A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
Shweta Ramdas 1, Jonathan Judd 2, Sarah E Graham 3, Stavroula Kanoni 4, Yuxuan Wang 5, Ida Surakka 3, Brandon Wenz 1, Shoa L Clarke 6, Alessandra Chesi 7, Andrew Wells 1, Konain Fatima Bhatti 4, Sailaja Vedantam 8, Thomas W Winkler 9, Adam E Locke 10, Eirini Marouli 4, Greg J M Zajac 11, Kuan-Han H Wu 12, Ioanna Ntalla 13, Qin Hui 14, Derek Klarin 15, Austin T Hilliard 16, Zeyuan Wang 14, Chao Xue 3, Gudmar Thorleifsson 17, Anna Helgadottir 17, Daniel F Gudbjartsson 18, Hilma Holm 17, Isleifur Olafsson 19, Mi Yeong Hwang 20, Sohee Han 20, Masato Akiyama 21, Saori Sakaue 22, Chikashi Terao 23, Masahiro Kanai 24, Wei Zhou 25, Ben M Brumpton 26, Humaira Rasheed 27, Aki S Havulinna 28, Yogasudha Veturi 29, Jennifer Allen Pacheco 30, Elisabeth A Rosenthal 31, Todd Lingren 32, QiPing Feng 33, Iftikhar J Kullo 34, Akira Narita 35, Jun Takayama 35, Hilary C Martin 36, Karen A Hunt 37, Bhavi Trivedi 37, Jeffrey Haessler 38, Franco Giulianini 39, Yuki Bradford 29, Jason E Miller 29, Archie Campbell 40, Kuang Lin 41, Iona Y Millwood 42, Asif Rasheed 43, George Hindy 44, Jessica D Faul 45, Wei Zhao 46, David R Weir 45, Constance Turman 47, Hongyan Huang 47, Mariaelisa Graff 48, Ananyo Choudhury 49, Dhriti Sengupta 49, Anubha Mahajan 50, Michael R Brown 51, Weihua Zhang 52, Ketian Yu 11, Ellen M Schmidt 11, Anita Pandit 11, Stefan Gustafsson 53, Xianyong Yin 11, Jian'an Luan 54, Jing-Hua Zhao 55, Fumihiko Matsuda 56, Hye-Mi Jang 20, Kyungheon Yoon 20, Carolina Medina-Gomez 57, Achilleas Pitsillides 5, Jouke Jan Hottenga 58, Andrew R Wood 59, Yingji Ji 59, Zishan Gao 60, Simon Haworth 61, Ruth E Mitchell 62, Jin Fang Chai 63, Mette Aadahl 64, Anne A Bjerregaard 65, Jie Yao 66, Ani Manichaikul 67, Wen-Jane Lee 68, Chao Agnes Hsiung 69, Helen R Warren 70, Julia Ramirez 4, Jette Bork-Jensen 71, Line L Kårhus 65, Anuj Goel 72, Maria Sabater-Lleal 73, Raymond Noordam 74, Pala Mauro 75, Floris Matteo 76, Aaron F McDaid 77, Pedro Marques-Vidal 78, Matthias Wielscher 79, Stella Trompet 80, Naveed Sattar 81, Line T Møllehave 65, Matthias Munz 82, Lingyao Zeng 83, Jianfeng Huang 84, Bin Yang 84, Alaitz Poveda 85, Azra Kurbasic 85, Sebastian Schönherr 86, Lukas Forer 86, Markus Scholz 87, Tessel E Galesloot 88, Jonathan P Bradfield 89, Sanni E Ruotsalainen 90, E Warwick Daw 91, Joseph M Zmuda 92, Jonathan S Mitchell 93, Christian Fuchsberger 93, Henry Christensen 94, Jennifer A Brody 95, Phuong Le 96, Mary F Feitosa 91, Mary K Wojczynski 91, Daiane Hemerich 97, Michael Preuss 97, Massimo Mangino 98, Paraskevi Christofidou 99, Niek Verweij 100, Jan W Benjamins 100, Jorgen Engmann 101, Tsao L Noah 102, Anurag Verma 1, Roderick C Slieker 103, Ken Sin Lo 104, Nuno R Zilhao 105, Marcus E Kleber 106, Graciela E Delgado 107, Shaofeng Huo 108, Daisuke D Ikeda 109, Hiroyuki Iha 109, Jian Yang 110, Jun Liu 111, Ayşe Demirkan 112, Hampton L Leonard 113, Jonathan Marten 114, Carina Emmel 115, Börge Schmidt 115, Laura J Smyth 116, Marisa Cañadas-Garre 117, Chaolong Wang 118, Masahiro Nakatochi 119, Andrew Wong 120, Nina Hutri-Kähönen 121, Xueling Sim 63, Rui Xia 122, Alicia Huerta-Chagoya 123, Juan Carlos Fernandez-Lopez 124, Valeriya Lyssenko 125, Suraj S Nongmaithem 126, Alagu Sankareswaran 127, Marguerite R Irvin 120, Christopher Oldmeadow 128, Han-Na Kim 129, Seungho Ryu 130, Paul R H J Timmers 131, Liubov Arbeeva 132, Rajkumar Dorajoo 133, Leslie A Lange 134, Gauri Prasad 135, Laura Lorés-Motta 136, Marc Pauper 136, Jirong Long 137, Xiaohui Li 66, Elizabeth Theusch 138, Fumihiko Takeuchi 139, Cassandra N Spracklen 140, Anu Loukola 90, Sailalitha Bollepalli 90, Sophie C Warner 141, Ya Xing Wang 142, Wen B Wei 143, Teresa Nutile 144, Daniela Ruggiero 145, Yun Ju Sung 146, Shufeng Chen 84, Fangchao Liu 84, Jingyun Yang 147, Katherine A Kentistou 148, Bernhard Banas 149, Anna Morgan 150, Karina Meidtner 151, Lawrence F Bielak 46, Jennifer A Smith 152, Prashantha Hebbar 153, Aliki-Eleni Farmaki 154, Edith Hofer 155, Maoxuan Lin 156, Maria Pina Concas 150, Simona Vaccargiu 157, Peter J van der Most 158, Niina Pitkänen 159, Brian E Cade 160, Sander W van der Laan 161, Kumaraswamy Naidu Chitrala 162, Stefan Weiss 163, Amy R Bentley 164, Ayo P Doumatey 164, Adebowale A Adeyemo 164, Jong Young Lee 165, Eva R B Petersen 166, Aneta A Nielsen 167, Hyeok Sun Choi 168, Maria Nethander 169, Sandra Freitag-Wolf 170, Lorraine Southam 171, Nigel W Rayner 172, Carol A Wang 173, Shih-Yi Lin 174, Jun-Sing Wang 175, Christian Couture 176, Leo-Pekka Lyytikäinen 177, Kjell Nikus 178, Gabriel Cuellar-Partida 179, Henrik Vestergaard 180, Bertha Hidalgo 181, Olga Giannakopoulou 4, Qiuyin Cai 137, Morgan O Obura 182, Jessica van Setten 183, Karen Y He 184, Hua Tang 2, Natalie Terzikhan 185, Jae Hun Shin 168, Rebecca D Jackson 186, Alexander P Reiner 187, Lisa Warsinger Martin 188, Zhengming Chen 42, Liming Li 189, Takahisa Kawaguchi 56, Joachim Thiery 190, Joshua C Bis 95, Lenore J Launer 191, Huaixing Li 108, Mike A Nalls 113, Olli T Raitakari 192, Sahoko Ichihara 193, Sarah H Wild 194, Christopher P Nelson 141, Harry Campbell 148, Susanne Jäger 151, Toru Nabika 195, Fahd Al-Mulla 153, Harri Niinikoski 196, Peter S Braund 141, Ivana Kolcic 197, Peter Kovacs 198, Tota Giardoglou 199, Tomohiro Katsuya 200, Dominique de Kleijn 201, Gert J de Borst 201, Eung Kweon Kim 202, Hieab H H Adams 203, M Arfan Ikram 185, Xiaofeng Zhu 184, Folkert W Asselbergs 183, Adriaan O Kraaijeveld 183, Joline W J Beulens 204, Xiao-Ou Shu 137, Loukianos S Rallidis 205, Oluf Pedersen 71, Torben Hansen 71, Paul Mitchell 206, Alex W Hewitt 207, Mika Kähönen 208, Louis Pérusse 209, Claude Bouchard 210, Anke Tönjes 198, Yii-Der Ida Chen 66, Craig E Pennell 173, Trevor A Mori 211, Wolfgang Lieb 212, Andre Franke 213, Claes Ohlsson 214, Dan Mellström 215, Yoon Shin Cho 168, Hyejin Lee 216, Jian-Min Yuan 217, Woon-Puay Koh 218, Sang Youl Rhee 219, Jeong-Taek Woo 219, Iris M Heid 9, Klaus J Stark 9, Martina E Zimmermann 9, Henry Völzke 220, Georg Homuth 163, Michele K Evans 191, Alan B Zonderman 191, Ozren Polasek 221, Gerard Pasterkamp 161, Imo E Hoefer 161, Susan Redline 160, Katja Pahkala 222, Albertine J Oldehinkel 223, Harold Snieder 158, Ginevra Biino 224, Reinhold Schmidt 225, Helena Schmidt 226, Stefania Bandinelli 227, George Dedoussis 199, Thangavel Alphonse Thanaraj 153, Patricia A Peyser 46, Norihiro Kato 139, Matthias B Schulze 228, Giorgia Girotto 229, Carsten A Böger 230, Bettina Jung 230, Peter K Joshi 148, David A Bennett 147, Philip L De Jager 231, Xiangfeng Lu 84, Vasiliki Mamakou 232, Morris Brown 233, Mark J Caulfield 70, Patricia B Munroe 70, Xiuqing Guo 66, Marina Ciullo 145, Jost B Jonas 234, Nilesh J Samani 141, Jaakko Kaprio 90, Päivi Pajukanta 235, Teresa Tusié-Luna 236, Carlos A Aguilar-Salinas 237, Linda S Adair 238, Sonny Augustin Bechayda 239, H Janaka de Silva 240, Ananda R Wickremasinghe 241, Ronald M Krauss 242, Jer-Yuarn Wu 243, Wei Zheng 137, Anneke I den Hollander 136, Dwaipayan Bharadwaj 244, Adolfo Correa 245, James G Wilson 246, Lars Lind 247, Chew-Kiat Heng 248, Amanda E Nelson 249, Yvonne M Golightly 250, James F Wilson 131, Brenda Penninx 251, Hyung-Lae Kim 252, John Attia 253, Rodney J Scott 253, D C Rao 146, Donna K Arnett 254, Mark Walker 255, Laura J Scott 11, Heikki A Koistinen 256, Giriraj R Chandak 257, Josep M Mercader 258, Clicerio Gonzalez Villalpando 259, Lorena Orozco 260, Myriam Fornage 261, E Shyong Tai 262, Rob M van Dam 262, Terho Lehtimäki 177, Nish Chaturvedi 263, Mitsuhiro Yokota 264, Jianjun Liu 265, Dermot F Reilly 266, Amy Jayne McKnight 116, Frank Kee 116, Karl-Heinz Jöckel 115, Mark I McCarthy 267, Colin N A Palmer 268, Veronique Vitart 114, Caroline Hayward 114, Eleanor Simonsick 269, Cornelia M van Duijn 111, Zi-Bing Jin 270, Fan Lu 271, Haretsugu Hishigaki 109, Xu Lin 108, Winfried März 272, Vilmundur Gudnason 273, Jean-Claude Tardif 104, Guillaume Lettre 104, Leen M T Hart 274, Petra J M Elders 275, Daniel J Rader 276, Scott M Damrauer 277, Meena Kumari 278, Mika Kivimaki 279, Pim van der Harst 100, Tim D Spector 99, Ruth J F Loos 280, Michael A Province 91, Esteban J Parra 281, Miguel Cruz 282, Bruce M Psaty 283, Ivan Brandslund 284, Peter P Pramstaller 93, Charles N Rotimi 285, Kaare Christensen 286, Samuli Ripatti 287, Elisabeth Widén 90, Hakon Hakonarson 288, Struan F A Grant 289, Lambertus Kiemeney 88, Jacqueline de Graaf 88, Markus Loeffler 87, Florian Kronenberg 86, Dongfeng Gu 290, Jeanette Erdmann 82, Heribert Schunkert 83, Paul W Franks 85, Allan Linneberg 64, J Wouter Jukema 291, Amit V Khera 292, Minna Männikkö 293, Marjo-Riitta Jarvelin 294, Zoltan Kutalik 77, Cucca Francesco 295, Dennis O Mook-Kanamori 296, Ko Willems van Dijk 297, Hugh Watkins 298, David P Strachan 299, Niels Grarup 71, Peter Sever 300, Neil Poulter 301, Wayne Huey-Herng Sheu 302, Jerome I Rotter 66, Thomas M Dantoft 65, Fredrik Karpe 303, Matt J Neville 303, Nicholas J Timpson 62, Ching-Yu Cheng 304, Tien-Yin Wong 304, Chiea Chuen Khor 265, Hengtong Li 305, Charumathi Sabanayagam 304, Annette Peters 306, Christian Gieger 307, Andrew T Hattersley 308, Nancy L Pedersen 309, Patrik K E Magnusson 309, Dorret I Boomsma 310, Eco J C de Geus 310, L Adrienne Cupples 311, Joyce B J van Meurs 312, Arfan Ikram 185, Mohsen Ghanbari 313, Penny Gordon-Larsen 238, Wei Huang 314, Young Jin Kim 20, Yasuharu Tabara 56, Nicholas J Wareham 54, Claudia Langenberg 54, Eleftheria Zeggini 315, Jaakko Tuomilehto 316, Johanna Kuusisto 317, Markku Laakso 317, Erik Ingelsson 318, Goncalo Abecasis 319, John C Chambers 320, Jaspal S Kooner 321, Paul S de Vries 51, Alanna C Morrison 51, Scott Hazelhurst 322, Michèle Ramsay 49, Kari E North 48, Martha Daviglus 323, Peter Kraft 324, Nicholas G Martin 325, John B Whitfield 325, Shahid Abbas 43, Danish Saleheen 326, Robin G Walters 327, Michael V Holmes 328, Corri Black 329, Blair H Smith 268, Aris Baras 330, Anne E Justice 331, Julie E Buring 332, Paul M Ridker 332, Daniel I Chasman 332, Charles Kooperberg 38, Gen Tamiya 35, Masayuki Yamamoto 35, David A van Heel 37, Richard C Trembath 333, Wei-Qi Wei 334, Gail P Jarvik 335, Bahram Namjou 336, M Geoffrey Hayes 337, Marylyn D Ritchie 29, Pekka Jousilahti 338, Veikko Salomaa 338, Kristian Hveem 339, Bjørn Olav Åsvold 340, Michiaki Kubo 341, Yoichiro Kamatani 342, Yukinori Okada 343, Yoshinori Murakami 344, Bong-Jo Kim 345, Unnur Thorsteinsdottir 346, Kari Stefansson 346, Jifeng Zhang 3, Y Eugene Chen 3, Yuk-Lam Ho 347, Julie A Lynch 348, Philip S Tsao 349, Kyong-Mi Chang 350, Kelly Cho 351, Christopher J O'Donnell 351, John M Gaziano 351, Peter Wilson 352, Karen L Mohlke 353, Timothy M Frayling 59, Joel N Hirschhorn 354, Sekar Kathiresan 355, Michael Boehnke 11; Million Veterans Program; Global Lipids Genetics Consortium; Struan Grant 356, Pradeep Natarajan 357, Yan V Sun 14, Andrew P Morris 358, Panos Deloukas 359, Gina Peloso 5, Themistocles L Assimes 349, Cristen J Willer 360, Xiang Zhu 361, Christopher D Brown 362
Affiliations
Affiliations
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.- 2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
- 3Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI 48109, USA.
- 4William 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.
- 5Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118, USA.
- 6VA Palo Alto Health Care Systems, Palo Alto, CA, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
- 7Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 8Endocrinology, Boston Childrens Hospital, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA.
- 9Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
- 10McDonnell Genome Institute and Department of Medicine, Washington University, St. Louis, MO 63108, USA.
- 11Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
- 12Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
- 13Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK.
- 14Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA; Atlanta VA Health Care System, Decatur, GA, USA.
- 15Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA; Malcolm Randall VA Medical Center, Gainesville, FL, USA; Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL, USA.
- 16VA Palo Alto Health Care Systems, Palo Alto, CA, USA.
- 17deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 102, Iceland.
- 18deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 102, Iceland; School of Engineering and Natural Sciences, University of Iceland, Sæmundargötu 2, Reykjavik 102, Iceland.
- 19Department of Clinical Biochemistry, Landspitali - National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland.
- 20Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungbuk, South Korea.
- 21Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
- 22Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, The University of Tokyo, Tokyo, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
- 23Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
- 24Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
- 25Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
- 26K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, BS8 2BN Bristol, UK; Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
- 27K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, BS8 2BN Bristol, UK; Division of Medicine and Laboratory Sciences, University of Oslo, Oslo, Norway.
- 28Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Tukholmankatu 8, 00014 Helsinki, Finland; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
- 29Department of Genetics, Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
- 30Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
- 31Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.
- 32Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- 33Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- 34Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA.
- 35Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
- 36Wellcome Trust Sanger Institute, CB10 1SA Hinxton, UK.
- 37Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
- 38Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA 98109, USA.
- 39Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
- 40Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, EH4 2XU Edinburgh, UK; Usher Institute, The University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, EH16 4UX Edinburgh, UK.
- 41Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, OX3 7LF Oxford, UK.
- 42Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, OX3 7LF Oxford, UK; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, OX3 7LF Oxford, UK.
- 43Center for Non-Communicable Diseases, Karachi, SD, Pakistan & Faisalabad Institute of Cardiology, Faislabad, Pakistan.
- 44Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar.
- 45Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI 48104, USA.
- 46Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
- 47Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
- 48Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- 49Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- 50Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
- 51Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
- 52Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG London, UK; Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, UB1 3HW Middlesex, UK; Imperial College Healthcare NHS Trust, Imperial College London, W12 0HS London, UK.
- 53Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
- 54MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, CB2 0QQ Cambridge, UK.
- 55Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, CB1 8RN Cambridge, UK.
- 56Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
- 57Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
- 58Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, the Netherlands.
- 59Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, EX2 5DW Exeter, UK.
- 60Department of Clinical Acupuncture and Moxibustion, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
- 61MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, BS8 2BN Bristol, UK; Bristol Dental School, University of Bristol, Lower Maudlin Street, BS1 2LY Bristol, UK.
- 62MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, BS8 2BN Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield Grove, BS8 2BN Bristol, UK.
- 63Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117549, Singapore.
- 64Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- 65Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
- 66The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovations (Formerly LABioMed) at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
- 67Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA.
- 68Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; No. 1650, Sec. 4, Taiwan Boulevard, Taichung City 40705, Taiwan.
- 69Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
- 70William 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; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK.
- 71Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- 72Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DU Oxford, UK.
- 73Unit of Genomics of Complex Diseases. Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
- 74Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
- 75Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Rome, Italy.
- 76Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Rome, Italy; Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sardinia, Italy.
- 77University Center for Primary Care and Public Health, University of Lausanne, Rte de Berne 113, 1010 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
- 78Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, 1011 Lausanne, Switzerland.
- 79Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG London, UK.
- 80Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
- 81BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, UK.
- 82Institute for Cardiogenetics, University of Lübeck, DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, University Heart Center Lübeck, Lübeck and Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Dental and Craniofacial Sciences, Department of Periodontology and Synoptic Dentistry, Berlin, Germany.
- 83Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., partner site Munich Heart Alliance, Munich, Germany.
- 84Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
- 85Lund University Diabetes Centre, Lunds University, Malmö, Sweden.
- 86Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria and German Chronic Kidney Disease Study, Austria.
- 87Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Haertelstrasse 16-18, 04107 Leipzig, Germany; LIFE Research Centre for Civilization Diseases, University of Leipzig, Philipp-Rosenthal-Straße 27, 04103 Leipzig, Germany.
- 88Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.
- 89Quantinuum Research LLC, Wayne, PA 19087, USA.
- 90Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Tukholmankatu 8, 00014 Helsinki, Finland.
- 91Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
- 92Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15232, USA.
- 93Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via Galvani 31, 39100 Bolzano, Italy.
- 94Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark.
- 95Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
- 96Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada.
- 97The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 98Department of Twin Research and Genetic Epidemiology, King's College London, SE1 7EH London, UK; NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, SE1 9RT London, UK.
- 99Department of Twin Research and Genetic Epidemiology, King's College London, SE1 7EH London, UK.
- 100Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, the Netherlands.
Abstract
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.
Keywords: complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization.
Conflict of interest statement
Declaration of interests G.C.-P. is currently an employee of 23andMe Inc. M.J.C. is the Chief Scientist for Genomics England, a UK Government company. B.M. Psaty serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. G. Thorleifsson, A.H., D.F.G., H. Holm, U.T., and K.S. are employees of deCODE/Amgen Inc. V.S. has received honoraria for consultations from Novo Nordisk and Sanofi and has an ongoing research collaboration with Bayer Ltd. M. McCarthy has served on advisory panels for Pfizer, NovoNordisk, and Zoe Global and has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. M. McCarthy and A. Mahajan are employees of Genentech and holders of Roche stock. M.S. receives funding from Pfizer Inc. for a project unrelated to this work. M.E.K. is employed by SYNLAB MVZ Mannheim GmbH. W.M. has received grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH , grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, and other from Synlab Holding Deutschland GmbH, all outside the submitted work. A.V.K. has served as a consultant to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen, and Color Genomics; received speaking fees from Illumina and the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research, and reports a patent related to a genetic risk predictor (20190017119). S. Kathiresan is an employee of Verve Therapeutics and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics. He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, and Medscape; and he reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). D.K. accepts consulting fees from Regeneron Pharmaceuticals. D.O.M.-K. is a part-time clinical research consultant for Metabolon, Inc. D. Saleheen has received support from the British Heart Foundation, Pfizer, Regeneron, Genentech, and Eli Lilly pharmaceuticals. P.N. reports investigator-initated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche / Genentech, is a co-founder of TenSixteen Bio, is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. The spouse of C.J.W. is employed by Regeneron.
References
https://pubmed.ncbi.nlm.nih.gov/