Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
Butterworth Adam S 1Sherliker Paul 2Dedoussis George 3Stefansson Kari 4Haider Syed M. Ijlal 5Helgadottir Anna 6Kessler Thorsten 7Mucha S?ren 5Murgia Federico 8N?then Markus M 9Reinberger Tobias 5Thorleifsson Gudmar 6Ulirsch Jacob K 10EPIC-CVD Consortium Japan Biobank Arnar David O 11Nelson Christopher P 12Roberts Robert 13Thorgeirsson Gudmundur 11Thorsteinsdottir Unnur 4Hindy George 14Zhou Wei 15Grace Christopher 16Roselli Carolina 17Melander Olle 18Mu?oz Venegas Loreto 19O ?svold Bj?rn 20Brown Michael R 21de Vries Paul S 21G¨1ldener Ulrich 22Rallidis Loukianos S 23Ellinor Patrick T 24Farrall Martin 16Ruff Christian T 25Willer Cristen J 26Costanzo Maria C 27Ito Kaoru 28Holm Hilma 6Kullo Iftikhar J 29Webb Thomas R 12Nielsen Jonas B 30Khera Amit V 31Jang Dong-Keun 27Li Ling 22Atri Deepak S 32von Scheidt Moritz 7Giardoglou Panagiota 3Ishigaki Kazuyoshi 33Munz Matthias 5Kamanu Frederick K 25Hveem Kristian 34Zalloua Pierre 35Surakka Ida 36Weeks Elle M 27Schunkert Heribert 7Kastrati Adnan 7Pang Shichao 22Flannick Jason 37Bj?rkegren Johan LM 38Komuro Issei 39Marston Nicholas A 25Gudbjartsson Daniel F 40Orho-Melander Marju 18Erdmann Jeanette 41Kamatani Yoichiro 42Hopewell Jemma C 8Baras Aris 43Aragam Krishna G 44Deloukas Panos 45Goel Anuj 16Lotta Luca A 43Morrison Alanna C 21Meitinger Thomas 46Ibrahim Maysson 8Watkins Hugh 16Giannakopoulou Olga 47Jiang Tao 48Ma Lijiang 49Finucane Hilary K 50Clarke Robert 8Wang Minxian 51Boerwinkle Eric 52Kathiresan Sekar 53Samani Nilesh J 12Kanoni Stavroula 47Danesh John 54Wolford Brooke N 55P Burtt No?l 27Sabatine Marc S 25Ruusalepp Arno 56Koyama Satoshi 28Brumpton Ben 34Gupta Rajat M57
作者信息
- 1. BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge||British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke?ˉs Hospital||National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals||The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge
- 2. Medical Research Council Population Health Research Unit, CTSU - Nuffield Department of Population Health, Medical Sciences Division, University of Oxford
- 3. School of Health Science & Education, Department of Nutrition-Dietetics, Harokopio University
- 4. deCODE genetics/Amgen, Inc.||Faculty of Medicine, University of Iceland
- 5. Institute for Cardiogenetics, University of L¨1beck
- 6. deCODE genetics/Amgen, Inc.
- 7. German Heart Centre Munich, Department of Cardiology, Technical University of Munich||German Research Center for Cardiovascular Research (DZHK e.V.), partner site Munich Heart Alliance
- 8. CTSU - Nuffield Department of Population Health, Medical Sciences Division, University of Oxford
- 9. School of Medicine & University Hospital Bonn, Institute of Human Genetics, University of Bonn
- 10. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Biological and Biomedical Sciences, Harvard Medical School
- 11. deCODE genetics/Amgen, Inc.||Faculty of Medicine, University of Iceland||Department of Internal Medicine, Division of Cardiology, Landspitali ¨C National University Hospital of Iceland
- 12. Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Glenfield Hospital
- 13. Cardiovascular Genomics & Genetics, University of Arizona, College of Medicine
- 14. Department of Population Medicine, Qatar University College of Medicine
- 15. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard||Department of Computational Medicine & Bioinformatics, University of Michigan
- 16. Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford||Wellcome Centre for Human Genetics, University of Oxford
- 17. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard
- 18. Department of Clinical Sciences in Malm?, Lund University
- 19. Institute for Cardiogenetics, University of L¨1beck||DZHK (German Research Center for Cardiovascular Research), partner site Hamburg-L¨1beck-Kiel
- 20. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology||HUNT Research Centre, Norwegian University of Science and Technology||Department of Endocrinology, Clinic of Medicine
- 21. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston
- 22. German Heart Centre Munich, Department of Cardiology, Technical University of Munich
- 23. Second Department of Cardiology, Medical School, National and Kapodistrian University of Athens, University General Hospital Attikon
- 24. Cardiovascular Research Center, Massachusetts General Hospital||Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard
- 25. TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School
- 26. Department of Internal Medicine, Cardiology, University of Michigan||Department of Computational Medicine & Bioinformatics, University of Michigan||Department of Human Genetics, University of Michigan
- 27. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- 28. Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences
- 29. Department of Cardiovascular Medicine
- 30. Department of Internal Medicine, Cardiology, University of Michigan||K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology
- 31. Center for Genomic Medicine, Massachusetts General Hospital||Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard||Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- 32. Divisions of Cardiovascular Medicine and Genetics, Brigham and Women?ˉs Hospital, Harvard Medical School||Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard
- 33. Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences
- 34. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology||HUNT Research Centre, Norwegian University of Science and Technology
- 35. University of Balamand, East Med Res Institute, School of Medicine||Harvard T.H.Chan School of Public Health
- 36. Department of Internal Medicine, Cardiology, University of Michigan
- 37. Divisions of Cardiovascular Medicine and Genetics, Brigham and Women?ˉs Hospital, Harvard Medical School
- 38. Clinical Gene Networks AB||Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai||Integrated Cardio Metabolic Centre, Karolinska Institutet, Karolinska Universitetssjukhuset
- 39. Department of Cardiovascular Medicine, The University of Tokyo
- 40. deCODE genetics/Amgen, Inc.||School of Engineering and Natural Sciences, University of Iceland
- 41. Institute for Cardiogenetics, University of L¨1beck||DZHK (German Research Center for Cardiovascular Research)
- 42. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo
- 43. Regeneron Genetics Center, Regeneron Pharmaceuticals
- 44. Cardiovascular Research Center, Massachusetts General Hospital||Center for Genomic Medicine, Massachusetts General Hospital||Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard||Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- 45. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London||Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University
- 46. Institute of Human Genetics, Helmholtz Zentrum M¨1nchen, German Research Center for Environmental Health||Klinikum rechts der Isar, Institute of Human Genetics, Technical University of Munich||German Research Center for Cardiovascular Research (DZHK e.V.), partner site Munich Heart Alliance
- 47. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- 48. BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- 49. Department of Genetics and Genomic Science, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai||The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai
- 50. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
- 51. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard||Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- 52. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston||Human Genome Sequencing Center, Baylor College of Medicine
- 53. Verve Therapeutics
- 54. BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge||Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge||The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge||Human Genetics, Wellcome Sanger Institute||National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals||British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke?ˉs Hospital
- 55. Department of Computational Medicine & Bioinformatics, University of Michigan
- 56. Department of Cardiac Surgery and The Heart Clinic, Tartu University Hospital
- 57. Divisions of Cardiovascular Medicine and Genetics, Brigham and Women?ˉs Hospital, Harvard Medical School||Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard||Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- 折叠
Abstract
ABSTRACT
Rapid progress of the discovery of genetic loci associated with common, complex diseases has outpaced the elucidation of mechanisms pertinent to disease pathogenesis. To address relevant barriers for coronary artery disease (CAD), we combined genetic discovery analyses with downstream characterization of likely causal variants, genes, and biological pathways. Specifically, we conducted a genome-wide association study (GWAS) comprising 181,522 cases of CAD among 1,165,690 participants. We detected 241 associations, including 54 associations and 30 loci not previously linked to CAD. Next, we prioritized likely causal variants using functionally-informed fine-mapping, yielding 42 associations with fewer than five variants in the 95% credible set. Combining eight complementary predictors, we prioritized 185 candidate causal genes, including 94 genes supported by three or more predictors. Similarity-based clustering underscored a role for early developmental processes, cell cycle signaling, and vascular proliferation in the pathogenesis of CAD. Our analysis identifies and systematically characterizes risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.引用本文复制引用
Butterworth Adam S,Sherliker Paul,Dedoussis George,Stefansson Kari,Haider Syed M. Ijlal,Helgadottir Anna,Kessler Thorsten,Mucha S?ren,Murgia Federico,N?then Markus M,Reinberger Tobias,Thorleifsson Gudmar,Ulirsch Jacob K,EPIC-CVD Consortium,Japan Biobank,Arnar David O,Nelson Christopher P,Roberts Robert,Thorgeirsson Gudmundur,Thorsteinsdottir Unnur,Hindy George,Zhou Wei,Grace Christopher,Roselli Carolina,Melander Olle,Mu?oz Venegas Loreto,O ?svold Bj?rn,Brown Michael R,de Vries Paul S,G¨1ldener Ulrich,Rallidis Loukianos S,Ellinor Patrick T,Farrall Martin,Ruff Christian T,Willer Cristen J,Costanzo Maria C,Ito Kaoru,Holm Hilma,Kullo Iftikhar J,Webb Thomas R,Nielsen Jonas B,Khera Amit V,Jang Dong-Keun,Li Ling,Atri Deepak S,von Scheidt Moritz,Giardoglou Panagiota,Ishigaki Kazuyoshi,Munz Matthias,Kamanu Frederick K,Hveem Kristian,Zalloua Pierre,Surakka Ida,Weeks Elle M,Schunkert Heribert,Kastrati Adnan,Pang Shichao,Flannick Jason,Bj?rkegren Johan LM,Komuro Issei,Marston Nicholas A,Gudbjartsson Daniel F,Orho-Melander Marju,Erdmann Jeanette,Kamatani Yoichiro,Hopewell Jemma C,Baras Aris,Aragam Krishna G,Deloukas Panos,Goel Anuj,Lotta Luca A,Morrison Alanna C,Meitinger Thomas,Ibrahim Maysson,Watkins Hugh,Giannakopoulou Olga,Jiang Tao,Ma Lijiang,Finucane Hilary K,Clarke Robert,Wang Minxian,Boerwinkle Eric,Kathiresan Sekar,Samani Nilesh J,Kanoni Stavroula,Danesh John,Wolford Brooke N,P Burtt No?l,Sabatine Marc S,Ruusalepp Arno,Koyama Satoshi,Brumpton Ben,Gupta Rajat M.Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants[EB/OL].(2025-03-28)[2026-05-01].https://www.medrxiv.org/content/10.1101/2021.05.24.21257377.学科分类
医学研究方法/基础医学/遗传学
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