부산대학교 도서관

Million Veterans Program Keywords lipid biology; fine-mapping; functional genomics; post-GWAS; regulatory mechanism; complex traits; variant prioritization Summary A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology. Author Affiliation: (1) Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA (2) Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA (3) Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI 48109, USA (4) William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK (5) Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118, USA (6) VA Palo Alto Health Care Systems, Palo Alto, CA, USA (7) Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA (8) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA (9) Endocrinology, Boston Childrens Hospital, Boston, MA 02115, USA (10) Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA (11) Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany (12) McDonnell Genome Institute and Department of Medicine, Washington University, St. Louis, MO 63108, USA (13) Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA (14) Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA (15) Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK (16) Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA (17) Atlanta VA Health Care System, Decatur, GA, USA (18) Malcolm Randall VA Medical Center, Gainesville, FL, USA (19) Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL, USA (20) deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 102, Iceland (21) School of Engineering and Natural Sciences, University of Iceland, Sæmundargötu 2, Reykjavik 102, Iceland (22) Department of Clinical Biochemistry, Landspitali - National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland (23) Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungbuk, South Korea (24) Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (25) Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (26) Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan (27) Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, The University of Tokyo, Tokyo, Japan (28) Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (29) Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (30) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA (31) Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA (32) K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway (33) MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, BS8 2BN Bristol, UK (34) Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway (35) Division of Medicine and Laboratory Sciences, University of Oslo, Oslo, Norway (36) Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Tukholmankatu 8, 00014 Helsinki, Finland (37) Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland (38) Department of Genetics, Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA (39) Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA (40) Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA (41) Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA (42) Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA (43) Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA (44) Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan (45) Wellcome Trust Sanger Institute, CB10 1SA Hinxton, UK (46) Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK (47) Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA 98109, USA (48) Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA (49) Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, EH4 2XU Edinburgh, UK (50) Usher Institute, The University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, EH16 4UX Edinburgh, UK (51) Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, OX3 7LF Oxford, UK (52) Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, OX3 7LF Oxford, UK (53) Center for Non-Communicable Diseases, Karachi, SD, Pakistan & Faisalabad Institute of Cardiology, Faislabad, Pakistan (54) Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar (55) Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI 48104, USA (56) Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA (57) Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. 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Graham (3,420), Stavroula Kanoni (4,420), Yuxuan Wang (5,420), Ida Surakka (3), Brandon Wenz (1), Shoa L. Clarke (6,7), Alessandra Chesi (8), Andrew Wells (1), Konain Fatima Bhatti (4), Sailaja Vedantam (9,10), Thomas W. Winkler (11), Adam E. Locke (12), Eirini Marouli (4), Greg J.M. Zajac (13), Kuan-Han H. Wu (14), Ioanna Ntalla (15), Qin Hui (16,17), Derek Klarin (10,18,19), Austin T. Hilliard (6), Zeyuan Wang (16,17), Chao Xue (3), Gudmar Thorleifsson (20), Anna Helgadottir (20), Daniel F. Gudbjartsson (20,21), Hilma Holm (20), Isleifur Olafsson (22), Mi Yeong Hwang (23), Sohee Han (23), Masato Akiyama (24,25), Saori Sakaue (26,27,28), Chikashi Terao (29), Masahiro Kanai (10,24,30), Wei Zhou (10,14,31), Ben M. Brumpton (32,33,34), Humaira Rasheed (32,33,35), Aki S. Havulinna (36,37), Yogasudha Veturi (38), Jennifer Allen Pacheco (39), Elisabeth A. Rosenthal (40), Todd Lingren (41), QiPing Feng (42), Iftikhar J. Kullo (43), Akira Narita (44), Jun Takayama (44), Hilary C. 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Chandak (152,153,307), Josep M. Mercader (308,309,310), Clicerio Gonzalez Villalpando (312), Lorena Orozco (313), Myriam Fornage (148,314), E. Shyong Tai (78,315), Rob M. van Dam (78,315), Terho Lehtimäki (216,217), Nish Chaturvedi (316), Mitsuhiro Yokota (317), Jianjun Liu (144), Dermot F. Reilly (318), Amy Jayne McKnight (139), Frank Kee (139), Karl-Heinz Jöckel (138), Mark I. McCarthy (60,208), Colin N.A. Palmer (319), Veronique Vitart (137), Caroline Hayward (137), Eleanor Simonsick (320), Cornelia M. van Duijn (132,133), Zi-Bing Jin (173,321), Fan Lu (321), Haretsugu Hishigaki (129), Xu Lin (128), Winfried März (126,322,323), Vilmundur Gudnason (125,324), Jean-Claude Tardif (124), Guillaume Lettre (124), Leen M. t Hart (122,123,325), Petra J.M. Elders (326), Daniel J. Rader (327,407), Scott M. Damrauer (121,328), Meena Kumari (329), Mika Kivimaki (120), Pim van der Harst (118), Tim D. Spector (116), Ruth J.F. Loos (86,115,330), Michael A. Province (108), Esteban J. Parra (113), Miguel Cruz (331), Bruce M. Psaty (112,226,332), Ivan Brandslund (111,333), Peter P. Pramstaller (110), Charles N. Rotimi (334), Kaare Christensen (335), Samuli Ripatti (36,336,337), Elisabeth Widén (36), Hakon Hakonarson (338,339), Struan F.A. Grant (327,339,340), Lambertus Kiemeney (106), Jacqueline de Graaf (106), Markus Loeffler (104,105), Florian Kronenberg (103), Dongfeng Gu (101,341), Jeanette Erdmann (98), Heribert Schunkert (99,100), Paul W. Franks (102), Allan Linneberg (79,80), J. Wouter Jukema (96,342), Amit V. Khera (10,343,345,346), Minna Männikkö (346), Marjo-Riitta Jarvelin (62,347,348), Zoltan Kutalik (93,94), Cucca Francesco (349,350), Dennis O. Mook-Kanamori (351,352), Ko Willems van Dijk (353,354,355), Hugh Watkins (87,88), David P. Strachan (356), Niels Grarup (86), Peter Sever (357), Neil Poulter (358), Wayne Huey-Herng Sheu (359,360), Jerome I. Rotter (81), Thomas M. Dantoft (79), Fredrik Karpe (361,362), Matt J. Neville (361,362), Nicholas J. Timpson (33,77), Ching-Yu Cheng (363,364), Tien-Yin Wong (363,364), Chiea Chuen Khor (144), Hengtong Li (365), Charumathi Sabanayagam (363,364), Annette Peters (75,100,366), Christian Gieger (74,75,366), Andrew T. Hattersley (367), Nancy L. Pedersen (368), Patrik K.E. Magnusson (368), Dorret I. Boomsma (70,301), Eco J.C. de Geus (70,301), L. Adrienne Cupples (5,369), Joyce B.J. van Meurs (69,133), Arfan Ikram (133), Mohsen Ghanbari (133,370), Penny Gordon-Larsen (284,285), Wei Huang (371), Young Jin Kim (23), Yasuharu Tabara (68), Nicholas J. Wareham (66), Claudia Langenberg (66), Eleftheria Zeggini (45,207,372), Jaakko Tuomilehto (37,336,373), Johanna Kuusisto (374), Markku Laakso (374), Erik Ingelsson (7,65,375,376), Goncalo Abecasis (13,377), John C. Chambers (62,63,64,378), Jaspal S. Kooner (63,64,357,379), Paul S. de Vries (61), Alanna C. Morrison (61), Scott Hazelhurst (59,380), Michèle Ramsay (59), Kari E. North (58), Martha Daviglus (381), Peter Kraft (57,382), Nicholas G. Martin (383), John B. Whitfield (383), Shahid Abbas (53), Danish Saleheen (53,384,385), Robin G. Walters (51,52,386), Michael V. Holmes (51,52,362), Corri Black (387), Blair H. Smith (319), Aris Baras (377), Anne E. Justice (388), Julie E. Buring (48,310), Paul M. Ridker (48,310), Daniel I. Chasman (48,310), Charles Kooperberg (47), Gen Tamiya (44), Masayuki Yamamoto (44), David A. van Heel (46), Richard C. Trembath (389), Wei-Qi Wei (390), Gail P. Jarvik (391), Bahram Namjou (392), M. Geoffrey Hayes (39,393,394), Marylyn D. Ritchie (38), Pekka Jousilahti (37), Veikko Salomaa (37), Kristian Hveem (32,395,396), Bjørn Olav Åsvold (32,395,397), Michiaki Kubo (398), Yoichiro Kamatani (24,399), Yukinori Okada (24,26,400,401), Yoshinori Murakami (402), Bong-Jo Kim (403), Unnur Thorsteinsdottir (20,324), Kari Stefansson (20,324), Jifeng Zhang (3), Y. Eugene Chen (3), Yuk-Lam Ho (404), Julie A. Lynch (405,406), Philip S. Tsao (6,7,408), Kyong-Mi Chang (328,407), Kelly Cho (404,409), Christopher J. O'Donnell (404,409), John M. Gaziano (404,409), Peter Wilson (17,410), Karen L. Mohlke (168), Timothy M. Frayling (72), Joel N. Hirschhorn (9,10,411), Sekar Kathiresan (10,344,345), Michael Boehnke (13), Struan Grant (1,340), Pradeep Natarajan (10,343,412,413), Yan V. Sun (16,17), Andrew P. Morris (414), Panos Deloukas (4,415), Gina Peloso (5), Themistocles L. Assimes (6,7,408), Cristen J. Willer (3,14,416), Xiang Zhu [xiangzhu@psu.edu] (6,417,418,419,*), Christopher D. Brown [chrbro@upenn.edu] (1,**)