Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Stavroula Kanoni # 1, Sarah E Graham # 2, Yuxuan Wang # 3, Ida Surakka # 2, Shweta Ramdas # 4, Xiang Zhu # 5 6 7 8, Shoa L Clarke 7 9, Konain Fatima Bhatti 1, Sailaja Vedantam 10 11, Thomas W Winkler 12, Adam E Locke 13, Eirini Marouli 1, Greg J M Zajac 14, Kuan-Han H Wu 15, Ioanna Ntalla 16, Qin Hui 17 18, Derek Klarin 7 19, Austin T Hilliard 7, Zeyuan Wang 17 18, Chao Xue 2, 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 24 26 27, Chikashi Terao 28, Masahiro Kanai 11 24 29, Wei Zhou 11 15 30, Ben M Brumpton 31 32 33, Humaira Rasheed 31 32 34, Aki S Havulinna 35 36, Yogasudha Veturi 37, Jennifer Allen Pacheco 38, Elisabeth A Rosenthal 39, Todd Lingren 40, QiPing Feng 41, Iftikhar J Kullo 42, Akira Narita 43, Jun Takayama 43, Hilary C Martin 44, Karen A Hunt 45, Bhavi Trivedi 45, Jeffrey Haessler 46, Franco Giulianini 47, Yuki Bradford 37, Jason E Miller 37, Archie Campbell 48 49, Kuang Lin 50, Iona Y Millwood 50 51, Asif Rasheed 52, George Hindy 53, Jessica D Faul 54, Wei Zhao 54 55, David R Weir 54, Constance Turman 56, Hongyan Huang 56, Mariaelisa Graff 57, Ananyo Choudhury 58, Dhriti Sengupta 58, Anubha Mahajan 59, Michael R Brown 60, Weihua Zhang 61 62, Ketian Yu 14, Ellen M Schmidt 14, Anita Pandit 14, Stefan Gustafsson 63, Xianyong Yin 14, Jian'an Luan 64, Jing-Hua Zhao 65, Fumihiko Matsuda 66, Hye-Mi Jang 23, Kyungheon Yoon 23, Carolina Medina-Gomez 67, Achilleas Pitsillides 3, Jouke Jan Hottenga 68 69, Andrew R Wood 70, Yingji Ji 70, Zishan Gao 71 72 73, Simon Haworth 32 74, Noha A Yousri 75 76, Ruth E Mitchell 32 77, Jin Fang Chai 78, Mette Aadahl 79 80, Anne A Bjerregaard 79, Jie Yao 81, Ani Manichaikul 82, Chii-Min Hwu 83, Yi-Jen Hung 84, Helen R Warren 85 86, Julia Ramirez 85 87, Jette Bork-Jensen 88, Line L Kårhus 79, Anuj Goel 59 89, Maria Sabater-Lleal 90 91, Raymond Noordam 92, Pala Mauro 93, Floris Matteo 93 94, Aaron F McDaid 95 96, Pedro Marques-Vidal 97, Matthias Wielscher 98, Stella Trompet 99 100, Naveed Sattar 101, Line T Møllehave 79, Matthias Munz 102, Lingyao Zeng 103 104, Jianfeng Huang 105, Bin Yang 105, Alaitz Poveda 106, Azra Kurbasic 106, Claudia Lamina 107 108, Lukas Forer 107 108, Markus Scholz 109 110, Tessel E Galesloot 111, Jonathan P Bradfield 112, Sanni E Ruotsalainen 35, EWarwick Daw 113, Joseph M Zmuda 114, Jonathan S Mitchell 115, Christian Fuchsberger 115, Henry Christensen 116, Jennifer A Brody 117, Miguel Vazquez-Moreno 118, Mary F Feitosa 113, Mary K Wojczynski 113, Zhe Wang 119, Michael H Preuss 119, Massimo Mangino 120 121, Paraskevi Christofidou 120, Niek Verweij 122, Jan W Benjamins 122, Jorgen Engmann 123 124, Noah L Tsao 125, Anurag Verma 4, Roderick C Slieker 126 127, Ken Sin Lo 128, Nuno R Zilhao 129, Phuong Le 130, Marcus E Kleber 131 132, Graciela E Delgado 131, Shaofeng Huo 133, Daisuke D Ikeda 134, Hiroyuki Iha 134, Jian Yang 135 136 137, Jun Liu 138 139, Ayşe Demirkan 139 140, Hampton L Leonard 141 142, Jonathan Marten 143, Mirjam Frank 144, Börge Schmidt 144, Laura J Smyth 145, Marisa Cañadas-Garre 145 146 147 148, Chaolong Wang 149 150, Masahiro Nakatochi 151, Andrew Wong 152, Nina Hutri-Kähönen 153, Xueling Sim 78, Rui Xia 154, Alicia Huerta-Chagoya 155 156 157, Juan Carlos Fernandez-Lopez 158, Valeriya Lyssenko 106 159, Suraj S Nongmaithem 160, Swati Bayyana 161 160, Heather M Stringham 14, Marguerite R Irvin 162, Christopher Oldmeadow 163, Han-Na Kim 164 165, Seungho Ryu 166 167, Paul R H J Timmers 143 168, Liubov Arbeeva 169, Rajkumar Dorajoo 150 170, Leslie A Lange 171, Gauri Prasad 172 173, Laura Lorés-Motta 174, Marc Pauper 174, Jirong Long 175, Xiaohui Li 81, Elizabeth Theusch 176, Fumihiko Takeuchi 177, Cassandra N Spracklen 178 179, Anu Loukola 35, Sailalitha Bollepalli 35, Sophie C Warner 180 181, Ya Xing Wang 182, Wen B Wei 183, Teresa Nutile 184, Daniela Ruggiero 184 185, Yun Ju Sung 186, Shufeng Chen 105, Fangchao Liu 105, Jingyun Yang 187 188, Katherine A Kentistou 168, Bernhard Banas 189, Giuseppe Giovanni Nardone 190, Karina Meidtner 191 192, Lawrence F Bielak 55, Jennifer A Smith 54 55, Prashantha Hebbar 193, Aliki-Eleni Farmaki 194 195, Edith Hofer 196 197, Maoxuan Lin 198, Maria Pina Concas 190, Simona Vaccargiu 199, Peter J van der Most 200, Niina Pitkänen 201 202, Brian E Cade 203 204, Sander W van der Laan 205, Kumaraswamy Naidu Chitrala 206 207, Stefan Weiss 208, Amy R Bentley 209, Ayo P Doumatey 209, Adebowale A Adeyemo 209, Jong Young Lee 210, Eva R B Petersen 211, Aneta A Nielsen 212, Hyeok Sun Choi 213, Maria Nethander 214 215, Sandra Freitag-Wolf 216, Lorraine Southam 44 217, Nigel W Rayner 44 59 217 218, Carol A Wang 219, Shih-Yi Lin 220 221 222, Jun-Sing Wang 223 224, Christian Couture 225, Leo-Pekka Lyytikäinen 226 227, Kjell Nikus 228 229, Gabriel Cuellar-Partida 230, Henrik Vestergaard 88 231, Bertha Hidalgo 232, Olga Giannakopoulou 1, Qiuyin Cai 175, Morgan O Obura 126, Jessica van Setten 233, Xiaoyin Li 234, Jingjing Liang 234, Hua Tang 235, Natalie Terzikhan 139, Jae Hun Shin 213, Rebecca D Jackson 236, Alexander P Reiner 237, Lisa Warsinger Martin 238, Zhengming Chen 50 51, Liming Li 239, Takahisa Kawaguchi 66, Joachim Thiery 109 240, Joshua C Bis 117, Lenore J Launer 206, Huaixing Li 133, Mike A Nalls 241 242, Olli T Raitakari 201 202 243, Sahoko Ichihara 244, Sarah H Wild 245, Christopher P Nelson 180 181, Harry Campbell 168, Susanne Jäger 191 192, Toru Nabika 246, Fahd Al-Mulla 193, Harri Niinikoski 247 248, Peter S Braund 180 181, Ivana Kolcic 249, Peter Kovacs 250, Tota Giardoglou 251, Tomohiro Katsuya 252 253, Dominique de Kleijn 254, Gert J de Borst 254, Eung Kweon Kim 255, Hieab H H Adams 139 256 257, M Arfan Ikram 139, Xiaofeng Zhu 234, Folkert W Asselbergs 233, Adriaan O Kraaijeveld 233, Joline W J Beulens 126 258, Xiao-Ou Shu 175, Loukianos S Rallidis 259, Oluf Pedersen 88, Torben Hansen 88, Paul Mitchell 260, Alex W Hewitt 261 262, Mika Kähönen 263 264, Louis Pérusse 225 265, Claude Bouchard 266, Anke Tönjes 250, Yii-Der Ida Chen 81, Craig E Pennell 219, Trevor A Mori 267, Wolfgang Lieb 268, Andre Franke 269, Claes Ohlsson 214 270, Dan Mellström 214 271, Yoon Shin Cho 213, Hyejin Lee 272, Jian-Min Yuan 273 274, Woon-Puay Koh 275 276, Sang Youl Rhee 277, Jeong-Taek Woo 277, Iris M Heid 12, Klaus J Stark 12, Martina E Zimmermann 12, Henry Völzke 278, Georg Homuth 208, Michele K Evans 279, Alan B Zonderman 279, Ozren Polasek 249 280, Gerard Pasterkamp 205, Imo E Hoefer 205, Susan Redline 203 204, Katja Pahkala 201 202 281, Albertine J Oldehinkel 282, Harold Snieder 200, Ginevra Biino 283, Reinhold Schmidt 196, Helena Schmidt 284, Stefania Bandinelli 285, George Dedoussis 194, Thangavel Alphonse Thanaraj 193, Sharon L R Kardia 55, Patricia A Peyser 55, Norihiro Kato 177, Matthias B Schulze 191 192 286, Giorgia Girotto 190 287, Carsten A Böger 189 288 289, Bettina Jung 189 288 289, Peter K Joshi 168, David A Bennett 187 188, Philip L De Jager 11 290, Xiangfeng Lu 105, Vasiliki Mamakou 291 292, Morris Brown 86 293, Mark J Caulfield 85 86, Patricia B Munroe 85 86, Xiuqing Guo 81, Marina Ciullo 184 185, Jost B Jonas 182 294 295 296, Nilesh J Samani 180 181, Jaakko Kaprio 35, Päivi Pajukanta 297, Teresa Tusié-Luna 298, Carlos A Aguilar-Salinas 299, Linda S Adair 300 301, Sonny Augustin Bechayda 302 303, H Janaka de Silva 304, Ananda R Wickremasinghe 305, Ronald M Krauss 306, Jer-Yuarn Wu 307, Wei Zheng 175, Anneke Iden Hollander 174, Dwaipayan Bharadwaj 173 308, Adolfo Correa 309, James G Wilson 310, Lars Lind 311, Chew-Kiat Heng 312, Amanda E Nelson 169 313, Yvonne M Golightly 57 169 314 315, James F Wilson 143 168, Brenda Penninx 69 316, Hyung-Lae Kim 317, John Attia 163 318, Rodney J Scott 163 318, D C Rao 319, Donna K Arnett 320, Steven C Hunt 75 321, Mark Walker 322, Heikki A Koistinen 36 323 324, Giriraj R Chandak 160 325, Josep M Mercader 156 326 327, Maria C Costanzo 156, Dongkeun Jang 156, Noël P Burtt 156, Clicerio Gonzalez Villalpando 328, Lorena Orozco 329, Myriam Fornage 154 330, EShyong Tai 78 331, Rob M van Dam 78 332, Terho Lehtimäki 226 227, Nish Chaturvedi 152, Mitsuhiro Yokota 333, Jianjun Liu 150, Dermot F Reilly 334, Amy Jayne McKnight 145, Frank Kee 145, Karl-Heinz Jöckel 144, Mark I McCarthy 59 218, Colin N A Palmer 335, Veronique Vitart 143, Caroline Hayward 143, Eleanor Simonsick 336, Cornelia M van Duijn 138 139, Zi-Bing Jin 337 338, Jia Qu 338, Haretsugu Hishigaki 134, Xu Lin 133, Winfried März 131 339 340, Vilmundur Gudnason 129 341, Jean-Claude Tardif 128, Guillaume Lettre 128, Leen M 't Hart 127 342 343 344, Petra J M Elders 345 346, Scott M Damrauer 4 125 347, Meena Kumari 348, Mika Kivimaki 124, Pim van der Harst 122 233, Tim D Spector 120, Ruth J F Loos 88 119 349, Michael A Province 113, Esteban J Parra 130, Miguel Cruz 118, Bruce M Psaty 117 350 351, Ivan Brandslund 116 352, Peter P Pramstaller 115, Charles N Rotimi 209, Kaare Christensen 353, Samuli Ripatti 35 354 355, Elisabeth Widén 35, Hakon Hakonarson 356 357, Struan F A Grant 4 357 358, Lambertus A L M Kiemeney 111, Jacqueline de Graaf 111, Markus Loeffler 109 110, Florian Kronenberg 107 108, Dongfeng Gu 105 359, Jeanette Erdmann 360, Heribert Schunkert 103 104, Paul W Franks 106, Allan Linneberg 79 80, J Wouter Jukema 99 361, Amit V Khera 11 362 363 364 365, Minna Männikkö 366, Marjo-Riitta Jarvelin 98 367 368, Zoltan Kutalik 95 96, Cucca Francesco 369 370, Dennis O Mook-Kanamori 371 372, Ko Willems van Dijk 373 374 375, Hugh Watkins 59 89, David P Strachan 376, Niels Grarup 88, Peter Sever 377, Neil Poulter 378, Lee-Ming Chuang 379, Jerome I Rotter 81, Thomas M Dantoft 79, Fredrik Karpe 380 381, Matt J Neville 380 381, Nicholas J Timpson 32 77, Ching-Yu Cheng 382 383, Tien-Yin Wong 382 383, Chiea Chuen Khor 150, Hengtong Li 384, Charumathi Sabanayagam 382 383, Annette Peters 73 104 192, Christian Gieger 72 73 192, Andrew T Hattersley 385, Nancy L Pedersen 386, Patrik K E Magnusson 386, Dorret I Boomsma 68 69, Allegonda H M Willemsen 68 69, LAdrienne Cupples 3 387, Joyce B J van Meurs 67 139, Mohsen Ghanbari 139 388, Penny Gordon-Larsen 300 301, Wei Huang 389, Young Jin Kim 23, Yasuharu Tabara 66, Nicholas J Wareham 64, Claudia Langenberg 64 390, Eleftheria Zeggini 44 217 391, Johanna Kuusisto 392, Markku Laakso 392, Erik Ingelsson 9 63 393 394, Goncalo Abecasis 14 395, John C Chambers 61 62 396 397, Jaspal S Kooner 62 378 398 399, Paul S de Vries 60, Alanna C Morrison 60, Scott Hazelhurst 58 400, Michèle Ramsay 58, Kari E North 57, Martha Daviglus 401, Peter Kraft 56 402, Nicholas G Martin 403, John B Whitfield 403, Shahid Abbas 52 404, Danish Saleheen 52 405 406, Robin G Walters 50 51 407, Michael V Holmes 50 51 408, Corri Black 409, Blair H Smith 410, Aris Baras 395, Anne E Justice 411, Julie E Buring 47 327, Paul M Ridker 47 327, Daniel I Chasman 47 327, Charles Kooperberg 46, Gen Tamiya 43, Masayuki Yamamoto 43, David A van Heel 45, Richard C Trembath 412, Wei-Qi Wei 413, Gail P Jarvik 414, Bahram Namjou 415, M Geoffrey Hayes 38 416 417, Marylyn D Ritchie 37, Pekka Jousilahti 36, Veikko Salomaa 36, Kristian Hveem 31 418 419, Bjørn Olav Åsvold 31 418 420, Michiaki Kubo 421, Yoichiro Kamatani 422 423, Yukinori Okada 26 422 424 425, Yoshinori Murakami 426, Bong-Jo Kim 23, Unnur Thorsteinsdottir 20 427, Kari Stefansson 20 428, Jifeng Zhang 2, YEugene Chen 2, Yuk-Lam Ho 429, Julie A Lynch 430 431, Daniel J Rader 4, Philip S Tsao 7 9 432, Kyong-Mi Chang 433 434, Kelly Cho 429 435, Christopher J O'Donnell 429 435, John M Gaziano 429 435, Peter W F Wilson 18 436, Timothy M Frayling 70, Joel N Hirschhorn 10 11 437, Sekar Kathiresan 11 363 364, Karen L Mohlke 178, Yan V Sun 17 18, Andrew P Morris 428, Michael Boehnke # 14, Christopher D Brown # 4, Pradeep Natarajan # 11 438 439 440, Panos Deloukas # 1 441, Cristen J Willer # 442 443 444, Themistocles L Assimes # 7 9 432, Gina M Peloso # 445
Affiliations
Affiliations
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
- Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, 48109, USA.
- Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Ave, Boston, MA, 02118, USA.
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Statistics, The Pennsylvania State University, University Park, PA, USA.
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA.
- 7VA Palo Alto Health Care Systems, Palo Alto, CA, USA.
- Department of Statistics, Stanford University, Stanford, CA, USA.
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
- Boston Children's Hospital, EndocrinologyBoston, MA, 02115, USA.
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
- McDonnell Genome Institute and Department of Medicine, Washington University, St. Louis, MO, 63108, USA.
- Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
- Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
- Atlanta VA Health Care System, Decatur, GA, USA.
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
- deCODE Genetics/Amgen, Inc. Sturlugata 8, Reykjavik, 102, Iceland.
- School of Engineering and Natural Sciences, University of Iceland, Sæmundargötu 2, Reykjavik, 102, Iceland.
- Department of Clinical Biochemistry, Landspitali - National University Hospital of Iceland, Hringbraut, Reykjavik, 101, Iceland.
- Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungcheongbuk-Do, South Korea.
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
- K.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, Bristol, BS8 2BN, UK.
- Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
- Division of Medicine and Laboratory Sciences, University of Oslo, Oslo, Norway.
- Institute 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.
- Department of Genetics, Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA.
- Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60618, USA.
- Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA.
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
- Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
- Fred Hutchinson Cancer Center, Division of Public Health Sciences, Seattle, WA, 9810, USA.
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
- Usher Institute, The University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, EH16 4UX, UK.
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
- Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
- Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.
- Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar.
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA.
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
- Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA.
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
- 58Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
- Human Genetics Center, Department of Epidemiology, School of Public Health, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
- Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK.
- Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, Middlesex, UB1 3HW, UK.
- Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
- Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, UK.
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- Amsterdam Public Health Research Institute, Amsterdam UMC, the Netherlands.
- Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK.
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, 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.
- Bristol Dental School, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY, UK.
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.
- Department of Computer and Systems Engineering, Alexandria University, Alexandria, Egypt.
- Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield Grove, Bristol, BS8 2BN, UK.
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, 117549, Singapore.
- Center 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.
- The 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.
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22903, USA.
- Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
- Institute of Preventive Medicine, National Defense Medical Center, Postbox 90048~700, Sanhsia Dist, New Taipei City, 237101, Taiwan.
- 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.
- NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
- Aragon Institute of Engineering Research, University of Zaragoza and Centro de Investigación Biomédica en Red - Bioingeniería, Biomateriales Y Nanomedicina, Spain.
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
- Unit of Genomics of Complex Diseases, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
- Istituto Di Ricerca Genetica E Biomedica, Consiglio Nazionale Delle Ricerche, Rome, Italy.
- Dipartimento Di Scienze Biomediche, Università Degli Studi Di Sassari, Sardinia, Italy.
- University Center for Primary Care and Public Health, University of Lausanne, Rte de Berne 113, 1010, Lausanne, Switzerland.
- Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland.
- Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
- Dept of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Abstract
Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.
Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.
Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
Keywords: Cholesterol; GWAS; Genetics; Genome-wide association study; Lipids.
Conflict of interest statement
Ioanna Ntalla is an employee and stock owner of Gilead Sciences since August 2019. Derek Klarin accepts consulting fees from Regeneron Pharmaceuticals. All deCODE-affiliated authors (Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir, Kari Stefansson) are employees of deCODE/Amgen Inc. As of January 2020, Anubha Mahajan is an employee of Genentech, and a holder of Roche stock. Markus Scholz receives funding from Pfizer Inc. for a project not related to this research. Marcus E Kleber is employed by SYNLAB MVZ Mannheim GmbH. Gabriel Cuellar-Partida contributed to this work while employed at The University of Queensland, but he is now an employee of 23andMe Inc. Mark J Caulfield is Chief Scientist for Genomics England, a UK Government company. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Mark I 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. As of June 2019, Mark I McCarthy is an employee of Genentech, and a holder of Roche stock. Winfried März 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, other from Synlab Holding Deutschland GmbH, all outside the submitted work. Bruce M Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Amit V Khera has served as a consultant to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen, and Color Genomics; received speaking fees from Illumina, 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). Dennis O Mook-Kanamori is a part-time clinical research consultant for Metabolon, Inc. Danish Saleheen has received support from the British Heart Foundation, Pfizer, Regeneron, Genentech, and Eli Lilly pharmaceuticals. Veikko Salomaa has received honoraria for consultations from Novo Nordisk and Sanofi and has ongoing research collaboration with Bayer Ltd, all unrelated to the present study. Sekar 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; 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). Cristen J Willer’s spouse is employed by Regeneron.
References
https://pubmed.ncbi.nlm.nih.gov/