honghuang1 aArking, Dan, E1 aTrompet, Stella1 aLi, Guo1 aKrijthe, Bouwe, P1 aChasman, Daniel, I1 aBarnard, John1 aKleber, Marcus, E1 aDörr, Marcus1 aOzaki, Kouichi1 aSmith, Albert, V1 aMüller-Nurasyid, Martina1 aWalter, Stefan1 aAgarwal, Sunil, K1 aBis, Joshua, C1 aBrody, Jennifer, A1 aChen, Lin, Y1 aEverett, Brendan, M1 aFord, Ian1 aFranco, Oscar, H1 aHarris, Tamara, B1 aHofman, Albert1 aKääb, Stefan1 aMahida, Saagar1 aKathiresan, Sekar1 aKubo, Michiaki1 aLauner, Lenore, J1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aMcKnight, Barbara1 aMcManus, David, D1 aPeters, Annette1 aPsaty, Bruce, M1 aRose, Lynda, M1 aRotter, Jerome, I1 aSilbernagel, Guenther1 aSmith, Jonathan, D1 aSotoodehnia, Nona1 aStott, David, J1 aTaylor, Kent, D1 aTomaschitz, Andreas1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aMurabito, Joanne, M1 aSinner, Moritz, F1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aMärz, Winfried1 aChung, Mina1 aAlbert, Christine, M1 aStricker, Bruno, H1 aTanaka, Toshihiro1 aHeckbert, Susan, R1 aJukema, Wouter1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/682004219nas a2200913 4500008004100000022001400041245008500055210006900140260001300209300001100222490000700233520168500240653001601925653000901941653002201950653002101972653002501993653001902018653004002037653001102077653003802088653003402126653001302160653001102173653000902184653001602193653003602209653002402245653001702269653001402286653001602300653001102316100003002327700002002357700001902377700002202396700002002418700002002438700001502458700001602473700002102489700003002510700002202540700002002562700002102582700001802603700002102621700002002642700001602662700002302678700001902701700001802720700002202738700002002760700002102780700002102801700002302822700001702845700002602862700002402888700001602912700002602928700001902954700001902973700002802992700002403020700002303044700001603067700001803083700002003101700002103121700002003142700002003162700002203182700002003204700002303224700002203247856003603269 2014 eng d a1524-462800aPredicting stroke through genetic risk functions: the CHARGE Risk Score Project.0 aPredicting stroke through genetic risk functions the CHARGE Risk c2014 Feb a403-120 v453 aBACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.
METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.
RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).
CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.
10aAge Factors10aAged10aAged, 80 and over10aArea Under Curve10aCase-Control Studies10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aROC Curve10aSex Factors10aStroke1 aIbrahim-Verbaas, Carla, A1 aFornage, Myriam1 aBis, Joshua, C1 aChoi, Seung, Hoan1 aPsaty, Bruce, M1 aMeigs, James, B1 aRao, Madhu1 aNalls, Mike1 aFontes, João, D1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aEhret, Georg, B1 aFox, Caroline, S1 aMalik, Rainer1 aDichgans, Martin1 aSchmidt, Helena1 aLahti, Jari1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Kenneth1 aRotter, Jerome, I1 aTaylor, Kent, D1 aFolsom, Aaron, R1 aBoerwinkle, Eric1 aRosamond, Wayne, D1 aShahar, Eyal1 aGottesman, Rebecca, F1 aKoudstaal, Peter, J1 aAmin, Najaf1 aWieberdink, Renske, G1 aDehghan, Abbas1 aHofman, Albert1 aUitterlinden, André, G1 aDeStefano, Anita, L1 aDebette, Stephanie1 aXue, Luting1 aBeiser, Alexa1 aWolf, Philip, A1 aDeCarli, Charles1 aIkram, Arfan, M1 aSeshadri, Sudha1 aMosley, Thomas, H1 aLongstreth, W T1 aDuijn, Cornelia, M1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/622004329nas a2200781 4500008004100000022001400041245012500055210006900180260001300249300001000262490000700272520197700279653001902256653002802275653003702303653003802340653003402378653001102412653001402423653003602437653003102473653001702504653001102521100002102532700001802553700002002571700002102591700001902612700002702631700002502658700002502683700002902708700002202737700003002759700002002789700002802809700002002837700002802857700002002885700002202905700001902927700002002946700002802966700002002994700002203014700002203036700002003058700002003078700002103098700001903119700002403138700002203162700001903184700002303203700002203226700001803248700002303266700002003289700002003309700002203329700002003351700002403371710002603395710002603421710001903447710004503466856003603511 2014 eng d a1524-462800aShared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.0 aShared genetic susceptibility to ischemic stroke and coronary ar c2014 Jan a24-360 v453 aBACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.
RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).
CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
10aBrain Ischemia10aCoronary Artery Disease10aData Interpretation, Statistical10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPhenotype10aPolymorphism, Single Nucleotide10aReproducibility of Results10aRisk Factors10aStroke1 aDichgans, Martin1 aMalik, Rainer1 aKönig, Inke, R1 aRosand, Jonathan1 aClarke, Robert1 aGretarsdottir, Solveig1 aThorleifsson, Gudmar1 aMitchell, Braxton, D1 aAssimes, Themistocles, L1 aLevi, Christopher1 aO'Donnell, Christopher, J1 aFornage, Myriam1 aThorsteinsdottir, Unnur1 aPsaty, Bruce, M1 aHengstenberg, Christian1 aSeshadri, Sudha1 aErdmann, Jeanette1 aBis, Joshua, C1 aPeters, Annette1 aBoncoraglio, Giorgio, B1 aMärz, Winfried1 aMeschia, James, F1 aKathiresan, Sekar1 aIkram, Arfan, M1 aMcPherson, Ruth1 aStefansson, Kari1 aSudlow, Cathie1 aReilly, Muredach, P1 aThompson, John, R1 aSharma, Pankaj1 aHopewell, Jemma, C1 aChambers, John, C1 aWatkins, Hugh1 aRothwell, Peter, M1 aRoberts, Robert1 aMarkus, Hugh, S1 aSamani, Nilesh, J1 aFarrall, Martin1 aSchunkert, Heribert1 aMETASTROKE Consortium1 aCARDIoGRAM consortium1 aC4D Consortium1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/637005955nas a2201657 4500008004100000022001400041245011000055210006900165260001600234300001100250490000700261520138800268653001001656653000901666653002201675653002101697653001901718653001801737653001001755653001101765653002201776653001901798653001701817653003401834653001301868653001101881653001101892653000901903653001601912653001401928653003601942653002801978653002702006653001902033653002702052653002602079100002102105700001402126700001402140700001602154700002202170700002202192700001702214700002002231700002102251700002102272700001302293700002002306700001702326700001502343700001702358700002002375700001402395700002702409700001802436700002202454700001602476700001902492700001702511700002102528700002302549700002002572700001802592700002202610700001802632700001502650700001202665700001702677700001502694700001802709700001902727700001902746700001902765700002502784700002602809700002102835700002502856700002102881700001902902700002502921700001702946700002502963700001202988700002303000700002003023700002603043700002903069700002303098700002803121700001803149700002003167700002303187700002103210700001903231700001803250700002803268700001903296700002403315700002303339700002803362700001703390700002203407700002203429700002403451700002403475700002003499700002303519700002203542700001603564700001703580700002403597700002003621700001803641700002003659700002103679700001603700700001903716700002203735700002803757700002303785700003003808700001903838700001903857700002503876700002103901700002003922700002103942700002203963700001603985700002004001700002504021700002404046700002104070700002604091700002504117700002104142700002204163700002304185710005304208856003604261 2014 eng d a1537-660500aWhole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.0 aWholeexome sequencing identifies rare and lowfrequency coding va c2014 Feb 06 a233-450 v943 aElevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
10aAdult10aAged10aApolipoproteins E10aCholesterol, LDL10aCohort Studies10aDyslipidemias10aExome10aFemale10aFollow-Up Studies10aGene Frequency10aGenetic Code10aGenome-Wide Association Study10aGenotype10aHumans10aLipase10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aProprotein Convertase 910aProprotein Convertases10aReceptors, LDL10aSequence Analysis, DNA10aSerine Endopeptidases1 aLange, Leslie, A1 aHu, Youna1 aZhang, He1 aXue, Chenyi1 aSchmidt, Ellen, M1 aTang, Zheng-Zheng1 aBizon, Chris1 aLange, Ethan, M1 aSmith, Joshua, D1 aTurner, Emily, H1 aJun, Goo1 aKang, Hyun, Min1 aPeloso, Gina1 aAuer, Paul1 aLi, Kuo-Ping1 aFlannick, Jason1 aZhang, Ji1 aFuchsberger, Christian1 aGaulton, Kyle1 aLindgren, Cecilia1 aLocke, Adam1 aManning, Alisa1 aSim, Xueling1 aRivas, Manuel, A1 aHolmen, Oddgeir, L1 aGottesman, Omri1 aLu, Yingchang1 aRuderfer, Douglas1 aStahl, Eli, A1 aDuan, Qing1 aLi, Yun1 aDurda, Peter1 aJiao, Shuo1 aIsaacs, Aaron1 aHofman, Albert1 aBis, Joshua, C1 aCorrea, Adolfo1 aGriswold, Michael, E1 aJakobsdottir, Johanna1 aSmith, Albert, V1 aSchreiner, Pamela, J1 aFeitosa, Mary, F1 aZhang, Qunyuan1 aHuffman, Jennifer, E1 aCrosby, Jacy1 aWassel, Christina, L1 aDo, Ron1 aFranceschini, Nora1 aMartin, Lisa, W1 aRobinson, Jennifer, G1 aAssimes, Themistocles, L1 aCrosslin, David, R1 aRosenthal, Elisabeth, A1 aTsai, Michael1 aRieder, Mark, J1 aFarlow, Deborah, N1 aFolsom, Aaron, R1 aLumley, Thomas1 aFox, Ervin, R1 aCarlson, Christopher, S1 aPeters, Ulrike1 aJackson, Rebecca, D1 aDuijn, Cornelia, M1 aUitterlinden, André, G1 aLevy, Daniel1 aRotter, Jerome, I1 aTaylor, Herman, A1 aGudnason, Vilmundur1 aSiscovick, David, S1 aFornage, Myriam1 aBorecki, Ingrid, B1 aHayward, Caroline1 aRudan, Igor1 aChen, Eugene1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSætrom, Pål1 aHveem, Kristian1 aBoehnke, Michael1 aGroop, Leif1 aMcCarthy, Mark1 aMeitinger, Thomas1 aBallantyne, Christie, M1 aGabriel, Stacey, B1 aO'Donnell, Christopher, J1 aPost, Wendy, S1 aNorth, Kari, E1 aReiner, Alexander, P1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aAltshuler, David1 aKathiresan, Sekar1 aLin, Dan-Yu1 aJarvik, Gail, P1 aCupples, Adrienne, L1 aKooperberg, Charles1 aWilson, James, G1 aNickerson, Deborah, A1 aAbecasis, Goncalo, R1 aRich, Stephen, S1 aTracy, Russell, P1 aWiller, Cristen, J1 aNHLBI Grand Opportunity Exome Sequencing Project uhttps://chs-nhlbi.org/node/657704486nas a2200901 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520184700254653001002101653002202111653002302133653002802156653001902184653004002203653001002243653001102253653001902264653003802283653003402321653003802355653001102393653000902404653001102413653003602424653002902460653001702489100002202506700001802528700001902546700001902565700001402584700002102598700002102619700002002640700002402660700001902684700002802703700002002731700002202751700001202773700002402785700002402809700002102833700002002854700002102874700001902895700002102914700001602935700002002951700001502971700001902986700002003005700001803025700002103043700001803064700002203082700002403104700002303128700002303151700001903174700002603193700002203219700001903241700001903260700002103279700002103300700002403321700002403345700002003369700002003389710006503409710007403474856003603548 2015 eng d a1460-208300aAssociation of exome sequences with plasma C-reactive protein levels in >9000 participants.0 aAssociation of exome sequences with plasma Creactive protein lev c2015 Jan 15 a559-710 v243 aC-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.
10aAdult10aAfrican Americans10aC-Reactive Protein10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aExome10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHepatocyte Nuclear Factor 1-alpha10aHumans10aMale10aPlasma10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-610aRisk Factors1 aSchick, Ursula, M1 aAuer, Paul, L1 aBis, Joshua, C1 aLin, Honghuang1 aWei, Peng1 aPankratz, Nathan1 aLange, Leslie, A1 aBrody, Jennifer1 aStitziel, Nathan, O1 aKim, Daniel, S1 aCarlson, Christopher, S1 aFornage, Myriam1 aHaessler, Jeffery1 aHsu, Li1 aJackson, Rebecca, D1 aKooperberg, Charles1 aLeal, Suzanne, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aTracy, Russell1 aArdissino, Diego1 aShah, Svati1 aWiller, Cristen1 aLoos, Ruth1 aMelander, Olle1 aMcPherson, Ruth1 aHovingh, Kees1 aReilly, Muredach1 aWatkins, Hugh1 aGirelli, Domenico1 aFontanillas, Pierre1 aChasman, Daniel, I1 aGabriel, Stacey, B1 aGibbs, Richard1 aNickerson, Deborah, A1 aKathiresan, Sekar1 aPeters, Ulrike1 aDupuis, Josée1 aWilson, James, G1 aRich, Stephen, S1 aMorrison, Alanna, C1 aBenjamin, Emelia, J1 aGross, Myron, D1 aReiner, Alex, P1 aCohorts for Heart and Aging Research in Genomic Epidemiology1 aNational Heart, Lung, and Blood Institute GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659706191nas 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/669108133nas a2201957 4500008004100000022001400041245012800055210006900183260001600252300001100268490000800279520256000287653000902847653002002856653001602876653002102892653002102913653003002934653001102964653002002975653001102995653004103006653005103047653000903098653001603107653003603123653004203159653001703201100002403218700001803242700003103260700002303291700002503314700001503339700001803354700002003372700002303392700002103415700002103436700001803457700002203475700001503497700002803512700002103540700001703561700002203578700001403600700001803614700001903632700002203651700001903673700001503692700001703707700002003724700002603744700002103770700002203791700002503813700002103838700003103859700002203890700002403912700002503936700002103961700002303982700002404005700001904029700002304048700002304071700002104094700002504115700002004140700001904160700001804179700002104197700001404218700001904232700002604251700002404277700002004301700001504321700002004336700003404356700002104390700002304411700002604434700002204460700002604482700001804508700001904526700001904545700002204564700002204586700002304608700002004631700002004651700002104671700002104692700002304713700002104736700002004757700002404777700002104801700002304822700002004845700002204865700001904887700001904906700003704925700002104962700002104983700002205004700002305026700002205049700002405071700002105095700002505116700002005141700002405161700001805185700001805203700002105221700002905242700001905271700002105290700002305311700002005334700002305354700001905377700001805396700001705414700001505431700001905446700002205465700002305487700001505510700002105525700002605546700002305572700002205595700001805617700001805635700002505653700002005678700002105698700002205719700002105741700002405762700002405786700001905810700002505829700002405854700002705878700002105905700001805926700001905944700002105963700002005984700002406004700002406028700001906052710002306071710002106094710002406115856003606139 2015 eng d a1474-547X00aHMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.0 aHMGcoenzyme A reductase inhibition type 2 diabetes and bodyweigh c2015 Jan 24 a351-610 v3853 aBACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).
INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
FUNDING: The funding sources are cited at the end of the paper.
10aAged10aBody Mass Index10aBody Weight10aCholesterol, HDL10aCholesterol, LDL10aDiabetes Mellitus, Type 210aFemale10aGenetic Testing10aHumans10aHydroxymethylglutaryl CoA Reductases10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRandomized Controlled Trials as Topic10aRisk Factors1 aSwerdlow, Daniel, I1 aPreiss, David1 aKuchenbaecker, Karoline, B1 aHolmes, Michael, V1 aEngmann, Jorgen, E L1 aShah, Tina1 aSofat, Reecha1 aStender, Stefan1 aJohnson, Paul, C D1 aScott, Robert, A1 aLeusink, Maarten1 aVerweij, Niek1 aSharp, Stephen, J1 aGuo, Yiran1 aGiambartolomei, Claudia1 aChung, Christina1 aPeasey, Anne1 aAmuzu, Antoinette1 aLi, KaWah1 aPalmen, Jutta1 aHoward, Philip1 aCooper, Jackie, A1 aDrenos, Fotios1 aLi, Yun, R1 aLowe, Gordon1 aGallacher, John1 aStewart, Marlene, C W1 aTzoulaki, Ioanna1 aBuxbaum, Sarah, G1 avan der A, Daphne, L1 aForouhi, Nita, G1 aOnland-Moret, Charlotte, N1 aSchouw, Yvonne, T1 aSchnabel, Renate, B1 aHubacek, Jaroslav, A1 aKubinova, Ruzena1 aBaceviciene, Migle1 aTamosiunas, Abdonas1 aPajak, Andrzej1 aTopor-Madry, Roman1 aStepaniak, Urszula1 aMalyutina, Sofia1 aBaldassarre, Damiano1 aSennblad, Bengt1 aTremoli, Elena1 ade Faire, Ulf1 aVeglia, Fabrizio1 aFord, Ian1 aJukema, Wouter1 aWestendorp, Rudi, G J1 ade Borst, Gert, Jan1 ade Jong, Pim, A1 aAlgra, Ale1 aSpiering, Wilko1 avan der Zee, Anke, H Maitland1 aKlungel, Olaf, H1 ade Boer, Anthonius1 aDoevendans, Pieter, A1 aEaton, Charles, B1 aRobinson, Jennifer, G1 aDuggan, David1 aKjekshus, John1 aDowns, John, R1 aGotto, Antonio, M1 aKeech, Anthony, C1 aMarchioli, Roberto1 aTognoni, Gianni1 aSever, Peter, S1 aPoulter, Neil, R1 aWaters, David, D1 aPedersen, Terje, R1 aAmarenco, Pierre1 aNakamura, Haruo1 aMcMurray, John, J V1 aLewsey, James, D1 aChasman, Daniel, I1 aRidker, Paul, M1 aMaggioni, Aldo, P1 aTavazzi, Luigi1 aRay, Kausik, K1 aSeshasai, Sreenivasa, Rao Kondap1 aManson, JoAnn, E1 aPrice, Jackie, F1 aWhincup, Peter, H1 aMorris, Richard, W1 aLawlor, Debbie, A1 aSmith, George Davey1 aBen-Shlomo, Yoav1 aSchreiner, Pamela, J1 aFornage, Myriam1 aSiscovick, David, S1 aCushman, Mary1 aKumari, Meena1 aWareham, Nick, J1 aVerschuren, W, M Monique1 aRedline, Susan1 aPatel, Sanjay, R1 aWhittaker, John, C1 aHamsten, Anders1 aDelaney, Joseph, A1 aDale, Caroline1 aGaunt, Tom, R1 aWong, Andrew1 aKuh, Diana1 aHardy, Rebecca1 aKathiresan, Sekar1 aCastillo, Berta, A1 aHarst, Pim1 aBrunner, Eric, J1 aTybjaerg-Hansen, Anne1 aMarmot, Michael, G1 aKrauss, Ronald, M1 aTsai, Michael1 aCoresh, Josef1 aHoogeveen, Ronald, C1 aPsaty, Bruce, M1 aLange, Leslie, A1 aHakonarson, Hakon1 aDudbridge, Frank1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aKivimaki, Mika1 aTimpson, Nicholas, J1 aLangenberg, Claudia1 aAsselbergs, Folkert, W1 aVoevoda, Mikhail1 aBobak, Martin1 aPikhart, Hynek1 aWilson, James, G1 aReiner, Alex, P1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aSattar, Naveed1 aDIAGRAM Consortium1 aMAGIC Consortium1 aInterAct Consortium uhttps://chs-nhlbi.org/node/686303793nas a2200553 4500008004100000022001400041245013800055210006900193260001500262300001200277490000700289520217800296100001902474700001802493700002002511700001902531700002002550700001502570700003002585700002302615700002102638700002302659700002402682700002302706700001902729700002002748700002202768700001802790700001902808700002302827700002502850700001702875700002102892700001702913700002402930700002002954700002002974700001802994700001703012700002103029700001903050700002103069700002903090700002103119700002103140700002003161700002203181856003603203 2016 eng d a1558-359700aDiagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.0 aDiagnostic Yield and Clinical Utility of Sequencing Familial Hyp c2016 Jun 7 a2578-890 v673 aBACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement.
OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.
METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.
RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.
CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.
1 aKhera, Amit, V1 aWon, Hong-Hee1 aPeloso, Gina, M1 aLawson, Kim, S1 aBartz, Traci, M1 aDeng, Xuan1 avan Leeuwen, Elisabeth, M1 aNatarajan, Pradeep1 aEmdin, Connor, A1 aBick, Alexander, G1 aMorrison, Alanna, C1 aBrody, Jennifer, A1 aGupta, Namrata1 aNomura, Akihiro1 aKessler, Thorsten1 aDuga, Stefano1 aBis, Joshua, C1 aDuijn, Cornelia, M1 aCupples, Adrienne, L1 aPsaty, Bruce1 aRader, Daniel, J1 aDanesh, John1 aSchunkert, Heribert1 aMcPherson, Ruth1 aFarrall, Martin1 aWatkins, Hugh1 aLander, Eric1 aWilson, James, G1 aCorrea, Adolfo1 aBoerwinkle, Eric1 aMerlini, Piera, Angelica1 aArdissino, Diego1 aSaleheen, Danish1 aGabriel, Stacey1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/701006025nas a2201489 4500008004100000022001400041245009200055210006900147260001500216300000900231490000700240520184700247100002002094700002002114700002202134700002002156700002502176700002402201700002602225700002002251700002202271700002002293700001602313700002002329700002302349700002302372700002102395700001902416700002102435700001702456700002102473700001602494700002302510700001602533700002002549700002102569700002102590700002102611700002302632700002402655700002802679700002302707700002002730700002402750700001802774700002202792700002202814700002002836700002002856700001202876700002402888700002402912700001902936700002202955700002202977700002302999700002503022700002403047700001903071700002503090700002003115700001703135700002203152700002203174700001203196700002403208700002103232700001703253700001803270700002803288700001803316700002303334700001903357700002103376700001803397700001903415700002603434700001703460700002403477700002503501700001903526700002303545700001803568700002003586700002303606700002103629700002103650700002103671700002603692700002203718700001903740700002603759700001903785700002003804700002203824700002303846700002403869700002203893700002103915700001903936700002703955700002303982700002604005700001804031700001804049700002804067700002604095700002004121700002404141700002104165700002104186700002304207700002204230700001804252700001604270700002004286700002104306700002004327700002104347700002104368700002204389700001804411700002304429700002504452700002204477856003604499 2016 eng d a1537-660500aExome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.0 aExome Genotyping Identifies Pleiotropic Variants Associated with c2016 Jul 7 a8-210 v993 aRed blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
1 aChami, Nathalie1 aChen, Ming-Huei1 aSlater, Andrew, J1 aEicher, John, D1 aEvangelou, Evangelos1 aTajuddin, Salman, M1 aLove-Gregory, Latisha1 aKacprowski, Tim1 aSchick, Ursula, M1 aNomura, Akihiro1 aGiri, Ayush1 aLessard, Samuel1 aBrody, Jennifer, A1 aSchurmann, Claudia1 aPankratz, Nathan1 aYanek, Lisa, R1 aManichaikul, Ani1 aPazoki, Raha1 aMihailov, Evelin1 aHill, David1 aRaffield, Laura, M1 aBurt, Amber1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aO'Donoghue, Michelle, L1 aCrosslin, David, R1 ade Denus, Simon1 aDubé, Marie-Pierre1 aElliott, Paul1 aEngström, Gunnar1 aEvans, Michele, K1 aFloyd, James, S1 aFornage, Myriam1 aGao, He1 aGreinacher, Andreas1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHernesniemi, Jussi1 aHighland, Heather, M1 aHirschhorn, Joel, N1 aHofman, Albert1 aIrvin, Marguerite, R1 aKähönen, Mika1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLi, Jin1 aLiewald, David, C M1 aLinneberg, Allan1 aLiu, Yongmei1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMathias, Rasika, A1 aMelander, Olle1 aMetspalu, Andres1 aMononen, Nina1 aNalls, Mike, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aO'Donnell, Chris, J1 aOrho-Melander, Marju1 aPedersen, Oluf1 aPetersmann, Astrid1 aPolfus, Linda1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRaitoharju, Emma1 aRichard, Melissa1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchmidt, Frank1 aSmith, Albert, Vernon1 aStarr, John, M1 aTaylor, Kent, D1 aTeumer, Alexander1 aThuesen, Betina, H1 aTorstenson, Eric, S1 aTracy, Russell, P1 aTzoulaki, Ioanna1 aZakai, Neil, A1 aVacchi-Suzzi, Caterina1 aDuijn, Cornelia, M1 avan Rooij, Frank, J A1 aCushman, Mary1 aDeary, Ian, J1 aEdwards, Digna, R Velez1 aVergnaud, Anne-Claire1 aWallentin, Lars1 aWaterworth, Dawn, M1 aWhite, Harvey, D1 aWilson, James, G1 aZonderman, Alan, B1 aKathiresan, Sekar1 aGrarup, Niels1 aEsko, Tõnu1 aLoos, Ruth, J F1 aLange, Leslie, A1 aFaraday, Nauder1 aAbumrad, Nada, A1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aAuer, Paul, L1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aLettre, Guillaume uhttps://chs-nhlbi.org/node/713804937nas a2201345 4500008004100000022001400041245012400055210006900179260001300248300001200261490000700273520113500280100001601415700001901431700002301450700002301473700002301496700001901519700001801538700002401556700001801580700001801598700001701616700001901633700002001652700002201672700002301694700001901717700001901736700001801755700001901773700001601792700001401808700002601822700001501848700002601863700001601889700001301905700001301918700001901931700002201950700002001972700002101992700002002013700001402033700001902047700001802066700002402084700002202108700001902130700002402149700002002173700001202193700002702205700002202232700002002254700002402274700002802298700002402326700002102350700002402371700002102395700002202416700002802438700002102466700002702487700003002514700002002544700001502564700002402579700002002603700001702623700002302640700001902663700001902682700002202701700002202723700001802745700002202763700001902785700001902804700001402823700001802837700001402855700002102869700002302890700002802913700001702941700001902958700001902977700001702996700002003013700002103033700002403054700002503078700002303103700002303126700002103149700002603170700002203196700002003218700002003238700002003258700002003278700002903298700001703327700002303344710002603367710002303393710002603416710002503442710006603467710002203533856003603555 2016 eng d a1546-171800aMeta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.0 aMetaanalysis identifies common and rare variants influencing blo c2016 Oct a1162-700 v483 aMeta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
1 aLiu, Chunyu1 aKraja, Aldi, T1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aFranceschini, Nora1 aBis, Joshua, C1 aRice, Kenneth1 aMorrison, Alanna, C1 aLu, Yingchang1 aWeiss, Stefan1 aGuo, Xiuqing1 aPalmas, Walter1 aMartin, Lisa, W1 aChen, Yii-Der Ida1 aSurendran, Praveen1 aDrenos, Fotios1 aCook, James, P1 aAuer, Paul, L1 aChu, Audrey, Y1 aGiri, Ayush1 aZhao, Wei1 aJakobsdottir, Johanna1 aLin, Li-An1 aStafford, Jeanette, M1 aAmin, Najaf1 aMei, Hao1 aYao, Jie1 aVoorman, Arend1 aLarson, Martin, G1 aGrove, Megan, L1 aSmith, Albert, V1 aHwang, Shih-Jen1 aChen, Han1 aHuan, Tianxiao1 aKosova, Gulum1 aStitziel, Nathan, O1 aKathiresan, Sekar1 aSamani, Nilesh1 aSchunkert, Heribert1 aDeloukas, Panos1 aLi, Man1 aFuchsberger, Christian1 aPattaro, Cristian1 aGorski, Mathias1 aKooperberg, Charles1 aPapanicolaou, George, J1 aRossouw, Jacques, E1 aFaul, Jessica, D1 aKardia, Sharon, L R1 aBouchard, Claude1 aRaffel, Leslie, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aVasan, Ramachandran, S1 aO'Donnell, Christopher, J1 aTaylor, Kent, D1 aLiu, Kiang1 aBottinger, Erwin, P1 aGottesman, Omri1 aDaw, Warwick1 aGiulianini, Franco1 aGanesh, Santhi1 aSalfati, Elias1 aHarris, Tamara, B1 aLauner, Lenore, J1 aDörr, Marcus1 aFelix, Stephan, B1 aRettig, Rainer1 aVölzke, Henry1 aKim, Eric1 aLee, Wen-Jane1 aLee, I-Te1 aSheu, Wayne, H-H1 aTsosie, Krystal, S1 aEdwards, Digna, R Velez1 aLiu, Yongmei1 aCorrea, Adolfo1 aWeir, David, R1 aVölker, Uwe1 aRidker, Paul, M1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aReiner, Alexander, P1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aEdwards, Todd, L1 aChakravarti, Aravinda1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aLoos, Ruth, J F1 aFornage, Myriam1 aEhret, Georg, B1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aChasman, Daniel, I1 aCHD Exome+ Consortium1 aExomeBP Consortium1 aGoT2DGenes Consortium1 aT2D-GENES Consortium1 aMyocardial Infarction Genetics and CARDIoGRAM Exome Consortia1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/726405480nas a2201321 4500008004100000022001400041245007700055210006900132260001600201520175400217100002301971700001901994700002402013700001902037700001802056700002102074700002302095700001702118700002002135700001802155700001702173700002002190700002002210700002802230700002502258700001802283700002402301700001702325700002402342700002102366700002002387700001902407700001302426700003102439700001602470700001702486700002302503700001802526700002202544700002502566700002002591700002102611700001902632700001902651700002102670700002102691700002202712700002202734700002302756700001902779700001802798700001902816700001802835700001902853700002002872700002402892700001902916700002202935700002002957700001902977700002502996700002203021700002303043700002003066700002303086700001903109700002603128700002203154700002103176700002003197700001603217700002503233700002303258700002303281700002203304700002603326700002103352700002203373700002003395700002203415700002003437700002303457700002803480700002203508700002203530700001703552700002303569700002503592700001803617700002403635700002103659700002103680700002103701700002203722700001803744700001903762700002203781700002403803700002203827700002003849700002903869700002003898700002103918700002203939700002103961700002303982700001904005700002204024700002404046700003004070710002204100856003604122 2016 eng d a1942-326800aMultiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.0 aMultiethnic ExomeWide Association Study of Subclinical Atheroscl c2016 Nov 213 aBACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.
METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).
CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.
1 aNatarajan, Pradeep1 aBis, Joshua, C1 aBielak, Lawrence, F1 aCox, Amanda, J1 aDörr, Marcus1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 aIsaacs, Aaron1 aJhun, Min, A1 aKavousi, Maryam1 aLi-Gao, Ruifang1 aLyytikäinen, Leo-Pekka1 aMarioni, Riccardo, E1 aSchminke, Ulf1 aStitziel, Nathan, O1 aTada, Hayato1 avan Setten, Jessica1 aSmith, Albert, V1 aVojinovic, Dina1 aYanek, Lisa, R1 aYao, Jie1 aYerges-Armstrong, Laura, M1 aAmin, Najaf1 aBaber, Usman1 aBorecki, Ingrid, B1 aCarr, Jeffrey1 aChen, Yii-Der Ida1 aCupples, Adrienne, L1 ade Jong, Pim, A1 ade Koning, Harry1 ade Vos, Bob, D1 aDemirkan, Ayse1 aFuster, Valentin1 aFranco, Oscar, H1 aGoodarzi, Mark, O1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHoffmann, Udo1 aHofman, Albert1 aIšgum, Ivana1 aJukema, Wouter1 aKähönen, Mika1 aKardia, Sharon, L R1 aKral, Brian, G1 aLauner, Lenore, J1 aMassaro, Joseph1 aMehran, Roxana1 aMitchell, Braxton, D1 aMosley, Thomas, H1 ade Mutsert, Renée1 aNewman, Anne, B1 aNguyen, Khanh-Dung1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOudkerk, Matthijs1 aPankow, James, S1 aPeloso, Gina, M1 aPost, Wendy1 aProvince, Michael, A1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRivadeneira, Fernando1 aRosendaal, Frits1 aSartori, Samantha1 aTaylor, Kent, D1 aTeumer, Alexander1 aTrompet, Stella1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Lugt, Aad1 aVölker, Uwe1 aWardlaw, Joanna, M1 aWassel, Christina, L1 aWeiss, Stefan1 aWojczynski, Mary, K1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBowden, Donald, W1 aDeary, Ian, J1 aDehghan, Abbas1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aLehtimäki, Terho1 aMathias, Rasika1 aMook-Kanamori, Dennis, O1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRotter, Jerome, I1 aWilson, James, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aKathiresan, Sekar1 aPeyser, Patricia, A1 aO'Donnell, Christopher, J1 aCHARGE Consortium uhttps://chs-nhlbi.org/node/725706109nas a2201525 4500008004100000022001400041245009200055210006900147260001500216300001000231490000700241520179700248100002002045700002002065700002002085700002002105700002002125700001902145700002402164700002202188700002202210700002102232700001802253700002302271700001602294700002302310700002102333700002102354700001602375700001702391700001702408700002502425700002102450700001202471700002602483700002302509700002102532700002102553700001602574700002302590700002802613700001702641700002302658700002002681700002102701700001802722700002302740700002202763700001802785700001902803700002602822700002302848700002102871700002302892700002002915700002502935700002002960700002002980700002203000700002403022700002203046700002003068700002103088700002403109700001903133700002403152700002003176700001803196700002403214700002003238700002603258700002203284700002203306700002403328700002803352700002403380700001703404700002203421700002203443700002103465700002503486700002103511700001203532700001703544700002103561700002103582700001803603700002103621700002103642700001603663700002703679700001903706700002303725700002203748700002203770700002503792700001903817700002803836700002403864700002003888700002103908700002003929700002003949700002103969700002003990700001604010700002404026700002204050700001804072700002404090700001704114700001904131700001904150700002604169700002804195700002104223700001904244700002104263700002204284700002204306700002004328700001804348700002004366700002204386700002304408710003804431710003204469710004604501856003604547 2016 eng d a1537-660500aPlatelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.0 aPlateletRelated Variants Identified by Exomechip Metaanalysis in c2016 Jul 7 a40-550 v993 aPlatelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
1 aEicher, John, D1 aChami, Nathalie1 aKacprowski, Tim1 aNomura, Akihiro1 aChen, Ming-Huei1 aYanek, Lisa, R1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aSlater, Andrew, J1 aPankratz, Nathan1 aPolfus, Linda1 aSchurmann, Claudia1 aGiri, Ayush1 aBrody, Jennifer, A1 aLange, Leslie, A1 aManichaikul, Ani1 aHill, David1 aPazoki, Raha1 aElliot, Paul1 aEvangelou, Evangelos1 aTzoulaki, Ioanna1 aGao, He1 aVergnaud, Anne-Claire1 aMathias, Rasika, A1 aBecker, Diane, M1 aBecker, Lewis, C1 aBurt, Amber1 aCrosslin, David, R1 aLyytikäinen, Leo-Pekka1 aNikus, Kjell1 aHernesniemi, Jussi1 aKähönen, Mika1 aRaitoharju, Emma1 aMononen, Nina1 aRaitakari, Olli, T1 aLehtimäki, Terho1 aCushman, Mary1 aZakai, Neil, A1 aNickerson, Deborah, A1 aRaffield, Laura, M1 aQuarells, Rakale1 aWiller, Cristen, J1 aPeloso, Gina, M1 aAbecasis, Goncalo, R1 aLiu, Dajiang, J1 aDeloukas, Panos1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aFornage, Myriam1 aRichard, Melissa1 aTardif, Jean-Claude1 aRioux, John, D1 aDubé, Marie-Pierre1 ade Denus, Simon1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSmith, Albert, Vernon1 aHarris, Tamara, B1 aLauner, Lenore, J1 aGudnason, Vilmundur1 aEdwards, Digna, R Velez1 aTorstenson, Eric, S1 aLiu, Yongmei1 aTracy, Russell, P1 aRotter, Jerome, I1 aRich, Stephen, S1 aHighland, Heather, M1 aBoerwinkle, Eric1 aLi, Jin1 aLange, Ethan1 aWilson, James, G1 aMihailov, Evelin1 aMägi, Reedik1 aHirschhorn, Joel1 aMetspalu, Andres1 aEsko, Tõnu1 aVacchi-Suzzi, Caterina1 aNalls, Mike, A1 aZonderman, Alan, B1 aEvans, Michele, K1 aEngström, Gunnar1 aOrho-Melander, Marju1 aMelander, Olle1 aO'Donoghue, Michelle, L1 aWaterworth, Dawn, M1 aWallentin, Lars1 aWhite, Harvey, D1 aFloyd, James, S1 aBartz, Traci, M1 aRice, Kenneth, M1 aPsaty, Bruce, M1 aStarr, J, M1 aLiewald, David, C M1 aHayward, Caroline1 aDeary, Ian, J1 aGreinacher, Andreas1 aVölker, Uwe1 aThiele, Thomas1 aVölzke, Henry1 avan Rooij, Frank, J A1 aUitterlinden, André, G1 aFranco, Oscar, H1 aDehghan, Abbas1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aKathiresan, Sekar1 aFaraday, Nauder1 aAuer, Paul, L1 aReiner, Alex, P1 aLettre, Guillaume1 aJohnson, Andrew, D1 aGlobal Lipids Genetics Consortium1 aCARDIoGRAM Exome Consortium1 aMyocardial Infarction Genetics Consortium uhttps://chs-nhlbi.org/node/713909668nas a2203061 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2017 eng d a1546-171800aExome-wide association study of plasma lipids in >300,000 individuals.0 aExomewide association study of plasma lipids in 300000 individua c2017 Dec a1758-17660 v493 aWe screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aExome10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aHumans10aLipids10aMacular Degeneration10aPhenotype10aRisk Factors1 aLiu, Dajiang, J1 aPeloso, Gina, M1 aYu, Haojie1 aButterworth, Adam, S1 aWang, Xiao1 aMahajan, Anubha1 aSaleheen, Danish1 aEmdin, Connor1 aAlam, Dewan1 aAlves, Alexessander, Couto1 aAmouyel, Philippe1 aDi Angelantonio, Emanuele1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aAuer, Paul, L1 aBaber, Usman1 aBallantyne, Christie, M1 aBang, Lia, E1 aBenn, Marianne1 aBis, Joshua, C1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrandslund, Ivan1 aBrown, Morris1 aBusonero, Fabio1 aCaulfield, Mark, J1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Eugene1 aChen, Yii-Der Ida1 aChowdhury, Raj1 aChristensen, Cramer1 aChu, Audrey, Y1 aConnell, John, M1 aCucca, Francesco1 aCupples, Adrienne, L1 aDamrauer, Scott, M1 aDavies, Gail1 aDeary, Ian, J1 aDedoussis, George1 aDenny, Joshua, C1 aDominiczak, Anna1 aDubé, Marie-Pierre1 aEbeling, Tapani1 aEiriksdottir, Gudny1 aEsko, Tõnu1 aFarmaki, Aliki-Eleni1 aFeitosa, Mary, F1 aFerrario, Marco1 aFerrieres, Jean1 aFord, Ian1 aFornage, Myriam1 aFranks, Paul, W1 aFrayling, Timothy, M1 aFrikke-Schmidt, Ruth1 aFritsche, Lars, G1 aFrossard, Philippe1 aFuster, Valentin1 aGanesh, Santhi, K1 aGao, Wei1 aGarcia, Melissa, E1 aGieger, Christian1 aGiulianini, Franco1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGrarup, Niels1 aGroop, Leif1 aGrove, Megan, L1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHirschhorn, Joel, N1 aHolmen, Oddgeir, L1 aHuffman, Jennifer1 aHuo, Yong1 aHveem, Kristian1 aJabeen, Sehrish1 aJackson, Anne, U1 aJakobsdottir, Johanna1 aJarvelin, Marjo-Riitta1 aJensen, Gorm, B1 aJørgensen, Marit, E1 aJukema, Wouter1 aJustesen, Johanne, M1 aKamstrup, Pia, R1 aKanoni, Stavroula1 aKarpe, Fredrik1 aKee, Frank1 aKhera, Amit, V1 aKlarin, Derek1 aKoistinen, Heikki, A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo1 aLangenberg, Claudia1 aLangsted, Anne1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLiewald, David, C M1 aLin, Li, An1 aLinneberg, Allan1 aLoos, Ruth, J F1 aLu, Yingchang1 aLu, Xiangfeng1 aMägi, Reedik1 aMälarstig, Anders1 aManichaikul, Ani1 aManning, Alisa, K1 aMäntyselkä, Pekka1 aMarouli, Eirini1 aMasca, Nicholas, G D1 aMaschio, Andrea1 aMeigs, James, B1 aMelander, Olle1 aMetspalu, Andres1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMulas, Antonella1 aMüller-Nurasyid, Martina1 aMunroe, Patricia, B1 aNeville, Matt, J1 aNielsen, Jonas, B1 aNielsen, Sune, F1 aNordestgaard, Børge, G1 aOrdovas, Jose, M1 aMehran, Roxana1 aO'Donnell, Christoper, J1 aOrho-Melander, Marju1 aMolony, Cliona, M1 aMuntendam, Pieter1 aPadmanabhan, Sandosh1 aPalmer, Colin, N A1 aPasko, Dorota1 aPatel, Aniruddh, P1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPisinger, Charlotta1 aPistis, Giorgio1 aPolasek, Ozren1 aPoulter, Neil1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRasheed, Asif1 aRauramaa, Rainer1 aReilly, Dermot, F1 aReiner, Alex, P1 aRenstrom, Frida1 aRich, Stephen, S1 aRidker, Paul, M1 aRioux, John, D1 aRobertson, Neil, R1 aRoden, Dan, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSanna, Serena1 aSattar, Naveed1 aSchmidt, Ellen, M1 aScott, Robert, A1 aSever, Peter1 aSevilla, Raquel, S1 aShaffer, Christian, M1 aSim, Xueling1 aSivapalaratnam, Suthesh1 aSmall, Kerrin, S1 aSmith, Albert, V1 aSmith, Blair, H1 aSomayajula, Sangeetha1 aSoutham, Lorraine1 aSpector, Timothy, D1 aSpeliotes, Elizabeth, K1 aStarr, John, M1 aStirrups, Kathleen, E1 aStitziel, Nathan1 aStrauch, Konstantin1 aStringham, Heather, M1 aSurendran, Praveen1 aTada, Hayato1 aTall, Alan, R1 aTang, Hua1 aTardif, Jean-Claude1 aTaylor, Kent, D1 aTrompet, Stella1 aTsao, Philip, S1 aTuomilehto, Jaakko1 aTybjaerg-Hansen, Anne1 avan Zuydam, Natalie, R1 aVarbo, Anette1 aVarga, Tibor, V1 aVirtamo, Jarmo1 aWaldenberger, Melanie1 aWang, Nan1 aWareham, Nick, J1 aWarren, Helen, R1 aWeeke, Peter, E1 aWeinstock, Joshua1 aWessel, Jennifer1 aWilson, James, G1 aWilson, Peter, W F1 aXu, Ming1 aYaghootkar, Hanieh1 aYoung, Robin1 aZeggini, Eleftheria1 aZhang, He1 aZheng, Neil, S1 aZhang, Weihua1 aZhang, Yan1 aZhou, Wei1 aZhou, Yanhua1 aZoledziewska, Magdalena1 aHowson, Joanna, M M1 aDanesh, John1 aMcCarthy, Mark, I1 aCowan, Chad, A1 aAbecasis, Goncalo1 aDeloukas, Panos1 aMusunuru, Kiran1 aWiller, Cristen, J1 aKathiresan, Sekar1 aCharge Diabetes Working Group1 aEPIC-InterAct Consortium1 aEPIC-CVD Consortium1 aGOLD Consortium1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/757306999nas a2202113 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2017 eng d a1546-171800aLarge-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.0 aLargescale analyses of common and rare variants identify 12 new c2017 Jun a946-9520 v493 aAtrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.
1 aChristophersen, Ingrid, E1 aRienstra, Michiel1 aRoselli, Carolina1 aYin, Xiaoyan1 aGeelhoed, Bastiaan1 aBarnard, John1 aLin, Honghuang1 aArking, Dan, E1 aSmith, Albert, V1 aAlbert, Christine, M1 aChaffin, Mark1 aTucker, Nathan, R1 aLi, Molong1 aKlarin, Derek1 aBihlmeyer, Nathan, A1 aLow, Siew-Kee1 aWeeke, Peter, E1 aMüller-Nurasyid, Martina1 aSmith, Gustav1 aBrody, Jennifer, A1 aNiemeijer, Maartje, N1 aDörr, Marcus1 aTrompet, Stella1 aHuffman, Jennifer1 aGustafsson, Stefan1 aSchurmann, Claudia1 aKleber, Marcus, E1 aLyytikäinen, Leo-Pekka1 aSeppälä, Ilkka1 aMalik, Rainer1 aHorimoto, Andrea, R V R1 aPerez, Marco1 aSinisalo, Juha1 aAeschbacher, Stefanie1 aThériault, Sébastien1 aYao, Jie1 aRadmanesh, Farid1 aWeiss, Stefan1 aTeumer, Alexander1 aChoi, Seung, Hoan1 aWeng, Lu-Chen1 aClauss, Sebastian1 aDeo, Rajat1 aRader, Daniel, J1 aShah, Svati, H1 aSun, Albert1 aHopewell, Jemma, C1 aDebette, Stephanie1 aChauhan, Ganesh1 aYang, Qiong1 aWorrall, Bradford, B1 aParé, Guillaume1 aKamatani, Yoichiro1 aHagemeijer, Yanick, P1 aVerweij, Niek1 aSiland, Joylene, E1 aKubo, Michiaki1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aBis, Joshua, C1 aPerz, Siegfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aMagnani, Jared, W1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShoemaker, Benjamin1 aPadmanabhan, Sandosh1 aHaessler, Jeffrey1 aBartz, Traci, M1 aWaldenberger, Melanie1 aLichtner, Peter1 aArendt, Marina1 aKrieger, Jose, E1 aKähönen, Mika1 aRisch, Lorenz1 aMansur, Alfredo, J1 aPeters, Annette1 aSmith, Blair, H1 aLind, Lars1 aScott, Stuart, A1 aLu, Yingchang1 aBottinger, Erwin, B1 aHernesniemi, Jussi1 aLindgren, Cecilia, M1 aWong, Jorge, A1 aHuang, Jie1 aEskola, Markku1 aMorris, Andrew, P1 aFord, Ian1 aReiner, Alex, P1 aDelgado, Graciela1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aSandhu, Roopinder, K1 aLi, Man1 aBoerwinkle, Eric1 aEisele, Lewin1 aLannfelt, Lars1 aRost, Natalia1 aAnderson, Christopher, D1 aTaylor, Kent, D1 aCampbell, Archie1 aMagnusson, Patrik, K1 aPorteous, David1 aHocking, Lynne, J1 aVlachopoulou, Efthymia1 aPedersen, Nancy, L1 aNikus, Kjell1 aOrho-Melander, Marju1 aHamsten, Anders1 aHeeringa, Jan1 aDenny, Joshua, C1 aKriebel, Jennifer1 aDarbar, Dawood1 aNewton-Cheh, Christopher1 aShaffer, Christian1 aMacfarlane, Peter, W1 aHeilmann-Heimbach, Stefanie1 aAlmgren, Peter1 aHuang, Paul, L1 aSotoodehnia, Nona1 aSoliman, Elsayed, Z1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aVölker, Uwe1 aJöckel, Karl-Heinz1 aSinner, Moritz, F1 aLin, Henry, J1 aGuo, Xiuqing1 aDichgans, Martin1 aIngelsson, Erik1 aKooperberg, Charles1 aMelander, Olle1 aLoos, Ruth, J F1 aLaurikka, Jari1 aConen, David1 aRosand, Jonathan1 aHarst, Pim1 aLokki, Marja-Liisa1 aKathiresan, Sekar1 aPereira, Alexandre1 aJukema, Wouter1 aHayward, Caroline1 aRotter, Jerome, I1 aMärz, Winfried1 aLehtimäki, Terho1 aStricker, Bruno, H1 aChung, Mina, K1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aRoden, Dan, M1 aKääb, Stefan1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aTanaka, Toshihiro1 aLunetta, Kathryn, L1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aMETASTROKE Consortium of the ISGC1 aNeurology Working Group of the CHARGE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/739609467nas 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.
1 aWain, Louise, V1 aVaez, Ahmad1 aJansen, Rick1 aJoehanes, Roby1 avan der Most, Peter, J1 aErzurumluoglu, Mesut1 aO'Reilly, Paul, F1 aCabrera, Claudia, P1 aWarren, Helen, R1 aRose, Lynda, M1 aVerwoert, Germaine, C1 aHottenga, Jouke-Jan1 aStrawbridge, Rona, J1 aEsko, Tõnu1 aArking, Dan, E1 aHwang, Shih-Jen1 aGuo, Xiuqing1 aKutalik, Zoltán1 aTrompet, Stella1 aShrine, Nick1 aTeumer, Alexander1 aRied, Janina, S1 aBis, Joshua, C1 aSmith, Albert, V1 aAmin, Najaf1 aNolte, Ilja, M1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aWareham, Nicholas, J1 aHofer, Edith1 aJoshi, Peter, K1 aKristiansson, Kati1 aTraglia, Michela1 aHavulinna, Aki, S1 aGoel, Anuj1 aNalls, Mike, A1 aSõber, Siim1 aVuckovic, Dragana1 aLuan, Jian'an1 aM, Fabiola, del Greco1 aAyers, Kristin, L1 aMarrugat, Jaume1 aRuggiero, Daniela1 aLopez, Lorna, M1 aNiiranen, Teemu1 aEnroth, Stefan1 aJackson, Anne, U1 aNelson, Christopher, P1 aHuffman, Jennifer, E1 aZhang, Weihua1 aMarten, Jonathan1 aGandin, Ilaria1 aHarris, Sarah, E1 aZemunik, Tatijana1 aLu, Yingchang1 aEvangelou, Evangelos1 aShah, Nabi1 ade Borst, Martin, H1 aMangino, Massimo1 aPrins, Bram, P1 aCampbell, Archie1 aLi-Gao, Ruifang1 aChauhan, Ganesh1 aOldmeadow, Christopher1 aAbecasis, Goncalo1 aAbedi, Maryam1 aBarbieri, Caterina, M1 aBarnes, Michael, R1 aBatini, Chiara1 aBeilby, John1 aBlake, Tineka1 aBoehnke, Michael1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrown, Morris1 aBrumat, Marco1 aCampbell, Harry1 aChambers, John, C1 aCocca, Massimiliano1 aCollins, Francis1 aConnell, John1 aCordell, Heather, J1 aDamman, Jeffrey, J1 aDavies, Gail1 ade Geus, Eco, J1 ade Mutsert, Renée1 aDeelen, Joris1 aDemirkale, Yusuf1 aDoney, Alex, S F1 aDörr, Marcus1 aFarrall, Martin1 aFerreira, Teresa1 aFrånberg, Mattias1 aGao, He1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGiulianini, Franco1 aGow, Alan, J1 aHamsten, Anders1 aHarris, Tamara, B1 aHofman, Albert1 aHolliday, Elizabeth, G1 aHui, Jennie1 aJarvelin, Marjo-Riitta1 aJohansson, Asa1 aJohnson, Andrew, D1 aJousilahti, Pekka1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKhaw, Kay-Tee1 aKolcic, Ivana1 aKoskinen, Seppo1 aLangenberg, Claudia1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aMach, François1 aMamasoula, Chrysovalanto1 aMenni, Cristina1 aMifsud, Borbala1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNandakumar, Priyanka1 aNguyen, Quang, Tri1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalotie, Aarno1 aParé, Guillaume1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPoulter, Neil1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRen, Meixia1 aRice, Kenneth1 aRidker, Paul, M1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRotter, Jerome, I1 aRudan, Igor1 aSaba, Yasaman1 aPierre, Aude, Saint1 aSala, Cinzia, F1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aScott, Rodney1 aSeelen, Marc, A1 aShields, Denis, C1 aSiscovick, David1 aSorice, Rossella1 aStanton, Alice1 aStott, David, J1 aSundström, Johan1 aSwertz, Morris1 aTaylor, Kent, D1 aThom, Simon1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, André, G1 aVölker, Uwe1 aVollenweider, Peter1 aWild, Sarah1 aWillemsen, Gonneke1 aWright, Alan, F1 aYao, Jie1 aThériault, Sébastien1 aConen, David1 aAttia, John1 aSever, Peter1 aDebette, Stephanie1 aMook-Kanamori, Dennis, O1 aZeggini, Eleftheria1 aSpector, Tim, D1 aHarst, Pim1 aPalmer, Colin, N A1 aVergnaud, Anne-Claire1 aLoos, Ruth, J F1 aPolasek, Ozren1 aStarr, John, M1 aGirotto, Giorgia1 aHayward, Caroline1 aKooner, Jaspal, S1 aLindgren, Cecila, M1 aVitart, Veronique1 aSamani, Nilesh, J1 aTuomilehto, Jaakko1 aGyllensten, Ulf1 aKnekt, Paul1 aDeary, Ian, J1 aCiullo, Marina1 aElosua, Roberto1 aKeavney, Bernard, D1 aHicks, Andrew, A1 aScott, Robert, A1 aGasparini, Paolo1 aLaan, Maris1 aLiu, Yongmei1 aWatkins, Hugh1 aHartman, Catharina, A1 aSalomaa, Veikko1 aToniolo, Daniela1 aPerola, Markus1 aWilson, James, F1 aSchmidt, Helena1 aZhao, Jing Hua1 aLehtimäki, Terho1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aPeters, Annette1 aRettig, Rainer1 aJames, Alan1 aJukema, Wouter1 aStrachan, David, P1 aPalmas, Walter1 aMetspalu, Andres1 aIngelsson, Erik1 aBoomsma, Dorret, I1 aFranco, Oscar, H1 aBochud, Murielle1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aElliott, Paul1 aChasman, Daniel, I1 aChakravarti, Aravinda1 aKnight, Joanne1 aMorris, Andrew, P1 aLevy, Daniel1 aTobin, Martin, D1 aSnieder, Harold1 aCaulfield, Mark, J1 aEhret, Georg, B uhttps://chs-nhlbi.org/node/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, Vilmundur1 aGuo, Xiuqing1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHarris, Sarah, E1 aHartman, Catharina, A1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHofer, Edith1 aHofman, Albert1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aIngelsson, Erik1 aJames, Alan1 aJansen, Rick1 aJarvelin, Marjo-Riitta1 aJoehanes, Roby1 aJohansson, Asa1 aJohnson, Andrew, D1 aJoshi, Peter, K1 aJousilahti, Pekka1 aJukema, Wouter1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKeavney, Bernard, D1 aKhaw, Kay-Tee1 aKnekt, Paul1 aKnight, Joanne1 aKolcic, Ivana1 aKooner, Jaspal, S1 aKoskinen, Seppo1 aKristiansson, Kati1 aKutalik, Zoltán1 aLaan, Maris1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLopez, Lorna, M1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aMamasoula, Chrysovalanto1 aMarrugat, Jaume1 aMarten, Jonathan1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNalls, Mike, A1 aNandakumar, Priyanka1 aNelson, Christopher, P1 aNiiranen, Teemu1 aNolte, Ilja, M1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aO'Reilly, Paul, F1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPalotie, Aarno1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPramstaller, Peter, P1 aNguyen, Quang, Tri1 aRaitakari, Olli, T1 aRen, Meixia1 aRettig, Rainer1 aRice, Kenneth1 aRidker, Paul, M1 aRied, Janina, S1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRose, Lynda, M1 aRotter, Jerome, I1 aRudan, Igor1 aRuggiero, Daniela1 aSaba, Yasaman1 aSala, Cinzia, F1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aSchmidt, Helena1 aShrine, Nick1 aSiscovick, David1 aSmith, Albert, V1 aSnieder, Harold1 aSõber, Siim1 aSorice, Rossella1 aStarr, John, M1 aStott, David, J1 aStrachan, David, P1 aStrawbridge, Rona, J1 aSundström, Johan1 aSwertz, Morris, A1 aTaylor, Kent, D1 aTeumer, Alexander1 aTobin, Martin, D1 aTomaszewski, Maciej1 aToniolo, Daniela1 aTraglia, Michela1 aTrompet, Stella1 aTuomilehto, Jaakko1 aTzourio, Christophe1 aUitterlinden, André, G1 aVaez, Ahmad1 avan der Most, Peter, J1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aVerwoert, Germaine, C1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVuckovic, Dragana1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWright, Alan, F1 aYao, Jie1 aZemunik, Tatijana1 aZhang, Weihua1 aAttia, John, R1 aButterworth, Adam, S1 aChasman, Daniel, I1 aConen, David1 aCucca, Francesco1 aDanesh, John1 aHayward, Caroline1 aHowson, Joanna, M M1 aLaakso, Markku1 aLakatta, Edward, G1 aLangenberg, Claudia1 aMelander, Olle1 aMook-Kanamori, Dennis, O1 aPalmer, Colin, N A1 aRisch, Lorenz1 aScott, Robert, A1 aScott, Rodney, J1 aSever, Peter1 aSpector, Tim, D1 aHarst, Pim1 aWareham, Nicholas, J1 aZeggini, Eleftheria1 aLevy, Daniel1 aMunroe, Patricia, B1 aNewton-Cheh, Christopher1 aBrown, Morris, J1 aMetspalu, Andres1 aHung, Adriana, M1 aO'Donnell, Christopher, J1 aEdwards, Todd, L1 aPsaty, Bruce, M1 aTzoulaki, Ioanna1 aBarnes, Michael, R1 aWain, Louise, V1 aElliott, Paul1 aCaulfield, Mark, J1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/784508664nas a2202749 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2018 eng d a1546-171800aMulti-ethnic genome-wide association study for atrial fibrillation.0 aMultiethnic genomewide association study for atrial fibrillation c2018 Sep a1225-12330 v503 aAtrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
1 aRoselli, Carolina1 aChaffin, Mark, D1 aWeng, Lu-Chen1 aAeschbacher, Stefanie1 aAhlberg, Gustav1 aAlbert, Christine, M1 aAlmgren, Peter1 aAlonso, Alvaro1 aAnderson, Christopher, D1 aAragam, Krishna, G1 aArking, Dan, E1 aBarnard, John1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aBihlmeyer, Nathan, A1 aBis, Joshua, C1 aBloom, Heather, L1 aBoerwinkle, Eric1 aBottinger, Erwin, B1 aBrody, Jennifer, A1 aCalkins, Hugh1 aCampbell, Archie1 aCappola, Thomas, P1 aCarlquist, John1 aChasman, Daniel, I1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aChoi, Eue-Keun1 aChoi, Seung, Hoan1 aChristophersen, Ingrid, E1 aChung, Mina, K1 aCole, John, W1 aConen, David1 aCook, James1 aCrijns, Harry, J1 aCutler, Michael, J1 aDamrauer, Scott, M1 aDaniels, Brian, R1 aDarbar, Dawood1 aDelgado, Graciela1 aDenny, Joshua, C1 aDichgans, Martin1 aDörr, Marcus1 aDudink, Elton, A1 aDudley, Samuel, C1 aEsa, Nada1 aEsko, Tõnu1 aEskola, Markku1 aFatkin, Diane1 aFelix, Stephan, B1 aFord, Ian1 aFranco, Oscar, H1 aGeelhoed, Bastiaan1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGupta, Namrata1 aGustafsson, Stefan1 aGutmann, Rebecca1 aHamsten, Anders1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHernesniemi, Jussi1 aHocking, Lynne, J1 aHofman, Albert1 aHorimoto, Andrea, R V R1 aHuang, Jie1 aHuang, Paul, L1 aHuffman, Jennifer1 aIngelsson, Erik1 aIpek, Esra, Gucuk1 aIto, Kaoru1 aJimenez-Conde, Jordi1 aJohnson, Renee1 aJukema, Wouter1 aKääb, Stefan1 aKähönen, Mika1 aKamatani, Yoichiro1 aKane, John, P1 aKastrati, Adnan1 aKathiresan, Sekar1 aKatschnig-Winter, Petra1 aKavousi, Maryam1 aKessler, Thorsten1 aKietselaer, Bas, L1 aKirchhof, Paulus1 aKleber, Marcus, E1 aKnight, Stacey1 aKrieger, Jose, E1 aKubo, Michiaki1 aLauner, Lenore, J1 aLaurikka, Jari1 aLehtimäki, Terho1 aLeineweber, Kirsten1 aLemaitre, Rozenn, N1 aLi, Man1 aLim, Hong, Euy1 aLin, Henry, J1 aLin, Honghuang1 aLind, Lars1 aLindgren, Cecilia, M1 aLokki, Marja-Liisa1 aLondon, Barry1 aLoos, Ruth, J F1 aLow, Siew-Kee1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMacfarlane, Peter, W1 aMagnusson, Patrik, K1 aMahajan, Anubha1 aMalik, Rainer1 aMansur, Alfredo, J1 aMarcus, Gregory, M1 aMargolin, Lauren1 aMargulies, Kenneth, B1 aMärz, Winfried1 aMcManus, David, D1 aMelander, Olle1 aMohanty, Sanghamitra1 aMontgomery, Jay, A1 aMorley, Michael, P1 aMorris, Andrew, P1 aMüller-Nurasyid, Martina1 aNatale, Andrea1 aNazarian, Saman1 aNeumann, Benjamin1 aNewton-Cheh, Christopher1 aNiemeijer, Maartje, N1 aNikus, Kjell1 aNilsson, Peter1 aNoordam, Raymond1 aOellers, Heidi1 aOlesen, Morten, S1 aOrho-Melander, Marju1 aPadmanabhan, Sandosh1 aPak, Hui-Nam1 aParé, Guillaume1 aPedersen, Nancy, L1 aPera, Joanna1 aPereira, Alexandre1 aPorteous, David1 aPsaty, Bruce, M1 aPulit, Sara, L1 aPullinger, Clive, R1 aRader, Daniel, J1 aRefsgaard, Lena1 aRibasés, Marta1 aRidker, Paul, M1 aRienstra, Michiel1 aRisch, Lorenz1 aRoden, Dan, M1 aRosand, Jonathan1 aRosenberg, Michael, A1 aRost, Natalia1 aRotter, Jerome, I1 aSaba, Samir1 aSandhu, Roopinder, K1 aSchnabel, Renate, B1 aSchramm, Katharina1 aSchunkert, Heribert1 aSchurman, Claudia1 aScott, Stuart, A1 aSeppälä, Ilkka1 aShaffer, Christian1 aShah, Svati1 aShalaby, Alaa, A1 aShim, Jaemin1 aShoemaker, Benjamin1 aSiland, Joylene, E1 aSinisalo, Juha1 aSinner, Moritz, F1 aSlowik, Agnieszka1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Gustav1 aSmith, Jonathan, D1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSun, Albert1 aSun, Han1 aSvendsen, Jesper, H1 aTanaka, Toshihiro1 aTanriverdi, Kahraman1 aTaylor, Kent, D1 aTeder-Laving, Maris1 aTeumer, Alexander1 aThériault, Sébastien1 aTrompet, Stella1 aTucker, Nathan, R1 aTveit, Arnljot1 aUitterlinden, André, G1 aHarst, Pim1 aVan Gelder, Isabelle, C1 aVan Wagoner, David, R1 aVerweij, Niek1 aVlachopoulou, Efthymia1 aVölker, Uwe1 aWang, Biqi1 aWeeke, Peter, E1 aWeijs, Bob1 aWeiss, Raul1 aWeiss, Stefan1 aWells, Quinn, S1 aWiggins, Kerri, L1 aWong, Jorge, A1 aWoo, Daniel1 aWorrall, Bradford, B1 aYang, Pil-Sung1 aYao, Jie1 aYoneda, Zachary, T1 aZeller, Tanja1 aZeng, Lingyao1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/781109584nas a2203049 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2018 eng d a1546-171800aRefining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.0 aRefining the accuracy of validated target identification through c2018 Apr a559-5710 v503 aWe aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
1 aMahajan, Anubha1 aWessel, Jennifer1 aWillems, Sara, M1 aZhao, Wei1 aRobertson, Neil, R1 aChu, Audrey, Y1 aGan, Wei1 aKitajima, Hidetoshi1 aTaliun, Daniel1 aRayner, William1 aGuo, Xiuqing1 aLu, Yingchang1 aLi, Man1 aJensen, Richard, A1 aHu, Yao1 aHuo, Shaofeng1 aLohman, Kurt, K1 aZhang, Weihua1 aCook, James, P1 aPrins, Bram, Peter1 aFlannick, Jason1 aGrarup, Niels1 aTrubetskoy, Vassily, Vladimirov1 aKravic, Jasmina1 aKim, Young, Jin1 aRybin, Denis, V1 aYaghootkar, Hanieh1 aMüller-Nurasyid, Martina1 aMeidtner, Karina1 aLi-Gao, Ruifang1 aVarga, Tibor, V1 aMarten, Jonathan1 aLi, Jin1 aSmith, Albert, Vernon1 aAn, Ping1 aLigthart, Symen1 aGustafsson, Stefan1 aMalerba, Giovanni1 aDemirkan, Ayse1 aTajes, Juan, Fernandez1 aSteinthorsdottir, Valgerdur1 aWuttke, Matthias1 aLecoeur, Cécile1 aPreuss, Michael1 aBielak, Lawrence, F1 aGraff, Marielisa1 aHighland, Heather, M1 aJustice, Anne, E1 aLiu, Dajiang, J1 aMarouli, Eirini1 aPeloso, Gina, Marie1 aWarren, Helen, R1 aAfaq, Saima1 aAfzal, Shoaib1 aAhlqvist, Emma1 aAlmgren, Peter1 aAmin, Najaf1 aBang, Lia, B1 aBertoni, Alain, G1 aBombieri, Cristina1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBurtt, Noel, P1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aCho, Yoon Shin1 aChristensen, Cramer1 aEastwood, Sophie, V1 aEckardt, Kai-Uwe1 aFischer, Krista1 aGambaro, Giovanni1 aGiedraitis, Vilmantas1 aGrove, Megan, L1 ade Haan, Hugoline, G1 aHackinger, Sophie1 aHai, Yang1 aHan, Sohee1 aTybjærg-Hansen, Anne1 aHivert, Marie-France1 aIsomaa, Bo1 aJäger, Susanne1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKäräjämäki, AnneMari1 aKim, Bong-Jo1 aKim, Sung, Soo1 aKoistinen, Heikki, A1 aKovacs, Peter1 aKriebel, Jennifer1 aKronenberg, Florian1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Jung-Jin1 aLehne, Benjamin1 aLi, Huaixing1 aLin, Keng-Hung1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jun1 aLoh, Marie1 aMägi, Reedik1 aMamakou, Vasiliki1 aMcKean-Cowdin, Roberta1 aNadkarni, Girish1 aNeville, Matt1 aNielsen, Sune, F1 aNtalla, Ioanna1 aPeyser, Patricia, A1 aRathmann, Wolfgang1 aRice, Kenneth1 aRich, Stephen, S1 aRode, Line1 aRolandsson, Olov1 aSchönherr, Sebastian1 aSelvin, Elizabeth1 aSmall, Kerrin, S1 aStančáková, Alena1 aSurendran, Praveen1 aTaylor, Kent, D1 aTeslovich, Tanya, M1 aThorand, Barbara1 aThorleifsson, Gudmar1 aTin, Adrienne1 aTönjes, Anke1 aVarbo, Anette1 aWitte, Daniel, R1 aWood, Andrew, R1 aYajnik, Pranav1 aYao, Jie1 aYengo, Loic1 aYoung, Robin1 aAmouyel, Philippe1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aChowdhury, Raj1 aCollins, Francis, S1 aDedoussis, George1 aDehghan, Abbas1 aDeloukas, Panos1 aFerrario, Marco, M1 aFerrieres, Jean1 aFlorez, Jose, C1 aFrossard, Philippe1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHowson, Joanna, M M1 aIngelsson, Martin1 aKathiresan, Sekar1 aKee, Frank1 aKuusisto, Johanna1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLindgren, Cecilia, M1 aMännistö, Satu1 aMeitinger, Thomas1 aMelander, Olle1 aMohlke, Karen, L1 aMoitry, Marie1 aMorris, Andrew, D1 aMurray, Alison, D1 ade Mutsert, Renée1 aOrho-Melander, Marju1 aOwen, Katharine, R1 aPerola, Markus1 aPeters, Annette1 aProvince, Michael, A1 aRasheed, Asif1 aRidker, Paul, M1 aRivadineira, Fernando1 aRosendaal, Frits, R1 aRosengren, Anders, H1 aSalomaa, Veikko1 aSheu, Wayne, H-H1 aSladek, Rob1 aSmith, Blair, H1 aStrauch, Konstantin1 aUitterlinden, André, G1 aVarma, Rohit1 aWiller, Cristen, J1 aBlüher, Matthias1 aButterworth, Adam, S1 aChambers, John, Campbell1 aChasman, Daniel, I1 aDanesh, John1 aDuijn, Cornelia1 aDupuis, Josée1 aFranco, Oscar, H1 aFranks, Paul, W1 aFroguel, Philippe1 aGrallert, Harald1 aGroop, Leif1 aHan, Bok-Ghee1 aHansen, Torben1 aHattersley, Andrew, T1 aHayward, Caroline1 aIngelsson, Erik1 aKardia, Sharon, L R1 aKarpe, Fredrik1 aKooner, Jaspal, Singh1 aKöttgen, Anna1 aKuulasmaa, Kari1 aLaakso, Markku1 aLin, Xu1 aLind, Lars1 aLiu, Yongmei1 aLoos, Ruth, J F1 aMarchini, Jonathan1 aMetspalu, Andres1 aMook-Kanamori, Dennis1 aNordestgaard, Børge, G1 aPalmer, Colin, N A1 aPankow, James, S1 aPedersen, Oluf1 aPsaty, Bruce, M1 aRauramaa, Rainer1 aSattar, Naveed1 aSchulze, Matthias, B1 aSoranzo, Nicole1 aSpector, Timothy, D1 aStefansson, Kari1 aStumvoll, Michael1 aThorsteinsdottir, Unnur1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aWareham, Nicholas, J1 aWilson, James, G1 aZeggini, Eleftheria1 aScott, Robert, A1 aBarroso, Inês1 aFrayling, Timothy, M1 aGoodarzi, Mark, O1 aMeigs, James, B1 aBoehnke, Michael1 aSaleheen, Danish1 aMorris, Andrew, P1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aExomeBP Consortium1 aMAGIC Consortium1 aGIANT Consortium uhttps://chs-nhlbi.org/node/766806570nas a2201753 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2020 eng d a1476-468700aInherited causes of clonal haematopoiesis in 97,691 whole genomes.0 aInherited causes of clonal haematopoiesis in 97691 whole genomes c2020 10 a763-7680 v5863 aAge is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
1 aBick, Alexander, G1 aWeinstock, Joshua, S1 aNandakumar, Satish, K1 aFulco, Charles, P1 aBao, Erik, L1 aZekavat, Seyedeh, M1 aSzeto, Mindy, D1 aLiao, Xiaotian1 aLeventhal, Matthew, J1 aNasser, Joseph1 aChang, Kyle1 aLaurie, Cecelia1 aBurugula, Bala, Bharathi1 aGibson, Christopher, J1 aLin, Amy, E1 aTaub, Margaret, A1 aAguet, Francois1 aArdlie, Kristin1 aMitchell, Braxton, D1 aBarnes, Kathleen, C1 aMoscati, Arden1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aSilverman, Edwin, K1 aWeiss, Scott, T1 aPalmer, Nicholette, D1 aVasan, Ramachandran, S1 aBurchard, Esteban, G1 aKardia, Sharon, L R1 aHe, Jiang1 aKaplan, Robert, C1 aSmith, Nicholas, L1 aArnett, Donna, K1 aSchwartz, David, A1 aCorrea, Adolfo1 ade Andrade, Mariza1 aGuo, Xiuqing1 aKonkle, Barbara, A1 aCuster, Brian1 aPeralta, Juan, M1 aGui, Hongsheng1 aMeyers, Deborah, A1 aMcGarvey, Stephen, T1 aChen, Ida Yii-Der1 aShoemaker, Benjamin1 aPeyser, Patricia, A1 aBroome, Jai, G1 aGogarten, Stephanie, M1 aWang, Fei, Fei1 aWong, Quenna1 aMontasser, May, E1 aDaya, Michelle1 aKenny, Eimear, E1 aNorth, Kari, E1 aLauner, Lenore, J1 aCade, Brian, E1 aBis, Joshua, C1 aCho, Michael, H1 aLasky-Su, Jessica1 aBowden, Donald, W1 aCupples, Adrienne, L1 aC Y Mak, Angel1 aBecker, Lewis, C1 aSmith, Jennifer, A1 aKelly, Tanika, N1 aAslibekyan, Stella1 aHeckbert, Susan, R1 aTiwari, Hemant, K1 aYang, Ivana, V1 aHeit, John, A1 aLubitz, Steven, A1 aJohnsen, Jill, M1 aCurran, Joanne, E1 aWenzel, Sally, E1 aWeeks, Daniel, E1 aRao, Dabeeru, C1 aDarbar, Dawood1 aMoon, Jee-Young1 aTracy, Russell, P1 aButh, Erin, J1 aRafaels, Nicholas1 aLoos, Ruth, J F1 aDurda, Peter1 aLiu, Yongmei1 aHou, Lifang1 aLee, Jiwon1 aKachroo, Priyadarshini1 aFreedman, Barry, I1 aLevy, Daniel1 aBielak, Lawrence, F1 aHixson, James, E1 aFloyd, James, S1 aWhitsel, Eric, A1 aEllinor, Patrick, T1 aIrvin, Marguerite, R1 aFingerlin, Tasha, E1 aRaffield, Laura, M1 aArmasu, Sebastian, M1 aWheeler, Marsha, M1 aSabino, Ester, C1 aBlangero, John1 aWilliams, Keoki1 aLevy, Bruce, D1 aSheu, Wayne, Huey-Herng1 aRoden, Dan, M1 aBoerwinkle, Eric1 aManson, JoAnn, E1 aMathias, Rasika, A1 aDesai, Pinkal1 aTaylor, Kent, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aKooperberg, Charles1 aLaurie, Cathy, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aZhao, Hongyu1 aLange, Ethan1 aLange, Leslie1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aScheet, Paul1 aKitzman, Jacob, O1 aLander, Eric, S1 aEngreitz, Jesse, M1 aEbert, Benjamin, L1 aReiner, Alexander, P1 aJaiswal, Siddhartha1 aAbecasis, Goncalo1 aSankaran, Vijay, G1 aKathiresan, Sekar1 aNatarajan, Pradeep1 aNHLBI Trans-Omics for Precision Medicine Consortium uhttps://chs-nhlbi.org/node/862105153nas a2201369 4500008004100000022001400041245011700055210006900172260001500241300000900256490000700265520124400272100002301516700001901539700002101558700002701579700002001606700002201626700001901648700002601667700002601693700002001719700002001739700002301759700003001782700001901812700002301831700002901854700002801883700002401911700001901935700001901954700001201973700002401985700002102009700001702030700002502047700001902072700001802091700001502109700002402124700002002148700002002168700002202188700002002210700001702230700002602247700002602273700002102299700002402320700002302344700001802367700001902385700002102404700001902425700002102444700002202465700002102487700002102508700001902529700002102548700002202569700002002591700002102611700002002632700001902652700002202671700001802693700002202711700002402733700002002757700002302777700002002800700001802820700002202838700001402860700002002874700002002894700002202914700002402936700001802960700001702978700002402995700002103019700001803040700002403058700002003082700002203102700002303124700003003147700002503177700002503202700002603227700001903253700001903272700002103291700002003312700001403332700001903346700002503365700001703390700001903407700002103426700002203447700002703469700002203496700002503518700002203543700002403565700002103589700002003610700002003630700002003650710006503670710001203735856003603747 2021 eng d a2041-172300aChromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.0 aChromosome Xq23 is associated with lower atherogenic lipid conce c2021 04 12 a21820 v123 aAutosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
1 aNatarajan, Pradeep1 aPampana, Akhil1 aGraham, Sarah, E1 aRuotsalainen, Sanni, E1 aPerry, James, A1 ade Vries, Paul, S1 aBroome, Jai, G1 aPirruccello, James, P1 aHonigberg, Michael, C1 aAragam, Krishna1 aWolford, Brooke1 aBrody, Jennifer, A1 aAntonacci-Fulton, Lucinda1 aArden, Moscati1 aAslibekyan, Stella1 aAssimes, Themistocles, L1 aBallantyne, Christie, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aCade, Brian, E1 aDo, Ron1 aDoddapaneni, Harsha1 aEmery, Leslie, S1 aHung, Yi-Jen1 aIrvin, Marguerite, R1 aKhan, Alyna, T1 aLange, Leslie1 aLee, Jiwon1 aLemaitre, Rozenn, N1 aMartin, Lisa, W1 aMetcalf, Ginger1 aMontasser, May, E1 aMoon, Jee-Young1 aMuzny, Donna1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aStilp, Adrienne, M1 aTsai, Michael1 aWang, Fei, Fei1 aWeeks, Daniel, E1 aYanek, Lisa, R1 aWilson, James, G1 aAbecasis, Goncalo1 aArnett, Donna, K1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aChoi, Won, Jung1 aCorrea, Adolfo1 aCurran, Joanne, E1 aDaly, Mark, J1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aFornage, Myriam1 aFreedman, Barry, I1 aGabriel, Stacey1 aGermer, Soren1 aGibbs, Richard, A1 aHe, Jiang1 aHveem, Kristian1 aJarvik, Gail, P1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKenny, Eimear1 aKim, Ryan, W1 aKooperberg, Charles1 aLaurie, Cathy, C1 aLee, Seonwook1 aLloyd-Jones, Don, M1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aMathias, Rasika, A1 aMartinez, Karine, A Viaud1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aNickerson, Deborah, A1 aNorth, Kari, E1 aPalotie, Aarno1 aPark, Cheol, Joo1 aPsaty, Bruce, M1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSmith, Albert, V1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aKathiresan, Sekar1 aCupples, Adrienne, L1 aRotter, Jerome, I1 aMorrison, Alanna, C1 aRich, Stephen, S1 aRipatti, Samuli1 aWiller, Cristen1 aPeloso, Gina, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aFinnGen uhttps://chs-nhlbi.org/node/871105087nas a2201237 4500008004100000022001400041245010900055210006900164260001200233300001400245490000700259520156200266653002801828653003801856653003401894653001101928653003601939653001701975100002701992700001502019700002402034700002002058700002302078700001602101700002002117700001802137700001402155700001802169700001802187700002402205700002002229700002102249700002302270700001802293700002202311700002802333700002502361700002302386700002202409700002202431700002302453700002002476700001502496700001802511700001602529700001902545700002402564700002202588700002002610700001202630700002002642700002502662700001902687700002202706700002202728700002702750700002302777700002202800700001902822700002102841700001702862700002102879700001602900700002002916700002302936700002102959700002002980700002003000700002003020700001903040700002403059700001503083700002403098700002303122700002203145700002403167700002203191700001603213700001903229700002203248700002503270700002203295700002103317700002103338700002103359700001503380700002103395700002303416700002503439700002403464700002103488700002003509700002003529700002303549700002303572700001403595700001603609700002003625700003003645700002903675710003003704710003303734710001803767710002803785856003603813 2022 eng d a1546-170X00aLarge-scale genome-wide association study of coronary artery disease in genetically diverse populations.0 aLargescale genomewide association study of coronary artery disea c2022 08 a1679-16920 v283 aWe report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
10aCoronary Artery Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aTcheandjieu, Catherine1 aZhu, Xiang1 aHilliard, Austin, T1 aClarke, Shoa, L1 aNapolioni, Valerio1 aMa, Shining1 aLee, Kyung, Min1 aFang, Huaying1 aChen, Fei1 aLu, Yingchang1 aTsao, Noah, L1 aRaghavan, Sridharan1 aKoyama, Satoshi1 aGorman, Bryan, R1 aVujkovic, Marijana1 aKlarin, Derek1 aLevin, Michael, G1 aSinnott-Armstrong, Nasa1 aWojcik, Genevieve, L1 aPlomondon, Mary, E1 aMaddox, Thomas, M1 aWaldo, Stephen, W1 aBick, Alexander, G1 aPyarajan, Saiju1 aHuang, Jie1 aSong, Rebecca1 aHo, Yuk-Lam1 aBuyske, Steven1 aKooperberg, Charles1 aHaessler, Jeffrey1 aLoos, Ruth, J F1 aDo, Ron1 aVerbanck, Marie1 aChaudhary, Kumardeep1 aNorth, Kari, E1 aAvery, Christy, L1 aGraff, Mariaelisa1 aHaiman, Christopher, A1 aLe Marchand, Loïc1 aWilkens, Lynne, R1 aBis, Joshua, C1 aLeonard, Hampton1 aShen, Botong1 aLange, Leslie, A1 aGiri, Ayush1 aDikilitas, Ozan1 aKullo, Iftikhar, J1 aStanaway, Ian, B1 aJarvik, Gail, P1 aGordon, Adam, S1 aHebbring, Scott1 aNamjou, Bahram1 aKaufman, Kenneth, M1 aIto, Kaoru1 aIshigaki, Kazuyoshi1 aKamatani, Yoichiro1 aVerma, Shefali, S1 aRitchie, Marylyn, D1 aKember, Rachel, L1 aBaras, Aris1 aLotta, Luca, A1 aKathiresan, Sekar1 aHauser, Elizabeth, R1 aMiller, Donald, R1 aLee, Jennifer, S1 aSaleheen, Danish1 aReaven, Peter, D1 aCho, Kelly1 aGaziano, Michael1 aNatarajan, Pradeep1 aHuffman, Jennifer, E1 aVoight, Benjamin, F1 aRader, Daniel, J1 aChang, Kyong-Mi1 aLynch, Julie, A1 aDamrauer, Scott, M1 aWilson, Peter, W F1 aTang, Hua1 aSun, Yan, V1 aTsao, Philip, S1 aO'Donnell, Christopher, J1 aAssimes, Themistocles, L1 aRegeneron Genetics Center1 aCARDIoGRAMplusC4D Consortium1 aBiobank Japan1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/917608881nas a2202605 4500008004100000022001400041245012200055210006900177260001500246300001000261490000800271520141300279653001201692653001801704653002501722653002601747653002301773653003001796653001001826653003801836653002201874653002501896653003401921653001101955653002101966653001101987653001001998653003402008653003102042653002402073653001402097653003602111100001802147700001902165700002102184700002002205700001802225700003202243700001702275700001702292700003102309700003002340700002102370700002102391700002302412700001602435700002802451700002902479700001802508700002102526700002402547700001902571700001902590700002102609700002502630700002102655700002202676700002102698700002302719700001902742700001902761700001902780700002702799700001702826700002002843700002102863700002002884700002002904700001902924700002902943700002402972700001902996700002503015700002203040700001703062700002203079700002303101700002403124700002803148700002203176700002403198700002103222700002003243700002003263700002303283700002103306700003103327700002803358700001803386700002203404700002203426700002103448700002303469700003903492700002203531700002103553700001803574700001903592700001703611700001903628700001503647700002003662700001903682700001403701700002603715700001703741700002103758700002503779700002603804700002003830700002003850700002403870700001803894700002103912700001903933700001703952700001703969700002003986700002504006700002404031700002204055700002004077700001904097700002104116700001504137700001704152700001804169700002104187700002404208700002104232700001704253700002004270700002204290700002304312700002004335700002804355700003604383700002304419700002504442700002004467700002004487700002204507700001904529700002604548700002304574700001504597700002104612700002204633700002004655700002904675700002404704700002004728700002104748700002204769700002604791700002504817700001904842700002304861700002604884700002104910700002104931700001904952700002104971700002404992700001905016700002005035700002005055700001405075700001405089700001905103700002505122700003105147700002105178700001905199700002405218700002305242700001705265700001905282700001705301700001605318700002105334700001805355700002305373700001905396700002205415700002005437700001905457700002005476700002105496700002105517700002205538700002305560700002405583700002105607700002005628700002705648700003005675700001905705700001605724700001805740700002105758700002105779700002105800700001905821700001905840700002205859700002105881700002205902700002105924700002205945700002305967700002305990700002306013700001906036700002006055710006106075710006506136710003806201856003606239 2022 eng d a1537-660500aRare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.0 aRare coding variants in 35 genes associate with circulating lipi c2022 01 06 a81-960 v1093 aLarge-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
10aAlleles10aBlood Glucose10aCase-Control Studies10aComputational Biology10aDatabases, Genetic10aDiabetes Mellitus, Type 210aExome10aGenetic Predisposition to Disease10aGenetic Variation10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aLipids10aLiver10aMolecular Sequence Annotation10aMultifactorial Inheritance10aOpen Reading Frames10aPhenotype10aPolymorphism, Single Nucleotide1 aHindy, George1 aDornbos, Peter1 aChaffin, Mark, D1 aLiu, Dajiang, J1 aWang, Minxian1 aSelvaraj, Margaret, Sunitha1 aZhang, David1 aPark, Joseph1 aAguilar-Salinas, Carlos, A1 aAntonacci-Fulton, Lucinda1 aArdissino, Diego1 aArnett, Donna, K1 aAslibekyan, Stella1 aAtzmon, Gil1 aBallantyne, Christie, M1 aBarajas-Olmos, Francisco1 aBarzilai, Nir1 aBecker, Lewis, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBottinger, Erwin1 aBowden, Donald, W1 aBown, Matthew, J1 aBrody, Jennifer, A1 aBroome, Jai, G1 aBurtt, Noel, P1 aCade, Brian, E1 aCenteno-Cruz, Federico1 aChan, Edmund1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aCheng, Ching-Yu1 aChoi, Won, Jung1 aChowdhury, Raj1 aContreras-Cubas, Cecilia1 aCórdova, Emilio, J1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDanesh, John1 ade Vries, Paul, S1 aDeFronzo, Ralph, A1 aDoddapaneni, Harsha1 aDuggirala, Ravindranath1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aFlorez, Jose, C1 aFornage, Myriam1 aFreedman, Barry, I1 aFuster, Valentin1 aGaray-Sevilla, Ma, Eugenia1 aGarcía-Ortiz, Humberto1 aGermer, Soren1 aGibbs, Richard, A1 aGieger, Christian1 aGlaser, Benjamin1 aGonzalez, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGraff, Mariaelisa1 aGraham, Sarah, E1 aGrarup, Niels1 aGroop, Leif, C1 aGuo, Xiuqing1 aGupta, Namrata1 aHan, Sohee1 aHanis, Craig, L1 aHansen, Torben1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aIrvin, Marguerite, R1 aIslas-Andrade, Sergio1 aJarvik, Gail, P1 aKang, Hyun, Min1 aKardia, Sharon, L R1 aKelly, Tanika1 aKenny, Eimear, E1 aKhan, Alyna, T1 aKim, Bong-Jo1 aKim, Ryan, W1 aKim, Young, Jin1 aKoistinen, Heikki, A1 aKooperberg, Charles1 aKuusisto, Johanna1 aKwak, Soo, Heon1 aLaakso, Markku1 aLange, Leslie, A1 aLee, Jiwon1 aLee, Juyoung1 aLee, Seonwook1 aLehman, Donna, M1 aLemaitre, Rozenn, N1 aLinneberg, Allan1 aLiu, Jianjun1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aLyssenko, Valeriya1 aMa, Ronald, C W1 aMartin, Lisa, Warsinger1 aMartínez-Hernández, Angélica1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMcPherson, Ruth1 aMeigs, James, B1 aMeitinger, Thomas1 aMelander, Olle1 aMendoza-Caamal, Elvia1 aMetcalf, Ginger, A1 aMi, Xuenan1 aMohlke, Karen, L1 aMontasser, May, E1 aMoon, Jee-Young1 aMoreno-Macias, Hortensia1 aMorrison, Alanna, C1 aMuzny, Donna, M1 aNelson, Sarah, C1 aNilsson, Peter, M1 aO'Connell, Jeffrey, R1 aOrho-Melander, Marju1 aOrozco, Lorena1 aPalmer, Colin, N A1 aPalmer, Nicholette, D1 aPark, Cheol, Joo1 aPark, Kyong, Soo1 aPedersen, Oluf1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPost, Wendy, S1 aPreuss, Michael1 aPsaty, Bruce, M1 aQi, Qibin1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRevilla-Monsalve, Cristina1 aRich, Stephen, S1 aSamani, Nilesh1 aSchunkert, Heribert1 aSchurmann, Claudia1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSim, Xueling1 aSladek, Rob1 aSmall, Kerrin, S1 aSo, Wing, Yee1 aStilp, Adrienne, M1 aTai, Shyong, E1 aTam, Claudia, H T1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aThameem, Farook1 aTomlinson, Brian1 aTsai, Michael, Y1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 avan Dam, Rob, M1 aVasan, Ramachandran, S1 aMartinez, Karine, A Viaud1 aWang, Fei, Fei1 aWang, Xuzhi1 aWatkins, Hugh1 aWeeks, Daniel, E1 aWilson, James, G1 aWitte, Daniel, R1 aWong, Tien-Yin1 aYanek, Lisa, R1 aKathiresan, Sekar1 aRader, Daniel, J1 aRotter, Jerome, I1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aFlannick, Jason, A1 aKhera, Amit, V1 aPeloso, Gina, M1 aAMP-T2D-GENES, Myocardial Infarction Genetics Consortium1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aNHLBI TOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/8975