Multi-ethnic genome-wide association study for atrial fibrillation
Carolina Roselli(Broad Institute), Mark Chaffin(Broad Institute), Lu‐Chen Weng(Broad Institute), Stefanie Aeschbacher(University Hospital of Basel), Gustav Ahlberg(University of Copenhagen), Christine M. Albert(Brigham and Women's Hospital), Peter Almgren(Lund University), Álvaro Alonso(Emory University), Christopher D. Anderson(Broad Institute), Krishna G. Aragam(Broad Institute), Dan E. Arking(Johns Hopkins University), John Barnard(Cleveland Clinic), Traci M. Bartz(University of Washington), Emelia J. Benjamin(Boston University), Nathan A. Bihlmeyer(Johns Hopkins University), Joshua C. Bis(University of Washington), Heather L. Bloom(Emory University), Eric Boerwinkle(Baylor College of Medicine), Erwin B. Bottinger(Icahn School of Medicine at Mount Sinai), Jennifer A. Brody(University of Washington), Hugh Calkins(Johns Hopkins University), Archie Campbell(Edinburgh Cancer Research), Thomas P. Cappola(University of Pennsylvania), John F. Carlquist(University of Utah), Daniel I. Chasman(Broad Institute), Lin Y. Chen(University of Minnesota Medical Center), Yii-Der Ida Chen(The Lundquist Institute), Eue‐Keun Choi(Seoul National University Hospital), Seung Hoan Choi(Broad Institute), Ingrid E. Christophersen(Broad Institute), Mina K. Chung(Cleveland Clinic), John W. Cole(University of Maryland, Baltimore), David Conen(University Hospital of Basel), James P. Cook(University of Liverpool), Harry J. Crijns(Maastricht University), Michael J. Cutler(Intermountain Medical Center), Scott M. Damrauer(Philadelphia VA Medical Center), Brian R. Daniels(Broad Institute), Dawood Darbar(University of Illinois Chicago), Graciela Delgado(Heidelberg University), Joshua C. Denny(Vanderbilt University Medical Center), Martin Dichgans(German Center for Neurodegenerative Diseases), Marcus Dörr(Universitätsmedizin Greifswald), Elton Dudink(Maastricht University), Samuel C. Dudley(University of Minnesota), Nada Esa(University of Massachusetts Chan Medical School), Tōnu Esko(Broad Institute), Markku Eskola(Tampere University Hospital), Diane Fatkin(Victor Chang Cardiac Research Institute), Stephan B. Felix(Universitätsmedizin Greifswald), Ian Ford(University of Glasgow), Oscar H. Franco(Erasmus MC), Bastiaan Geelhoed(University Medical Center Groningen), Raji P. Grewal(Seton Hall University), Vilmundur Guðnason(University of Iceland), Xiuqing Guo(The Lundquist Institute), Namrata Gupta(Broad Institute), Stefan Gustafsson(Uppsala University), Rebecca Gutmann(University of Iowa), Anders Hamsten(Karolinska Institutet), Tamara B. Harris(National Institute on Aging), Caroline Hayward(Institute of Genetics and Cancer), Susan R. Heckbert(Kaiser Permanente Washington Health Research Institute), Jussi Hernesniemi(Tampere University), Lynne J. Hocking(University of Aberdeen), Albert Hofman(Erasmus MC), Andréa R. V. R. Horimoto(Universidade de São Paulo), Jie Huang(Boston VA Research Institute), Paul L. Huang(Massachusetts General Hospital), Jennifer E. Huffman(Institute of Genetics and Cancer), Erik Ingelsson(Uppsala University), Esra Gücük İpek(Johns Hopkins University), Kaoru Ito(RIKEN Center for Integrative Medical Sciences), Jordi Jiménez‐Conde(Universitat Autònoma de Barcelona), Renée Johnson(Victor Chang Cardiac Research Institute), J. Wouter Jukema(Leiden University Medical Center), Stefan Kääb(German Centre for Cardiovascular Research), Mika Kähönen(Tampere University), Yoichiro Kamatani(RIKEN Center for Integrative Medical Sciences), John P. Kane(University of California, San Francisco), Adnan Kastrati(München Klinik), Sekar Kathiresan(Broad Institute), Petra Katschnig‐Winter(Medical University of Graz), Maryam Kavousi(Erasmus MC), Thorsten Kessler(München Klinik), Bas Kietselaer(Maastricht University), Paulus Kirchhof(University Hospitals Birmingham NHS Foundation Trust), Marcus E. Kleber(Heidelberg University), Stacey Knight(University of Utah), José Eduardo Krieger(Universidade de São Paulo), Michiaki Kubo(RIKEN Center for Integrative Medical Sciences), Lenore J. Launer(National Institute on Aging), Jari Laurikka(Tampere University), Terho Lehtimäki(Tampere University), Kirsten Leineweber(Bayer (Germany)), Rozenn N. Lemaître(University of Washington), Man Li(Brigham and Women's Hospital), Hong Euy Lim(Korea University Medical Center), Henry J. Lin(Boston University), Honghuang Lin(Boston University), Lars Lind(Uppsala University), Cecilia M. Lindgren(Centre for Human Genetics), Marja‐Liisa Lokki(University of Helsinki), Barry London(University of Iowa), Ruth J. F. Loos(Child Health and Development Institute), Siew‐Kee Low(RIKEN Center for Integrative Medical Sciences), Yingchang Lu(Icahn School of Medicine at Mount Sinai), Leo‐Pekka Lyytikäinen(Tampere University), Peter W. Macfarlane(University of Glasgow), Patrik K. E. Magnusson(Karolinska Institutet), Anubha Mahajan(Centre for Human Genetics), Rainer Malik(LMU Klinikum), Alfredo José Mansur(Universidade de São Paulo), Gregory M. Marcus(University of California, San Francisco), Lauren Margolin(Broad Institute), Kenneth B. Margulies(University of Pennsylvania), Winfried März(Medical University of Graz), David D. McManus(University of Massachusetts Chan Medical School), Olle Melander(Lund University), Sanghamitra Mohanty(St David's Medical Center), Jay A. Montgomery(Vanderbilt University Medical Center), Michael P. Morley(University of Pennsylvania), Andrew P. Morris(University of Liverpool), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Andrea Natale(St David's Medical Center), Saman Nazarian(University of Pennsylvania), Benjamin Neumann(Ludwig-Maximilians-Universität München), Christopher Newton‐Cheh(Broad Institute), Maartje N. Niemeijer(Erasmus MC), Kjell Nikus(Tampere University Hospital), Peter M. Nilsson(Lund University), Raymond Noordam(Leiden University Medical Center), Heidi Oellers(Atrial Fibrillation NETwork), Morten S. Olesen(University of Copenhagen), Marju Orho‐Melander(Lund University), Sandosh Padmanabhan(University of Glasgow), Hui‐Nam Pak(Yonsei University Health System), Guillaume Paré(Population Health Research Institute), Nancy L. Pedersen(Karolinska Institutet), Joanna Pera(Jagiellonian University), Alexandre C. Pereira(Harvard University), David J. Porteous(Edinburgh Cancer Research), Bruce M. Psaty(Kaiser Permanente Washington Health Research Institute), Sara L. Pulit(Broad Institute), Clive R. Pullinger(University of California, San Francisco), Daniel J. Rader(University of Pennsylvania), Lena Refsgaard(University of Copenhagen), Marta Ribasès(Universitat Autònoma de Barcelona), Paul M. Ridker(Brigham and Women's Hospital), Michiel Rienstra(University Medical Center Groningen), Lorenz Risch(University of Bern), Dan M. Roden(Vanderbilt University Medical Center), Jonathan Rosand(Broad Institute), Michael A. Rosenberg(Massachusetts General Hospital), Natalia S. Rost(Broad Institute), Jerome I. Rotter(The Lundquist Institute), Samir Saba(University of Pittsburgh), Roopinder K. Sandhu(University of Alberta), Renate B. Schnabel(Universität Hamburg), Katharina Schramm(Helmholtz Zentrum München), Heribert Schunkert(München Klinik), Claudia Schurman(Icahn School of Medicine at Mount Sinai), Stuart A. Scott(Icahn School of Medicine at Mount Sinai), Ilkka Seppälä(Tampere University), Christian M. Shaffer(Vanderbilt University Medical Center), Svati H. Shah(Duke University), Alaa Shalaby(University of Pittsburgh), Jaemin Shim(Korea University), M. Benjamin Shoemaker(Vanderbilt University Medical Center), Joylene E. Siland(University Medical Center Groningen), Juha Sinisalo(Helsinki University Hospital), Moritz F. Sinner(German Centre for Cardiovascular Research), Agnieszka Słowik(Jagiellonian University), Albert V. Smith(University of Iceland), Blair H. Smith(University of Dundee), J. Gustav Smith(Broad Institute), Jonathan D. Smith(Broad Institute), Nicholas L. Smith(Kaiser Permanente Washington Health Research Institute), Elsayed Z. Soliman(Wake Forest University), Nona Sotoodehnia(University of Washington), Bruno H. Stricker(Dutch Health Care Inspectorate), Albert Y. Sun(Duke University), Han Sun(Cleveland Clinic), Jesper Hastrup Svendsen(University of Copenhagen), Toshihiro Tanaka(Tokyo Medical and Dental University), Kahraman Tanrıverdi(University of Massachusetts Chan Medical School), Kent D. Taylor(The Lundquist Institute), Maris Teder‐Laving(University of Tartu), Alexander Teumer(Universitätsmedizin Greifswald), Sébastien Thériault(Population Health Research Institute), Stella Trompet(Leiden University Medical Center), Nathan R. Tucker(Broad Institute), Arnljot Tveit(University of Oslo), André G. Uitterlinden(Erasmus MC), Pim van der Harst(University Medical Center Groningen), Isabelle C. Van Gelder(University Medical Center Groningen), David R. Van Wagoner(Cleveland Clinic), Niek Verweij(University Medical Center Groningen), Efthymia Vlachopoulou(University of Helsinki), Uwe Völker(Universität Greifswald), Biqi Wang(Boston University), Peter Weeke(Copenhagen University Hospital), Bob Weijs(Maastricht University), Raul Weiss(The Ohio State University), Stefan Weiß(Universität Greifswald), Quinn S. Wells(Vanderbilt University Medical Center), Kerri L. Wiggins(University of Washington), Jorge Wong(Hamilton Health Sciences), Daniel Woo(University of Cincinnati Medical Center), Bradford B. Worrall(University of Virginia Health System), Pil‐Sung Yang(Yonsei University Health System), Jie Yao(The Lundquist Institute), Zachary T. Yoneda(Vanderbilt University Medical Center), Tanja Zeller(Universität Hamburg), Lingyao Zeng(München Klinik), Steven A. Lubitz(Broad Institute), Kathryn L. Lunetta(Boston University), Patrick T. Ellinor(Broad Institute)
Cited by 803Open Access
Abstract
Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. 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. This large, multi-ethnic genome-wide association study identifies 97 loci significantly associated with atrial fibrillation. These loci are enriched for genes involved in cardiac development, electrophysiology, structure and contractile function.
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