06419nas a2201621 4500008004100000022001400041245011300055210006900168260001600237300001400253490000800267520184900275100002102124700002102145700002002166700002202186700002002208700002602228700001702254700002002271700002302291700002502314700002002339700001902359700001902378700002202397700002202419700002102441700002602462700002202488700002102510700002202531700002802553700001902581700001802600700002202618700002402640700002302664700002402687700001802711700002002729700002202749700002102771700002402792700001902816700002002835700002102855700001702876700002102893700002602914700002002940700002002960700001702980700002002997700002203017700001703039700001903056700001503075700002003090700002003110700002403130700001903154700002103173700001903194700002203213700002203235700002503257700001903282700002503301700002103326700002103347700002403368700001703392700002203409700002203431700002303453700003003476700002003506700002203526700002203548700001903570700002003589700001803609700002003627700002603647700002303673700002103696700002603717700002203743700002203765700002003787700002503807700002003832700002303852700002203875700002103897700002203918700002303940700002303963700001603986700002404002700002804026700001804054700001904072700002104091700002004112700002004132700002304152700002404175700002204199700002304221700001804244700002204262700002504284700001904309700001704328700002204345700001904367700002104386700001504407700002404422700002004446700002304466700002004489700002404509700002004533700001504553700002104568700002004589700002404609700002204633700002204655700002104677700001804698700002704716700001804743856003604761 2017 eng d a1558-823800aLarge-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.0 aLargescale genomewide analysis identifies genetic variants assoc c2017 May 01 a1798-18120 v1273 a
BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.
METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.
RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.
CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
FUNDING: For detailed information per study, see Acknowledgments.
1 aWild, Philipp, S1 aFelix, Janine, F1 aSchillert, Arne1 aTeumer, Alexander1 aChen, Ming-Huei1 aLeening, Maarten, J G1 aVölker, Uwe1 aGroßmann, Vera1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aShah, Sanjiv, J1 aPramana, Setia1 aLieb, Wolfgang1 aSchmidt, Reinhold1 aStanton, Alice, V1 aMalzahn, Dörthe1 aSmith, Albert, Vernon1 aSundström, Johan1 aMinelli, Cosetta1 aRuggiero, Daniela1 aLyytikäinen, Leo-Pekka1 aTiller, Daniel1 aSmith, Gustav1 aMonnereau, Claire1 aDi Tullio, Marco, R1 aMusani, Solomon, K1 aMorrison, Alanna, C1 aPers, Tune, H1 aMorley, Michael1 aKleber, Marcus, E1 aAragam, Jayashri1 aBenjamin, Emelia, J1 aBis, Joshua, C1 aBisping, Egbert1 aBroeckel, Ulrich1 aCheng, Susan1 aDeckers, Jaap, W1 aM, Fabiola, del Greco1 aEdelmann, Frank1 aFornage, Myriam1 aFranke, Lude1 aFriedrich, Nele1 aHarris, Tamara, B1 aHofer, Edith1 aHofman, Albert1 aHuang, Jie1 aHughes, Alun, D1 aKähönen, Mika1 aInvestigators, Knhi1 aKruppa, Jochen1 aLackner, Karl, J1 aLannfelt, Lars1 aLaskowski, Rafael1 aLauner, Lenore, J1 aLeosdottir, Margrét1 aLin, Honghuang1 aLindgren, Cecilia, M1 aLoley, Christina1 aMacRae, Calum, A1 aMascalzoni, Deborah1 aMayet, Jamil1 aMedenwald, Daniel1 aMorris, Andrew, P1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNappo, Stefania1 aNilsson, Peter, M1 aNuding, Sebastian1 aNutile, Teresa1 aPeters, Annette1 aPfeufer, Arne1 aPietzner, Diana1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aRuohonen, Saku, T1 aSacco, Ralph, L1 aSamdarshi, Tandaw, E1 aSchmidt, Helena1 aSharp, Andrew, S P1 aShields, Denis, C1 aSorice, Rossella1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSurendran, Praveen1 aThom, Simon1 aTöglhofer, Anna, M1 aUitterlinden, André, G1 aWachter, Rolf1 aVölzke, Henry1 aZiegler, Andreas1 aMünzel, Thomas1 aMärz, Winfried1 aCappola, Thomas, P1 aHirschhorn, Joel, N1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aFox, Ervin, R1 aDueker, Nicole, D1 aJaddoe, Vincent, W V1 aMelander, Olle1 aRuss, Martin1 aLehtimäki, Terho1 aCiullo, Marina1 aHicks, Andrew, A1 aLind, Lars1 aGudnason, Vilmundur1 aPieske, Burkert1 aBarron, Anthony, J1 aZweiker, Robert1 aSchunkert, Heribert1 aIngelsson, Erik1 aLiu, Kiang1 aArnett, Donna, K1 aPsaty, Bruce, M1 aBlankenberg, Stefan1 aLarson, Martin, G1 aFelix, Stephan, B1 aFranco, Oscar, H1 aZeller, Tanja1 aVasan, Ramachandran, S1 aDörr, Marcus uhttps://chs-nhlbi.org/node/737311426nas a2203589 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2018 eng d a1537-660500aGenome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.0 aGenome Analyses of 200000 Individuals Identify 58 Loci for Chron c2018 Nov 01 a691-7060 v1033 aC-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
1 aLigthart, Symen1 aVaez, Ahmad1 aVõsa, Urmo1 aStathopoulou, Maria, G1 ade Vries, Paul, S1 aPrins, Bram, P1 avan der Most, Peter, J1 aTanaka, Toshiko1 aNaderi, Elnaz1 aRose, Lynda, M1 aWu, Ying1 aKarlsson, Robert1 aBarbalic, Maja1 aLin, Honghuang1 aPool, Rene1 aZhu, Gu1 aMace, Aurelien1 aSidore, Carlo1 aTrompet, Stella1 aMangino, Massimo1 aSabater-Lleal, Maria1 aKemp, John, P1 aAbbasi, Ali1 aKacprowski, Tim1 aVerweij, Niek1 aSmith, Albert, V1 aHuang, Tao1 aMarzi, Carola1 aFeitosa, Mary, F1 aLohman, Kurt, K1 aKleber, Marcus, E1 aMilaneschi, Yuri1 aMueller, Christian1 aHuq, Mahmudul1 aVlachopoulou, Efthymia1 aLyytikäinen, Leo-Pekka1 aOldmeadow, Christopher1 aDeelen, Joris1 aPerola, Markus1 aZhao, Jing Hua1 aFeenstra, Bjarke1 aAmini, Marzyeh1 aLahti, Jari1 aSchraut, Katharina, E1 aFornage, Myriam1 aSuktitipat, Bhoom1 aChen, Wei-Min1 aLi, Xiaohui1 aNutile, Teresa1 aMalerba, Giovanni1 aLuan, Jian'an1 aBak, Tom1 aSchork, Nicholas1 aM, Fabiola, del Greco1 aThiering, Elisabeth1 aMahajan, Anubha1 aMarioni, Riccardo, E1 aMihailov, Evelin1 aEriksson, Joel1 aOzel, Ayse, Bilge1 aZhang, Weihua1 aNethander, Maria1 aCheng, Yu-Ching1 aAslibekyan, Stella1 aAng, Wei1 aGandin, Ilaria1 aYengo, Loic1 aPortas, Laura1 aKooperberg, Charles1 aHofer, Edith1 aRajan, Kumar, B1 aSchurmann, Claudia1 aHollander, Wouter, den1 aAhluwalia, Tarunveer, S1 aZhao, Jing1 aDraisma, Harmen, H M1 aFord, Ian1 aTimpson, Nicholas1 aTeumer, Alexander1 aHuang, Hongyan1 aWahl, Simone1 aLiu, Yongmei1 aHuang, Jie1 aUh, Hae-Won1 aGeller, Frank1 aJoshi, Peter, K1 aYanek, Lisa, R1 aTrabetti, Elisabetta1 aLehne, Benjamin1 aVozzi, Diego1 aVerbanck, Marie1 aBiino, Ginevra1 aSaba, Yasaman1 aMeulenbelt, Ingrid1 aO'Connell, Jeff, R1 aLaakso, Markku1 aGiulianini, Franco1 aMagnusson, Patrik, K E1 aBallantyne, Christie, M1 aHottenga, Jouke Jan1 aMontgomery, Grant, W1 aRivadineira, Fernando1 aRueedi, Rico1 aSteri, Maristella1 aHerzig, Karl-Heinz1 aStott, David, J1 aMenni, Cristina1 aFrånberg, Mattias1 aSt Pourcain, Beate1 aFelix, Stephan, B1 aPers, Tune, H1 aBakker, Stephan, J L1 aKraft, Peter1 aPeters, Annette1 aVaidya, Dhananjay1 aDelgado, Graciela1 aSmit, Johannes, H1 aGroßmann, Vera1 aSinisalo, Juha1 aSeppälä, Ilkka1 aWilliams, Stephen, R1 aHolliday, Elizabeth, G1 aMoed, Matthijs1 aLangenberg, Claudia1 aRäikkönen, Katri1 aDing, Jingzhong1 aCampbell, Harry1 aSale, Michèle, M1 aChen, Yii-der, I1 aJames, Alan, L1 aRuggiero, Daniela1 aSoranzo, Nicole1 aHartman, Catharina, A1 aSmith, Erin, N1 aBerenson, Gerald, S1 aFuchsberger, Christian1 aHernandez, Dena1 aTiesler, Carla, M T1 aGiedraitis, Vilmantas1 aLiewald, David1 aFischer, Krista1 aMellström, Dan1 aLarsson, Anders1 aWang, Yunmei1 aScott, William, R1 aLorentzon, Matthias1 aBeilby, John1 aRyan, Kathleen, A1 aPennell, Craig, E1 aVuckovic, Dragana1 aBalkau, Beverly1 aConcas, Maria, Pina1 aSchmidt, Reinhold1 ade Leon, Carlos, F Mendes1 aBottinger, Erwin, P1 aKloppenburg, Margreet1 aPaternoster, Lavinia1 aBoehnke, Michael1 aMusk, A, W1 aWillemsen, Gonneke1 aEvans, David, M1 aMadden, Pamela, A F1 aKähönen, Mika1 aKutalik, Zoltán1 aZoledziewska, Magdalena1 aKarhunen, Ville1 aKritchevsky, Stephen, B1 aSattar, Naveed1 aLachance, Genevieve1 aClarke, Robert1 aHarris, Tamara, B1 aRaitakari, Olli, T1 aAttia, John, R1 avan Heemst, Diana1 aKajantie, Eero1 aSorice, Rossella1 aGambaro, Giovanni1 aScott, Robert, A1 aHicks, Andrew, A1 aFerrucci, Luigi1 aStandl, Marie1 aLindgren, Cecilia, M1 aStarr, John, M1 aKarlsson, Magnus1 aLind, Lars1 aLi, Jun, Z1 aChambers, John, C1 aMori, Trevor, A1 ade Geus, Eco, J C N1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aAuvinen, Juha1 aBuckley, Brendan, M1 ade Craen, Anton, J M1 aWaldenberger, Melanie1 aStrauch, Konstantin1 aMeitinger, Thomas1 aScott, Rodney, J1 aMcEvoy, Mark1 aBeekman, Marian1 aBombieri, Cristina1 aRidker, Paul, M1 aMohlke, Karen, L1 aPedersen, Nancy, L1 aMorrison, Alanna, C1 aBoomsma, Dorret, I1 aWhitfield, John, B1 aStrachan, David, P1 aHofman, Albert1 aVollenweider, Peter1 aCucca, Francesco1 aJarvelin, Marjo-Riitta1 aJukema, Wouter1 aSpector, Tim, D1 aHamsten, Anders1 aZeller, Tanja1 aUitterlinden, André, G1 aNauck, Matthias1 aGudnason, Vilmundur1 aQi, Lu1 aGrallert, Harald1 aBorecki, Ingrid, B1 aRotter, Jerome, I1 aMärz, Winfried1 aWild, Philipp, S1 aLokki, Marja-Liisa1 aBoyle, Michael1 aSalomaa, Veikko1 aMelbye, Mads1 aEriksson, Johan, G1 aWilson, James, F1 aPenninx, Brenda, W J H1 aBecker, Diane, M1 aWorrall, Bradford, B1 aGibson, Greg1 aKrauss, Ronald, M1 aCiullo, Marina1 aZaza, Gianluigi1 aWareham, Nicholas, J1 aOldehinkel, Albertine, J1 aPalmer, Lyle, J1 aMurray, Sarah, S1 aPramstaller, Peter, P1 aBandinelli, Stefania1 aHeinrich, Joachim1 aIngelsson, Erik1 aDeary, Ian, J1 aMägi, Reedik1 aVandenput, Liesbeth1 aHarst, Pim1 aDesch, Karl, C1 aKooner, Jaspal, S1 aOhlsson, Claes1 aHayward, Caroline1 aLehtimäki, Terho1 aShuldiner, Alan, R1 aArnett, Donna, K1 aBeilin, Lawrence, J1 aRobino, Antonietta1 aFroguel, Philippe1 aPirastu, Mario1 aJess, Tine1 aKoenig, Wolfgang1 aLoos, Ruth, J F1 aEvans, Denis, A1 aSchmidt, Helena1 aSmith, George Davey1 aSlagboom, Eline1 aEiriksdottir, Gudny1 aMorris, Andrew, P1 aPsaty, Bruce, M1 aTracy, Russell, P1 aNolte, Ilja, M1 aBoerwinkle, Eric1 aVisvikis-Siest, Sophie1 aReiner, Alex, P1 aGross, Myron1 aBis, Joshua, C1 aFranke, Lude1 aFranco, Oscar, H1 aBenjamin, Emelia, J1 aChasman, Daniel, I1 aDupuis, Josée1 aSnieder, Harold1 aDehghan, Abbas1 aAlizadeh, Behrooz, Z1 aLifeLines Cohort Study1 aCHARGE Inflammation Working Group uhttps://chs-nhlbi.org/node/7920