03588nas a2200877 4500008004100000022001400041245007000055210006800125260001300193300001100206490000700217520113400224653001901358653001401377653002301391653002301414653001301437653003101450653003201481653003401513653001101547653001701558653001001575653001601585653002701601653001501628653001401643653001501657653002001672653001201692100001701704700002001721700001801741700002601759700002201785700001901807700002201826700002401848700002301872700001901895700002101914700001901935700001901954700002701973700002602000700002402026700001702050700001902067700002202086700003302108700002102141700001702162700002302179700002002202700002502222700001602247700002202263700002202285700003002307700001902337700002202356700001802378700002402396700002802420700001902448700002102467700003002488700002102518700002002539700002402559700002202583700002602605700002002631700002302651856003602674 2009 eng d a1546-171800aGenome-wide association study of blood pressure and hypertension.0 aGenomewide association study of blood pressure and hypertension c2009 Jun a677-870 v413 a
Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
10aBlood Pressure10aCell Line10aChromosome Mapping10aChromosomes, Human10aDiastole10aGene Expression Regulation10aGenetic Association Studies10aGenome-Wide Association Study10aHumans10aHypertension10aLiver10aLymphocytes10aMeta-Analysis as Topic10aOdds Ratio10aPhenotype10aPrevalence10aRisk Assessment10aSystole1 aLevy, Daniel1 aEhret, Georg, B1 aRice, Kenneth1 aVerwoert, Germaine, C1 aLauner, Lenore, J1 aDehghan, Abbas1 aGlazer, Nicole, L1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aAspelund, Thor1 aAulchenko, Yurii1 aLumley, Thomas1 aKöttgen, Anna1 aVasan, Ramachandran, S1 aRivadeneira, Fernando1 aEiriksdottir, Gudny1 aGuo, Xiuqing1 aArking, Dan, E1 aMitchell, Gary, F1 aMattace-Raso, Francesco, U S1 aSmith, Albert, V1 aTaylor, Kent1 aScharpf, Robert, B1 aHwang, Shih-Jen1 aSijbrands, Eric, J G1 aBis, Joshua1 aHarris, Tamara, B1 aGanesh, Santhi, K1 aO'Donnell, Christopher, J1 aHofman, Albert1 aRotter, Jerome, I1 aCoresh, Josef1 aBenjamin, Emelia, J1 aUitterlinden, André, G1 aHeiss, Gerardo1 aFox, Caroline, S1 aWitteman, Jacqueline, C M1 aBoerwinkle, Eric1 aWang, Thomas, J1 aGudnason, Vilmundur1 aLarson, Martin, G1 aChakravarti, Aravinda1 aPsaty, Bruce, M1 aDuijn, Cornelia, M uhttps://chs-nhlbi.org/node/109804054nas a2201033 4500008004100000022001400041245007700055210006900132260001300201300001100214490000700225520114900232653001901381653001401400653001901414653002201433653001701455653002001472653001801492653003401510653001101544653001701555653001401572653003601586653002801622100002201650700001901672700002601691700002001717700002101737700002201758700002001780700001901800700002201819700001901841700002101860700001901881700001601900700002001916700001801936700002101954700002601975700002202001700002102023700002202044700002002066700001802086700002102104700002002125700002402145700001702169700002202186700002102208700002202229700001902251700002602270700002302296700001602319700002502335700002502360700001802385700001902403700002802422700002302450700002202473700002502495700001902520700002302539700002402562700002002586700002302606700002002629700002002649700002002669700002202689700002402711700002302735700002002758700002002778700002602798700002402824700003002848700003002878700001702908700001802925700002202943700001902965856003602984 2009 eng d a1546-171800aMultiple loci influence erythrocyte phenotypes in the CHARGE Consortium.0 aMultiple loci influence erythrocyte phenotypes in the CHARGE Con c2009 Nov a1191-80 v413 aMeasurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
10aBlood Pressure10aCell Line10aCohort Studies10aEndothelial Cells10aErythrocytes10aGene Expression10aGenome, Human10aGenome-Wide Association Study10aHumans10aHypertension10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aGanesh, Santhi, K1 aZakai, Neil, A1 avan Rooij, Frank, J A1 aSoranzo, Nicole1 aSmith, Albert, V1 aNalls, Michael, A1 aChen, Ming-Huei1 aKöttgen, Anna1 aGlazer, Nicole, L1 aDehghan, Abbas1 aKuhnel, Brigitte1 aAspelund, Thor1 aYang, Qiong1 aTanaka, Toshiko1 aJaffe, Andrew1 aBis, Joshua, C M1 aVerwoert, Germaine, C1 aTeumer, Alexander1 aFox, Caroline, S1 aGuralnik, Jack, M1 aEhret, Georg, B1 aRice, Kenneth1 aFelix, Janine, F1 aRendon, Augusto1 aEiriksdottir, Gudny1 aLevy, Daniel1 aPatel, Kushang, V1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aHofman, Albert1 aSambrook, Jennifer, G1 aHernandez, Dena, G1 aZheng, Gang1 aBandinelli, Stefania1 aSingleton, Andrew, B1 aCoresh, Josef1 aLumley, Thomas1 aUitterlinden, André, G1 aVangils, Janine, M1 aLauner, Lenore, J1 aCupples, Adrienne, L1 aOostra, Ben, A1 aZwaginga, Jaap-Jan1 aOuwehand, Willem, H1 aThein, Swee-Lay1 aMeisinger, Christa1 aDeloukas, Panos1 aNauck, Matthias1 aSpector, Tim, D1 aGieger, Christian1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aFerrucci, Luigi1 aChakravarti, Aravinda1 aGreinacher, Andreas1 aO'Donnell, Christopher, J1 aWitteman, Jacqueline, C M1 aFurth, Susan1 aCushman, Mary1 aHarris, Tamara, B1 aLin, Jing-Ping uhttps://chs-nhlbi.org/node/114113785nas a2204513 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2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium uhttps://chs-nhlbi.org/node/132509449nas a2203037 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2011 eng d a1546-171800aGenome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.0 aGenomewide association study identifies six new loci influencing c2011 Sep 11 a1005-110 v433 aNumerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
10aArteries10aBlood Pressure10aCase-Control Studies10aFollow-Up Studies10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide1 aWain, Louise, V1 aVerwoert, Germaine, C1 aO'Reilly, Paul, F1 aShi, Gang1 aJohnson, Toby1 aJohnson, Andrew, D1 aBochud, Murielle1 aRice, Kenneth, M1 aHenneman, Peter1 aSmith, Albert, V1 aEhret, Georg, B1 aAmin, Najaf1 aLarson, Martin, G1 aMooser, Vincent1 aHadley, David1 aDörr, Marcus1 aBis, Joshua, C1 aAspelund, Thor1 aEsko, Tõnu1 aJanssens, Cecile, J W1 aZhao, Jing Hua1 aHeath, Simon1 aLaan, Maris1 aFu, Jingyuan1 aPistis, Giorgio1 aLuan, Jian'an1 aArora, Pankaj1 aLucas, Gavin1 aPirastu, Nicola1 aPichler, Irene1 aJackson, Anne, U1 aWebster, Rebecca, J1 aZhang, Feng1 aPeden, John, F1 aSchmidt, Helena1 aTanaka, Toshiko1 aCampbell, Harry1 aIgl, Wilmar1 aMilaneschi, Yuri1 aHottenga, Jouke-Jan1 aVitart, Veronique1 aChasman, Daniel, I1 aTrompet, Stella1 aBragg-Gresham, Jennifer, L1 aAlizadeh, Behrooz, Z1 aChambers, John, C1 aGuo, Xiuqing1 aLehtimäki, Terho1 aKuhnel, Brigitte1 aLopez, Lorna, M1 aPolasek, Ozren1 aBoban, Mladen1 aNelson, Christopher, P1 aMorrison, Alanna, C1 aPihur, Vasyl1 aGanesh, Santhi, K1 aHofman, Albert1 aKundu, Suman1 aMattace-Raso, Francesco, U S1 aRivadeneira, Fernando1 aSijbrands, Eric, J G1 aUitterlinden, André, G1 aHwang, Shih-Jen1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aLaitinen, Jaana1 aPouta, Anneli1 aZitting, Paavo1 aMcArdle, Wendy, L1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGlazer, Nicole, L1 aTaylor, Kent, D1 aHarris, Tamara, B1 aAlavere, Helene1 aHaller, Toomas1 aKeis, Aime1 aTammesoo, Mari-Liis1 aAulchenko, Yurii1 aBarroso, Inês1 aKhaw, Kay-Tee1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aEyheramendy, Susana1 aOrg, Elin1 aSõber, Siim1 aLu, Xiaowen1 aNolte, Ilja, M1 aPenninx, Brenda, W1 aCorre, Tanguy1 aMasciullo, Corrado1 aSala, Cinzia1 aGroop, Leif1 aVoight, Benjamin, F1 aMelander, Olle1 aO'Donnell, Christopher, J1 aSalomaa, Veikko1 ad'Adamo, Adamo, Pio1 aFabretto, Antonella1 aFaletra, Flavio1 aUlivi, Sheila1 aDel Greco, Fabiola, M1 aFacheris, Maurizio1 aCollins, Francis, S1 aBergman, Richard, N1 aBeilby, John, P1 aHung, Joseph1 aMusk, William1 aMangino, Massimo1 aShin, So-Youn1 aSoranzo, Nicole1 aWatkins, Hugh1 aGoel, Anuj1 aHamsten, Anders1 aGider, Pierre1 aLoitfelder, Marisa1 aZeginigg, Marion1 aHernandez, Dena1 aNajjar, Samer, S1 aNavarro, Pau1 aWild, Sarah, H1 aCorsi, Anna Maria1 aSingleton, Andrew1 aGeus, Eco, J C1 aWillemsen, Gonneke1 aParker, Alex, N1 aRose, Lynda, M1 aBuckley, Brendan1 aStott, David1 aOrrù, Marco1 aUda, Manuela1 avan der Klauw, Melanie, M1 aZhang, Weihua1 aLi, Xinzhong1 aScott, James1 aChen, Yii-Der Ida1 aBurke, Gregory, L1 aKähönen, Mika1 aViikari, Jorma1 aDöring, Angela1 aMeitinger, Thomas1 aDavies, Gail1 aStarr, John, M1 aEmilsson, Valur1 aPlump, Andrew1 aLindeman, Jan, H1 aHoen, Peter, A C 't1 aKönig, Inke, R1 aFelix, Janine, F1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aBreteler, Monique1 aDebette, Stephanie1 aDeStefano, Anita, L1 aFornage, Myriam1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aHolm, Hilma1 aStefansson, Kari1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aSamani, Nilesh, J1 aPreuss, Michael1 aRudan, Igor1 aHayward, Caroline1 aDeary, Ian, J1 aWichmann, H-Erich1 aRaitakari, Olli, T1 aPalmas, Walter1 aKooner, Jaspal, S1 aStolk, Ronald, P1 aJukema, Wouter1 aWright, Alan, F1 aBoomsma, Dorret, I1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWilson, James, F1 aFerrucci, Luigi1 aSchmidt, Reinhold1 aFarrall, Martin1 aSpector, Tim, D1 aPalmer, Lyle, J1 aTuomilehto, Jaakko1 aPfeufer, Arne1 aGasparini, Paolo1 aSiscovick, David1 aAltshuler, David1 aLoos, Ruth, J F1 aToniolo, Daniela1 aSnieder, Harold1 aGieger, Christian1 aMeneton, Pierre1 aWareham, Nicholas, J1 aOostra, Ben, A1 aMetspalu, Andres1 aLauner, Lenore1 aRettig, Rainer1 aStrachan, David, P1 aBeckmann, Jacques, S1 aWitteman, Jacqueline, C M1 aErdmann, Jeanette1 aDijk, Ko Willems1 aBoerwinkle, Eric1 aBoehnke, Michael1 aRidker, Paul, M1 aJarvelin, Marjo-Riitta1 aChakravarti, Aravinda1 aAbecasis, Goncalo, R1 aGudnason, Vilmundur1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aRao, Dabeeru, C1 aTobin, Martin, D1 aElliott, Paul1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aEchoGen consortium1 aAortaGen Consortium1 aCHARGE Consortium Heart Failure Working Group1 aKidneyGen Consortium1 aCKDGen Consortium1 aCardiogenics consortium1 aCardioGram uhttps://chs-nhlbi.org/node/132407496nas a2202305 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2011 eng d a1476-468700aNew gene functions in megakaryopoiesis and platelet formation.0 aNew gene functions in megakaryopoiesis and platelet formation c2011 Nov 30 a201-80 v4803 aPlatelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
10aAnimals10aBlood Platelets10aCell Size10aDrosophila melanogaster10aDrosophila Proteins10aEurope10aGene Expression Profiling10aGene Silencing10aGenome, Human10aGenome-Wide Association Study10aHematopoiesis10aHumans10aMegakaryocytes10aPlatelet Count10aProtein Interaction Maps10aTranscription, Genetic10aZebrafish10aZebrafish Proteins1 aGieger, Christian1 aRadhakrishnan, Aparna1 aCvejic, Ana1 aTang, Weihong1 aPorcu, Eleonora1 aPistis, Giorgio1 aSerbanovic-Canic, Jovana1 aElling, Ulrich1 aGoodall, Alison, H1 aLabrune, Yann1 aLopez, Lorna, M1 aMägi, Reedik1 aMeacham, Stuart1 aOkada, Yukinori1 aPirastu, Nicola1 aSorice, Rossella1 aTeumer, Alexander1 aVoss, Katrin1 aZhang, Weihua1 aRamirez-Solis, Ramiro1 aBis, Joshua, C1 aEllinghaus, David1 aGögele, Martin1 aHottenga, Jouke-Jan1 aLangenberg, Claudia1 aKovacs, Peter1 aO'Reilly, Paul, F1 aShin, So-Youn1 aEsko, Tõnu1 aHartiala, Jaana1 aKanoni, Stavroula1 aMurgia, Federico1 aParsa, Afshin1 aStephens, Jonathan1 aHarst, Pim1 avan der Schoot, Ellen1 aAllayee, Hooman1 aAttwood, Antony1 aBalkau, Beverley1 aBastardot, François1 aBasu, Saonli1 aBaumeister, Sebastian, E1 aBiino, Ginevra1 aBomba, Lorenzo1 aBonnefond, Amélie1 aCambien, Francois1 aChambers, John, C1 aCucca, Francesco1 aD'Adamo, Pio1 aDavies, Gail1 ade Boer, Rudolf, A1 aGeus, Eco, J C1 aDöring, Angela1 aElliott, Paul1 aErdmann, Jeanette1 aEvans, David, M1 aFalchi, Mario1 aFeng, Wei1 aFolsom, Aaron, R1 aFrazer, Ian, H1 aGibson, Quince, D1 aGlazer, Nicole, L1 aHammond, Chris1 aHartikainen, Anna-Liisa1 aHeckbert, Susan, R1 aHengstenberg, Christian1 aHersch, Micha1 aIllig, Thomas1 aLoos, Ruth, J F1 aJolley, Jennifer1 aKhaw, Kay, Tee1 aKuhnel, Brigitte1 aKyrtsonis, Marie-Christine1 aLagou, Vasiliki1 aLloyd-Jones, Heather1 aLumley, Thomas1 aMangino, Massimo1 aMaschio, Andrea1 aLeach, Irene, Mateo1 aMcKnight, Barbara1 aMemari, Yasin1 aMitchell, Braxton, D1 aMontgomery, Grant, W1 aNakamura, Yusuke1 aNauck, Matthias1 aNavis, Gerjan1 aNöthlings, Ute1 aNolte, Ilja, M1 aPorteous, David, J1 aPouta, Anneli1 aPramstaller, Peter, P1 aPullat, Janne1 aRing, Susan, M1 aRotter, Jerome, I1 aRuggiero, Daniela1 aRuokonen, Aimo1 aSala, Cinzia1 aSamani, Nilesh, J1 aSambrook, Jennifer1 aSchlessinger, David1 aSchreiber, Stefan1 aSchunkert, Heribert1 aScott, James1 aSmith, Nicholas, L1 aSnieder, Harold1 aStarr, John, M1 aStumvoll, Michael1 aTakahashi, Atsushi1 aTang, W, H Wilson1 aTaylor, Kent1 aTenesa, Albert1 aThein, Swee, Lay1 aTönjes, Anke1 aUda, Manuela1 aUlivi, Sheila1 avan Veldhuisen, Dirk, J1 aVisscher, Peter, M1 aVölker, Uwe1 aWichmann, H-Erich1 aWiggins, Kerri, L1 aWillemsen, Gonneke1 aYang, Tsun-Po1 aZhao, Jing, Hua1 aZitting, Paavo1 aBradley, John, R1 aDedoussis, George, V1 aGasparini, Paolo1 aHazen, Stanley, L1 aMetspalu, Andres1 aPirastu, Mario1 aShuldiner, Alan, R1 avan Pelt, Joost1 aZwaginga, Jaap-Jan1 aBoomsma, Dorret, I1 aDeary, Ian, J1 aFranke, Andre1 aFroguel, Philippe1 aGanesh, Santhi, K1 aJarvelin, Marjo-Riitta1 aMartin, Nicholas, G1 aMeisinger, Christa1 aPsaty, Bruce, M1 aSpector, Timothy, D1 aWareham, Nicholas, J1 aAkkerman, Jan-Willem, N1 aCiullo, Marina1 aDeloukas, Panos1 aGreinacher, Andreas1 aJupe, Steve1 aKamatani, Naoyuki1 aKhadake, Jyoti1 aKooner, Jaspal, S1 aPenninger, Josef1 aProkopenko, Inga1 aStemple, Derek1 aToniolo, Daniela1 aWernisch, Lorenz1 aSanna, Serena1 aHicks, Andrew, A1 aRendon, Augusto1 aFerreira, Manuel, A1 aOuwehand, Willem, H1 aSoranzo, Nicole uhttps://chs-nhlbi.org/node/135505476nas a2201057 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2012 eng d a1879-148400aGenetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.0 aGenetic determinants of the anklebrachial index a metaanalysis o c2012 May a138-470 v2223 aBACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.
METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.
RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.
CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
10aAdult10aAfrican Americans10aAged10aAnkle Brachial Index10aAryl Hydrocarbon Hydroxylases10aCytochrome P-450 CYP2B610aEuropean Continental Ancestry Group10aFemale10aHumans10aMale10aMiddle Aged10aOxidoreductases, N-Demethylating10aPeripheral Arterial Disease10aPolymorphism, Single Nucleotide10aRisk Factors10aTranscription Factor 7-Like 2 Protein1 aWassel, Christina, L1 aLamina, Claudia1 aNambi, Vijay1 aCoassin, Stefan1 aMukamal, Kenneth, J1 aGanesh, Santhi, K1 aJacobs, David, R1 aFranceschini, Nora1 aPapanicolaou, George, J1 aGibson, Quince1 aYanek, Lisa, R1 aHarst, Pim1 aFerguson, Jane, F1 aCrawford, Dana, C1 aWaite, Lindsay, L1 aAllison, Matthew, A1 aCriqui, Michael, H1 aMcDermott, Mary, M1 aMehra, Reena1 aCupples, Adrienne, L1 aHwang, Shih-Jen1 aRedline, Susan1 aKaplan, Robert, C1 aHeiss, Gerardo1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aTaylor, Herman, A1 aEraso, Luis, H1 aHaun, Margot1 aLi, Mingyao1 aMeisinger, Christa1 aO'Connell, Jeffrey, R1 aShuldiner, Alan, R1 aTybjærg-Hansen, Anne1 aFrikke-Schmidt, Ruth1 aKollerits, Barbara1 aRantner, Barbara1 aDieplinger, Benjamin1 aStadler, Marietta1 aMueller, Thomas1 aHaltmayer, Meinhard1 aKlein-Weigel, Peter1 aSummerer, Monika1 aWichmann, H-Erich1 aAsselbergs, Folkert, W1 aNavis, Gerjan1 aLeach, Irene, Mateo1 aBrown-Gentry, Kristin1 aGoodloe, Robert1 aAssimes, Themistocles, L1 aBecker, Diane, M1 aCooke, John, P1 aAbsher, Devin, M1 aOlin, Jeffrey, W1 aMitchell, Braxton, D1 aReilly, Muredach, P1 aMohler, Emile, R1 aNorth, Kari, E1 aReiner, Alexander, P1 aKronenberg, Florian1 aMurabito, Joanne, M uhttps://chs-nhlbi.org/node/586404413nas a2200889 4500008004100000022001400041245008200055210006900137260000900206300001100215490000600226520194300232653000902175653002202184653001102206653003402217653001302251653002502264653001102289653001702300653000902317653003602326653002302362653002102385100002302406700001702429700001602446700002502462700001802487700002702505700002402532700002202556700002302578700002402601700002202625700002602647700002102673700001702694700002002711700001702731700001902748700001902767700001602786700001802802700002202820700001902842700002202861700002002883700001702903700001902920700002702939700002602966700002802992700001803020700001903038700002003057700001703077700002003094700001903114700001403133700002203147700003003169700001903199700002203218700001703240700002303257700002403280700001803304700002403322700002203346700001503368700002503383700001803408710003903426710002203465856003603487 2013 eng d a1932-620300aGenome-wide association study of retinopathy in individuals without diabetes.0 aGenomewide association study of retinopathy in individuals witho c2013 ae542320 v83 aBACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.
RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.
CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
10aAged10aAged, 80 and over10aFemale10aGenome-Wide Association Study10aGenotype10aHistone Deacetylases10aHumans10aHypertension10aMale10aPolymorphism, Single Nucleotide10aRepressor Proteins10aRetinal Diseases1 aJensen, Richard, A1 aSim, Xueling1 aLi, Xiaohui1 aCotch, Mary, Frances1 aIkram, Kamran1 aHolliday, Elizabeth, G1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore, J1 aSmith, Albert, Vernon1 aBoerwinkle, Eric1 aCheung, Ning1 aHewitt, Alex, W1 aLiew, Gerald1 aMitchell, Paul1 aWang, Jie, Jin1 aAttia, John1 aScott, Rodney1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aTaylor, Kent1 aHofman, Albert1 ade Jong, Paulus, T V M1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aTay, Wan-Ting1 aTeo, Yik, Ying1 aSeielstad, Mark1 aLiu, Jianjun1 aCheng, Ching-Yu1 aSaw, Seang-Mei1 aAung, Tin1 aGanesh, Santhi, K1 aO'Donnell, Christopher, J1 aNalls, Mike, A1 aWiggins, Kerri, L1 aKuo, Jane, Z1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aKlein, Ronald1 aSiscovick, David, S1 aRotter, Jerome, I1 aTai, Shong1 aVingerling, Johannes1 aWong, Tien, Y1 aBlue Mountains Eye Study GWAS Team1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/607203970nas a2200877 4500008004100000022001400041245011500055210006900170260001600239300001000255490000700265520145800272653001901730653003401749653001101783653002501794653001401819653003601833653002801869100002201897700002301919700002201942700001701964700002201981700001902003700001702022700002102039700001802060700001502078700001702093700001902110700002002129700002702149700002302176700001802199700002402217700001702241700002002258700002702278700002902305700002202334700001602356700002202372700001502394700002202409700001302431700002002444700002402464700002302488700002202511700001902533700001202552700002102564700002202585700001402607700002102621700002402642700001302666700002802679700002602707700001902733700002302752700002102775700001402796700003002810700002402840700002402864700001902888700002002907700002002927700001702947700002002964700002602984710004603010856003603056 2014 eng d a1537-660500aEffects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations.0 aEffects of longterm averaging of quantitative blood pressure tra c2014 Jul 03 a49-650 v953 aBlood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.
10aBlood Pressure10aGenome-Wide Association Study10aHumans10aLongitudinal Studies10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aGanesh, Santhi, K1 aChasman, Daniel, I1 aLarson, Martin, G1 aGuo, Xiuqing1 aVerwoert, Germain1 aBis, Joshua, C1 aGu, Xiangjun1 aSmith, Albert, V1 aYang, Min-Lee1 aZhang, Yan1 aEhret, Georg1 aRose, Lynda, M1 aHwang, Shih-Jen1 aPapanicolau, George, J1 aSijbrands, Eric, J1 aRice, Kenneth1 aEiriksdottir, Gudny1 aPihur, Vasyl1 aRidker, Paul, M1 aVasan, Ramachandran, S1 aNewton-Cheh, Christopher1 aRaffel, Leslie, J1 aAmin, Najaf1 aRotter, Jerome, I1 aLiu, Kiang1 aLauner, Lenore, J1 aXu, Ming1 aCaulfield, Mark1 aMorrison, Alanna, C1 aJohnson, Andrew, D1 aVaidya, Dhananjay1 aDehghan, Abbas1 aLi, Guo1 aBouchard, Claude1 aHarris, Tamara, B1 aZhang, He1 aBoerwinkle, Eric1 aSiscovick, David, S1 aGao, Wei1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aHofman, Albert1 aWiller, Cristen, J1 aFranco, Oscar, H1 aHuo, Yong1 aWitteman, Jacqueline, C M1 aMunroe, Patricia, B1 aGudnason, Vilmundur1 aPalmas, Walter1 aDuijn, Cornelia1 aFornage, Myriam1 aLevy, Daniel1 aPsaty, Bruce, M1 aChakravarti, Aravinda1 aGlobal Blood Pressure Genetics Consortium uhttps://chs-nhlbi.org/node/656304315nas a2200901 4500008004100000022001400041245006300055210006000118260001600178300001200194490000700206520174600213653002201959653003701981653001802018653004002036653001802076653003402094653001302128653001102141653002002152653001502172653002702187653001402214653003602228653002802264100002302292700002502315700002002340700002602360700002302386700002002409700002102429700002202450700002002472700002002492700002302512700002202535700001902557700002002576700002502596700001802621700001902639700002102658700002102679700002402700700002102724700001602745700001402761700002102775700002302796700002002819700002202839700002102861700001902882700001502901700001902916700002102935700001902956700002802975700002303003700002103026700001803047700002503065700002003090700002303110700002503133700002203158700003003180700002303210700002103233700002203254700001903276710002203295710001103317710004903328856003603377 2014 eng d a1460-208300aTrans-ethnic meta-analysis of white blood cell phenotypes.0 aTransethnic metaanalysis of white blood cell phenotypes c2014 Dec 20 a6944-600 v233 aWhite blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.
10aAfrican Americans10aAsian Continental Ancestry Group10aBayes Theorem10aEuropean Continental Ancestry Group10aGenome, Human10aGenome-Wide Association Study10aGenotype10aHumans10aLeukocyte Count10aLeukocytes10aLinkage Disequilibrium10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci1 aKeller, Margaux, F1 aReiner, Alexander, P1 aOkada, Yukinori1 avan Rooij, Frank, J A1 aJohnson, Andrew, D1 aChen, Ming-Huei1 aSmith, Albert, V1 aMorris, Andrew, P1 aTanaka, Toshiko1 aFerrucci, Luigi1 aZonderman, Alan, B1 aLettre, Guillaume1 aHarris, Tamara1 aGarcia, Melissa1 aBandinelli, Stefania1 aQayyum, Rehan1 aYanek, Lisa, R1 aBecker, Diane, M1 aBecker, Lewis, C1 aKooperberg, Charles1 aKeating, Brendan1 aReis, Jared1 aTang, Hua1 aBoerwinkle, Eric1 aKamatani, Yoichiro1 aMatsuda, Koichi1 aKamatani, Naoyuki1 aNakamura, Yusuke1 aKubo, Michiaki1 aLiu, Simin1 aDehghan, Abbas1 aFelix, Janine, F1 aHofman, Albert1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aFranco, Oscar, H1 aLongo, Dan, L1 aSingleton, Andrew, B1 aPsaty, Bruce, M1 aEvans, Michelle, K1 aCupples, Adrienne, L1 aRotter, Jerome, I1 aO'Donnell, Christopher, J1 aTakahashi, Atsushi1 aWilson, James, G1 aGanesh, Santhi, K1 aNalls, Mike, A1 aCHARGE Hematology1 aCOGENT1 aBioBank Japan Project (RIKEN) Working Groups uhttps://chs-nhlbi.org/node/657306025nas 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/713805559nas a2201297 4500008004100000022001400041245013800055210006900193260001500262300001000277490000700287520188700294100002402181700002202205700002002227700002002247700001602267700002302283700001602306700002002322700001202342700002802354700002102382700002102403700002802424700002102452700001702473700002102490700002602511700002302537700002702560700002402587700002502611700001902636700001602655700002002671700002602691700002002717700002402737700002202761700002502783700002102808700001702829700001802846700001902864700002302883700002602906700001702932700001902949700002402968700002102992700002803013700002003041700002003061700002103081700002103102700002303123700001903146700002003165700002003185700001203205700002403217700002403241700002103265700002403286700002103310700002103331700002103352700002003373700002403393700002203417700001903439700001803458700001703476700002203493700002203515700001803537700002103555700002403576700002403600700002103624700002403645700002003669700002603689700002303715700002303738700001803761700001803779700001803797700002203815700002403837700002003861700002003881700002203901700002203923700001903945700002103964700002203985700002004007700001604027700002004043700002104063700001804084700002304102700002104125700001904146700002204165700002004187700001804207856003604225 2016 eng d a1537-660500aLarge-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.0 aLargeScale Exomewide Association Analysis Identifies Loci for Wh c2016 Jul 7 a22-390 v993 aWhite blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aEicher, John, D1 aChami, Nathalie1 aGiri, Ayush1 aBrody, Jennifer, A1 aHill, David1 aKacprowski, Tim1 aLi, Jin1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMihailov, Evelin1 aO'Donoghue, Michelle, L1 aPankratz, Nathan1 aPazoki, Raha1 aPolfus, Linda, M1 aSmith, Albert, Vernon1 aSchurmann, Claudia1 aVacchi-Suzzi, Caterina1 aWaterworth, Dawn, M1 aEvangelou, Evangelos1 aYanek, Lisa, R1 aBurt, Amber1 aChen, Ming-Huei1 avan Rooij, Frank, J A1 aFloyd, James, S1 aGreinacher, Andreas1 aHarris, Tamara, B1 aHighland, Heather, M1 aLange, Leslie, A1 aLiu, Yongmei1 aMägi, Reedik1 aNalls, Mike, A1 aMathias, Rasika, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aStarr, John, M1 aTardif, Jean-Claude1 aTzoulaki, Ioanna1 aEdwards, Digna, R Velez1 aWallentin, Lars1 aBartz, Traci, M1 aBecker, Lewis, C1 aDenny, Joshua, C1 aRaffield, Laura, M1 aRioux, John, D1 aFriedrich, Nele1 aFornage, Myriam1 aGao, He1 aHirschhorn, Joel, N1 aLiewald, David, C M1 aRich, Stephen, S1 aUitterlinden, Andre1 aBastarache, Lisa1 aBecker, Diane, M1 aBoerwinkle, Eric1 ade Denus, Simon1 aBottinger, Erwin, P1 aHayward, Caroline1 aHofman, Albert1 aHomuth, Georg1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLu, Yingchang1 aMetspalu, Andres1 aO'Donnell, Chris, J1 aQuarells, Rakale, C1 aRichard, Melissa1 aTorstenson, Eric, S1 aTaylor, Kent, D1 aVergnaud, Anne-Claire1 aZonderman, Alan, B1 aCrosslin, David, R1 aDeary, Ian, J1 aDörr, Marcus1 aElliott, Paul1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKähönen, Mika1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aSlater, Andrew, J1 aDehghan, Abbas1 aWhite, Harvey, D1 aGanesh, Santhi, K1 aLoos, Ruth, J F1 aEsko, Tõnu1 aFaraday, Nauder1 aWilson, James, G1 aCushman, Mary1 aJohnson, Andrew, D1 aEdwards, Todd, L1 aZakai, Neil, A1 aLettre, Guillaume1 aReiner, Alex, P1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/714606109nas 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/713902324nas a2200793 4500008004100000022001400041245015800055210006900213260001600282300000800298490000700306100002100313700002300334700002200357700002100379700001700400700002300417700002000440700001800460700002000478700001500498700001800513700002600531700002200557700002000579700001700599700002900616700002000645700001300665700001600678700002100694700002000715700002100735700001500756700002100771700001600792700001500808700002000823700002300843700002000866700002100886700002000907700002800927700002000955700002200975700002300997700002001020700002901040700002201069700002301091700002101114700002101135700002601156700001901182700002801201700002101229700002001250700002001270700001901290700002101309700002001330700002301350700003001373700002101403700002501424700002201449700002301471856003601494 2016 eng d a1537-660500aWhole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.0 aWholeExome Sequencing Identifies Loci Associated with Blood Cell c2016 Sep 01 a7850 v991 aPolfus, Linda, M1 aKhajuria, Rajiv, K1 aSchick, Ursula, M1 aPankratz, Nathan1 aPazoki, Raha1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aAuer, Paul, L1 aFloyd, James, S1 aHuang, Jie1 aLange, Leslie1 avan Rooij, Frank, J A1 aGibbs, Richard, A1 aMetcalf, Ginger1 aMuzny, Donna1 aVeeraraghavan, Narayanan1 aWalter, Klaudia1 aChen, Lu1 aYanek, Lisa1 aBecker, Lewis, C1 aPeloso, Gina, M1 aWakabayashi, Aoi1 aKals, Mart1 aMetspalu, Andres1 aEsko, Tõnu1 aFox, Keolu1 aWallace, Robert1 aFranceschini, Nora1 aMatijevic, Nena1 aRice, Kenneth, M1 aBartz, Traci, M1 aLyytikäinen, Leo-Pekka1 aKähönen, Mika1 aLehtimäki, Terho1 aRaitakari, Olli, T1 aLi-Gao, Ruifang1 aMook-Kanamori, Dennis, O1 aLettre, Guillaume1 aDuijn, Cornelia, M1 aFranco, Oscar, H1 aRich, Stephen, S1 aRivadeneira, Fernando1 aHofman, Albert1 aUitterlinden, André, G1 aWilson, James, G1 aPsaty, Bruce, M1 aSoranzo, Nicole1 aDehghan, Abbas1 aBoerwinkle, Eric1 aZhang, Xiaoling1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aJohnsen, Jill, M1 aReiner, Alexander, P1 aGanesh, Santhi, K1 aSankaran, Vijay, G uhttps://chs-nhlbi.org/node/726309668nas 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/757304127nas a2200853 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520188400256653003702140653001902177653001302196653001102209653001702220653003402237653001102271653000902282653001402291653003602305100001702341700002102358700002202379700001702401700001402418700002002432700001402452700002102466700001702487700002202504700001402526700001702540700001702557700001202574700002002586700001802606700001702624700001202641700002002653700001902673700002102692700001502713700001802728700001602746700001502762700002202777700002002799700001602819700001802835700001302853700001702866700001802883700001702901700001502918700001802933700002202951700001902973700001602992700002003008700002203028700001903050700002203069700002303091700001703114700002003131700001803151700001203169700001803181700001703199700002103216856003603237 2017 eng d a1942-326800aGenome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.0 aGenomeWide Association Study MetaAnalysis of LongTerm Average Bl c2017 Apr ae0015270 v103 aBACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.
METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively).
CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.
10aAsian Continental Ancestry Group10aBlood Pressure10aFar East10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aPhenotype10aPolymorphism, Single Nucleotide1 aLi, Changwei1 aKim, Yun, Kyoung1 aDorajoo, Rajkumar1 aLi, Huaixing1 aLee, I-Te1 aCheng, Ching-Yu1 aHe, Meian1 aSheu, Wayne, H-H1 aGuo, Xiuqing1 aGanesh, Santhi, K1 aHe, Jiang1 aLee, Juyoung1 aLiu, Jianjun1 aHu, Yao1 aRao, Dabeeru, C1 aTsai, Fuu-Jen1 aKoh, Jia, Yu1 aHu, Hua1 aLiang, Kae-Woei1 aPalmas, Walter1 aHixson, James, E1 aHan, Sohee1 aTeo, Yik-Ying1 aWang, Yiqin1 aChen, Jing1 aLu, Chieh, Hsiang1 aZheng, Yingfeng1 aGui, Lixuan1 aLee, Wen-Jane1 aYao, Jie1 aGu, Dongfeng1 aHan, Bok-Ghee1 aSim, Xueling1 aSun, Liang1 aZhao, Jinying1 aChen, Chien-Hsiun1 aKumari, Neelam1 aHe, Yunfeng1 aTaylor, Kent, D1 aRaffel, Leslie, J1 aMoon, Sanghoon1 aRotter, Jerome, I1 aChen, Yii-Der, Ida1 aWu, Tangchun1 aWong, Tien, Yin1 aWu, Jer-Yuarn1 aLin, Xu1 aTai, E-Shyong1 aKim, Bong-Jo1 aKelly, Tanika, N uhttps://chs-nhlbi.org/node/757104812nas a2201345 4500008004100000022001400041245014400055210006900199260001600268300001000284490000800294520106400302100002601366700001801392700002101410700001301431700002001444700002001464700002301484700002001507700002001527700001801547700002001565700001701585700002301602700001901625700002301644700001801667700002001685700002101705700002301726700001901749700001901768700002301787700001901810700001801829700001801847700002401865700001801889700002201907700002001929700002101949700002101970700002001991700002202011700002102033700002002054700001402074700002002088700001602108700001902124700002002143700002802163700002102191700001702212700002002229700001402249700002102263700002202284700002302306700001502329700001502344700001802359700002202377700002302399700002202422700001902444700002102463700001202484700002402496700002202520700001702542700002002559700002202579700002202601700002002623700001402643700002202657700002102679700002002700700002002720700002302740700002002763700002202783700002202805700001502827700002302842700002302865700002402888700002202912700001702934700001802951700001802969700001802987700002103005700002103026700001603047700002003063700002103083700002103104700002903125700002103154700002403175700003003199700001903229700002503248700002203273700002203295700002003317700002503337700002003362700002203382710002603404856003603430 2017 eng d a1537-660500aGenome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.0 aGenomewide Transethnic Metaanalysis Identifies Seven Genetic Loc c2017 Jan 05 a51-630 v1003 aGenome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.
1 avan Rooij, Frank, J A1 aQayyum, Rehan1 aSmith, Albert, V1 aZhou, Yi1 aTrompet, Stella1 aTanaka, Toshiko1 aKeller, Margaux, F1 aChang, Li-Ching1 aSchmidt, Helena1 aYang, Min-Lee1 aChen, Ming-Huei1 aHayes, James1 aJohnson, Andrew, D1 aYanek, Lisa, R1 aMueller, Christian1 aLange, Leslie1 aFloyd, James, S1 aGhanbari, Mohsen1 aZonderman, Alan, B1 aJukema, Wouter1 aHofman, Albert1 aDuijn, Cornelia, M1 aDesch, Karl, C1 aSaba, Yasaman1 aOzel, Ayse, B1 aSnively, Beverly, M1 aWu, Jer-Yuarn1 aSchmidt, Reinhold1 aFornage, Myriam1 aKlein, Robert, J1 aFox, Caroline, S1 aMatsuda, Koichi1 aKamatani, Naoyuki1 aWild, Philipp, S1 aStott, David, J1 aFord, Ian1 aSlagboom, Eline1 aYang, Jaden1 aChu, Audrey, Y1 aLambert, Amy, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aHofer, Edith1 aGinsburg, David1 aHu, Bella1 aKeating, Brendan1 aSchick, Ursula, M1 aBrody, Jennifer, A1 aLi, Jun, Z1 aChen, Zhao1 aZeller, Tanja1 aGuralnik, Jack, M1 aChasman, Daniel, I1 aPeters, Luanne, L1 aKubo, Michiaki1 aBecker, Diane, M1 aLi, Jin1 aEiriksdottir, Gudny1 aRotter, Jerome, I1 aLevy, Daniel1 aGrossmann, Vera1 aPatel, Kushang, V1 aChen, Chien-Hsiun1 aRidker, Paul, M1 aTang, Hua1 aLauner, Lenore, J1 aRice, Kenneth, M1 aLi-Gao, Ruifang1 aFerrucci, Luigi1 aEvans, Michelle, K1 aChoudhuri, Avik1 aTrompouki, Eirini1 aAbraham, Brian, J1 aYang, Song1 aTakahashi, Atsushi1 aKamatani, Yoichiro1 aKooperberg, Charles1 aHarris, Tamara, B1 aJee, Sun, Ha1 aCoresh, Josef1 aTsai, Fuu-Jen1 aLongo, Dan, L1 aChen, Yuan-Tsong1 aFelix, Janine, F1 aYang, Qiong1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aBecker, Lewis, C1 aMook-Kanamori, Dennis, O1 aWilson, James, G1 aGudnason, Vilmundur1 aO'Donnell, Christopher, J1 aDehghan, Abbas1 aCupples, Adrienne, L1 aNalls, Michael, A1 aMorris, Andrew, P1 aOkada, Yukinori1 aReiner, Alexander, P1 aZon, Leonard, I1 aGanesh, Santhi, K1 aBioBank Japan Project uhttps://chs-nhlbi.org/node/736402961nas a2200325 4500008004100000022001400041245012600055210006900181260001600250520195800266100002402224700002302248700002202271700002302293700001302316700002502329700002202354700001802376700002002394700002302414700002002437700002202457700001602479700001902495700002002514700001902534700002402553700002202577856003602599 2018 eng d a1096-865200aGeneralization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study.0 aGeneralization and fine mapping of red blood cell trait genetic c2018 Jun 153 aRed blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.
1 aHodonsky, Chani, Jo1 aSchurmann, Claudia1 aSchick, Ursula, M1 aKocarnik, Jonathan1 aTao, Ran1 avan Rooij, Frank, Ja1 aWassel, Christina1 aBuyske, Steve1 aFornage, Myriam1 aHindorff, Lucia, A1 aFloyd, James, S1 aGanesh, Santhi, K1 aLin, Dan-Yu1 aNorth, Kari, E1 aReiner, Alex, P1 aLoos, Ruth, Jf1 aKooperberg, Charles1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/779304296nas a2200973 4500008004100000022001400041245010700055210006900162260001600231520147300247100002301720700002101743700001901764700001801783700001901801700002301820700001901843700001701862700001901879700003001898700002601928700002801954700002801982700002102010700001702031700002202048700002302070700002202093700002202115700002102137700002402158700002302182700002002205700002402225700002002249700002102269700002302290700002402313700002402337700001902361700001902380700002002399700001902419700002502438700002302463700002402486700002002510700002302530700001602553700002202569700002002591700002002611700001702631700002202648700001802670700002402688700002402712700002302736700002402759700001902783700001502802700002302817700002502840700002502865700002202890700002402912700001902936700002602955700002602981700002103007700002103028700002203049700002303071700002003094700002703114700002103141700002003162700002103182700001903203700002003222700002303242700002103265856003603286 2021 eng d a1476-625600aA System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.0 aSystem for Phenotype Harmonization in the NHLBI TransOmics for P c2021 Apr 163 aGenotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
1 aStilp, Adrienne, M1 aEmery, Leslie, S1 aBroome, Jai, G1 aButh, Erin, J1 aKhan, Alyna, T1 aLaurie, Cecelia, A1 aWang, Fei, Fei1 aWong, Quenna1 aChen, Dongquan1 aD'Augustine, Catherine, M1 aHeard-Costa, Nancy, L1 aHohensee, Chancellor, R1 aJohnson, William, Craig1 aJuarez, Lucia, D1 aLiu, Jingmin1 aMutalik, Karen, M1 aRaffield, Laura, M1 aWiggins, Kerri, L1 ade Vries, Paul, S1 aKelly, Tanika, N1 aKooperberg, Charles1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aPeyser, Patricia, A1 aReiner, Alex, P1 aArnett, Donna, K1 aAslibekyan, Stella1 aBarnes, Kathleen, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aCade, Brian, E1 aChen, Ming-Huei1 aCorrea, Adolfo1 aCupples, Adrienne, L1 ade Andrade, Mariza1 aEllinor, Patrick, T1 aFornage, Myriam1 aFranceschini, Nora1 aGan, Weiniu1 aGanesh, Santhi, K1 aGraffelman, Jan1 aGrove, Megan, L1 aGuo, Xiuqing1 aHawley, Nicola, L1 aHsu, Wan-Ling1 aJackson, Rebecca, D1 aJaquish, Cashell, E1 aJohnson, Andrew, D1 aKardia, Sharon, L R1 aKelly, Shannon1 aLee, Jiwon1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNorth, Kari, E1 aNouraie, Seyed, Mehdi1 aOelsner, Elizabeth, C1 aPankratz, Nathan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aWeeks, Daniel, E1 aWeiss, Scott, T1 aWilson, Carla, G1 aYanek, Lisa, R1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aLaurie, Cathy, C uhttps://chs-nhlbi.org/node/8713