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Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.
1 aChristophersen, Ingrid, E1 aRienstra, Michiel1 aRoselli, Carolina1 aYin, Xiaoyan1 aGeelhoed, Bastiaan1 aBarnard, John1 aLin, Honghuang1 aArking, Dan, E1 aSmith, Albert, V1 aAlbert, Christine, M1 aChaffin, Mark1 aTucker, Nathan, R1 aLi, Molong1 aKlarin, Derek1 aBihlmeyer, Nathan, A1 aLow, Siew-Kee1 aWeeke, Peter, E1 aMüller-Nurasyid, Martina1 aSmith, Gustav1 aBrody, Jennifer, A1 aNiemeijer, Maartje, N1 aDörr, Marcus1 aTrompet, Stella1 aHuffman, Jennifer1 aGustafsson, Stefan1 aSchurmann, Claudia1 aKleber, Marcus, E1 aLyytikäinen, Leo-Pekka1 aSeppälä, Ilkka1 aMalik, Rainer1 aHorimoto, Andrea, R V R1 aPerez, Marco1 aSinisalo, Juha1 aAeschbacher, Stefanie1 aThériault, Sébastien1 aYao, Jie1 aRadmanesh, Farid1 aWeiss, Stefan1 aTeumer, Alexander1 aChoi, Seung, Hoan1 aWeng, Lu-Chen1 aClauss, Sebastian1 aDeo, Rajat1 aRader, Daniel, J1 aShah, Svati, H1 aSun, Albert1 aHopewell, Jemma, C1 aDebette, Stephanie1 aChauhan, Ganesh1 aYang, Qiong1 aWorrall, Bradford, B1 aParé, Guillaume1 aKamatani, Yoichiro1 aHagemeijer, Yanick, P1 aVerweij, Niek1 aSiland, Joylene, E1 aKubo, Michiaki1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aBis, Joshua, C1 aPerz, Siegfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aMagnani, Jared, W1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShoemaker, Benjamin1 aPadmanabhan, Sandosh1 aHaessler, Jeffrey1 aBartz, Traci, M1 aWaldenberger, Melanie1 aLichtner, Peter1 aArendt, Marina1 aKrieger, Jose, E1 aKähönen, Mika1 aRisch, Lorenz1 aMansur, Alfredo, J1 aPeters, Annette1 aSmith, Blair, H1 aLind, Lars1 aScott, Stuart, A1 aLu, Yingchang1 aBottinger, Erwin, B1 aHernesniemi, Jussi1 aLindgren, Cecilia, M1 aWong, Jorge, A1 aHuang, Jie1 aEskola, Markku1 aMorris, Andrew, P1 aFord, Ian1 aReiner, Alex, P1 aDelgado, Graciela1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aSandhu, Roopinder, K1 aLi, Man1 aBoerwinkle, Eric1 aEisele, Lewin1 aLannfelt, Lars1 aRost, Natalia1 aAnderson, Christopher, D1 aTaylor, Kent, D1 aCampbell, Archie1 aMagnusson, Patrik, K1 aPorteous, David1 aHocking, Lynne, J1 aVlachopoulou, Efthymia1 aPedersen, Nancy, L1 aNikus, Kjell1 aOrho-Melander, Marju1 aHamsten, Anders1 aHeeringa, Jan1 aDenny, Joshua, C1 aKriebel, Jennifer1 aDarbar, Dawood1 aNewton-Cheh, Christopher1 aShaffer, Christian1 aMacfarlane, Peter, W1 aHeilmann-Heimbach, Stefanie1 aAlmgren, Peter1 aHuang, Paul, L1 aSotoodehnia, Nona1 aSoliman, Elsayed, Z1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aVölker, Uwe1 aJöckel, Karl-Heinz1 aSinner, Moritz, F1 aLin, Henry, J1 aGuo, Xiuqing1 aDichgans, Martin1 aIngelsson, Erik1 aKooperberg, Charles1 aMelander, Olle1 aLoos, Ruth, J F1 aLaurikka, Jari1 aConen, David1 aRosand, Jonathan1 aHarst, Pim1 aLokki, Marja-Liisa1 aKathiresan, Sekar1 aPereira, Alexandre1 aJukema, Wouter1 aHayward, Caroline1 aRotter, Jerome, I1 aMärz, Winfried1 aLehtimäki, Terho1 aStricker, Bruno, H1 aChung, Mina, K1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aRoden, Dan, M1 aKääb, Stefan1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aTanaka, Toshihiro1 aLunetta, Kathryn, L1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aMETASTROKE Consortium of the ISGC1 aNeurology Working Group of the CHARGE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/739608664nas a2202749 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2018 eng d a1546-171800aMulti-ethnic genome-wide association study for atrial fibrillation.0 aMultiethnic genomewide association study for atrial fibrillation c2018 Sep a1225-12330 v503 aAtrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
1 aRoselli, Carolina1 aChaffin, Mark, D1 aWeng, Lu-Chen1 aAeschbacher, Stefanie1 aAhlberg, Gustav1 aAlbert, Christine, M1 aAlmgren, Peter1 aAlonso, Alvaro1 aAnderson, Christopher, D1 aAragam, Krishna, G1 aArking, Dan, E1 aBarnard, John1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aBihlmeyer, Nathan, A1 aBis, Joshua, C1 aBloom, Heather, L1 aBoerwinkle, Eric1 aBottinger, Erwin, B1 aBrody, Jennifer, A1 aCalkins, Hugh1 aCampbell, Archie1 aCappola, Thomas, P1 aCarlquist, John1 aChasman, Daniel, I1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aChoi, Eue-Keun1 aChoi, Seung, Hoan1 aChristophersen, Ingrid, E1 aChung, Mina, K1 aCole, John, W1 aConen, David1 aCook, James1 aCrijns, Harry, J1 aCutler, Michael, J1 aDamrauer, Scott, M1 aDaniels, Brian, R1 aDarbar, Dawood1 aDelgado, Graciela1 aDenny, Joshua, C1 aDichgans, Martin1 aDörr, Marcus1 aDudink, Elton, A1 aDudley, Samuel, C1 aEsa, Nada1 aEsko, Tõnu1 aEskola, Markku1 aFatkin, Diane1 aFelix, Stephan, B1 aFord, Ian1 aFranco, Oscar, H1 aGeelhoed, Bastiaan1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGupta, Namrata1 aGustafsson, Stefan1 aGutmann, Rebecca1 aHamsten, Anders1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHernesniemi, Jussi1 aHocking, Lynne, J1 aHofman, Albert1 aHorimoto, Andrea, R V R1 aHuang, Jie1 aHuang, Paul, L1 aHuffman, Jennifer1 aIngelsson, Erik1 aIpek, Esra, Gucuk1 aIto, Kaoru1 aJimenez-Conde, Jordi1 aJohnson, Renee1 aJukema, Wouter1 aKääb, Stefan1 aKähönen, Mika1 aKamatani, Yoichiro1 aKane, John, P1 aKastrati, Adnan1 aKathiresan, Sekar1 aKatschnig-Winter, Petra1 aKavousi, Maryam1 aKessler, Thorsten1 aKietselaer, Bas, L1 aKirchhof, Paulus1 aKleber, Marcus, E1 aKnight, Stacey1 aKrieger, Jose, E1 aKubo, Michiaki1 aLauner, Lenore, J1 aLaurikka, Jari1 aLehtimäki, Terho1 aLeineweber, Kirsten1 aLemaitre, Rozenn, N1 aLi, Man1 aLim, Hong, Euy1 aLin, Henry, J1 aLin, Honghuang1 aLind, Lars1 aLindgren, Cecilia, M1 aLokki, Marja-Liisa1 aLondon, Barry1 aLoos, Ruth, J F1 aLow, Siew-Kee1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMacfarlane, Peter, W1 aMagnusson, Patrik, K1 aMahajan, Anubha1 aMalik, Rainer1 aMansur, Alfredo, J1 aMarcus, Gregory, M1 aMargolin, Lauren1 aMargulies, Kenneth, B1 aMärz, Winfried1 aMcManus, David, D1 aMelander, Olle1 aMohanty, Sanghamitra1 aMontgomery, Jay, A1 aMorley, Michael, P1 aMorris, Andrew, P1 aMüller-Nurasyid, Martina1 aNatale, Andrea1 aNazarian, Saman1 aNeumann, Benjamin1 aNewton-Cheh, Christopher1 aNiemeijer, Maartje, N1 aNikus, Kjell1 aNilsson, Peter1 aNoordam, Raymond1 aOellers, Heidi1 aOlesen, Morten, S1 aOrho-Melander, Marju1 aPadmanabhan, Sandosh1 aPak, Hui-Nam1 aParé, Guillaume1 aPedersen, Nancy, L1 aPera, Joanna1 aPereira, Alexandre1 aPorteous, David1 aPsaty, Bruce, M1 aPulit, Sara, L1 aPullinger, Clive, R1 aRader, Daniel, J1 aRefsgaard, Lena1 aRibasés, Marta1 aRidker, Paul, M1 aRienstra, Michiel1 aRisch, Lorenz1 aRoden, Dan, M1 aRosand, Jonathan1 aRosenberg, Michael, A1 aRost, Natalia1 aRotter, Jerome, I1 aSaba, Samir1 aSandhu, Roopinder, K1 aSchnabel, Renate, B1 aSchramm, Katharina1 aSchunkert, Heribert1 aSchurman, Claudia1 aScott, Stuart, A1 aSeppälä, Ilkka1 aShaffer, Christian1 aShah, Svati1 aShalaby, Alaa, A1 aShim, Jaemin1 aShoemaker, Benjamin1 aSiland, Joylene, E1 aSinisalo, Juha1 aSinner, Moritz, F1 aSlowik, Agnieszka1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Gustav1 aSmith, Jonathan, D1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSun, Albert1 aSun, Han1 aSvendsen, Jesper, H1 aTanaka, Toshihiro1 aTanriverdi, Kahraman1 aTaylor, Kent, D1 aTeder-Laving, Maris1 aTeumer, Alexander1 aThériault, Sébastien1 aTrompet, Stella1 aTucker, Nathan, R1 aTveit, Arnljot1 aUitterlinden, André, G1 aHarst, Pim1 aVan Gelder, Isabelle, C1 aVan Wagoner, David, R1 aVerweij, Niek1 aVlachopoulou, Efthymia1 aVölker, Uwe1 aWang, Biqi1 aWeeke, Peter, E1 aWeijs, Bob1 aWeiss, Raul1 aWeiss, Stefan1 aWells, Quinn, S1 aWiggins, Kerri, L1 aWong, Jorge, A1 aWoo, Daniel1 aWorrall, Bradford, B1 aYang, Pil-Sung1 aYao, Jie1 aYoneda, Zachary, T1 aZeller, Tanja1 aZeng, Lingyao1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/7811