Exome-wide association study of plasma lipids in >300,000 individuals

Dajiang J. Liu, Gina M. Peloso, Haojie Yu, Adam S. Butterworth, Xiao Wang, Anubha Mahajan, Danish Saleheen, Connor Emdin, Dewan Alam, Alexessander Couto Alves, Philippe Amouyel, Emanuele DI Angelantonio, Dominique Arveiler, Themistocles L. Assimes, Paul L. Auer, Usman Baber, Christie M. Ballantyne, Lia E. Bang, Marianne Benn, Joshua C. BisMichael Boehnke, Eric Boerwinkle, Jette Bork-Jensen, Erwin P. Bottinger, Ivan Brandslund, Morris Brown, Fabio Busonero, Mark J. Caulfield, John C. Chambers, Daniel I. Chasman, Y. Eugene Chen, Yii Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y. Chu, John M. Connell, Francesco Cucca, L. Adrienne Cupples, Scott M. Damrauer, Gail Davies, Ian J. Deary, George Dedoussis, Joshua C. Denny, Anna Dominiczak, Marie Pierre Dubé, Tapani Ebeling, Gudny Eiriksdottir, Toñu Esko, Aliki Eleni Farmaki, Mary F. Feitosa, Marco Ferrario, Jean Ferrieres, Ian Ford, Myriam Fornage, Paul W. Franks, Timothy M. Frayling, Ruth Frikke-Schmidt, Lars G. Fritsche, Philippe Frossard, Valentin Fuster, Santhi K. Ganesh, Wei Gao, Melissa E. Garcia, Christian Gieger, Franco Giulianini, Mark O. Goodarzi, Harald Grallert, Niels Grarup, Leif Groop, Megan L. Grove, Vilmundur Gudnason, Torben Hansen, Tamara B. Harris, Caroline Hayward, Joel N. Hirschhorn, Oddgeir L. Holmen, Jennifer Huffman, Yong Huo, Kristian Hveem, Sehrish Jabeen, Anne U. Jackson, Johanna Jakobsdottir, Marjo Riitta Jarvelin, Gorm B. Jensen, Marit E. Jørgensen, J. Wouter Jukema, Johanne M. Justesen, Pia R. Kamstrup, Stavroula Kanoni, Fredrik Karpe, Frank Kee, Amit V. Khera, Derek Klarin, Heikki A. Koistinen, Jaspal S. Kooner, Charles Kooperberg, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo Lakka, Claudia Langenberg, Anne Langsted, Lenore J. Launer, Torsten Lauritzen, David C. MLiewald, Li An Lin, Allan Linneberg, Ruth J.F. Loos, Yingchang Lu, Xiangfeng Lu, Reedik Mägi, Anders Malarstig, Ani Manichaikul, Alisa K. Manning, Pekka Mäntyselkä, Eirini Marouli, Nicholas G.D. Masca, Andrea Maschio, James B. Meigs, Olle Melander, Andres Metspalu, Andrew P. Morris, Alanna C. Morrison, Antonella Mulas, Martina Müller-Nurasyid, Patricia B. Munroe, Matt J. Neville, Sune F. Nielsen, Jonas B. Nielsen, Børge G. Nordestgaard, Jose M. Ordovas, Roxana Mehran, Christoper J. O'Donnell, Marju Orho-Melander, Cliona M. Molony, Pieter Muntendam, Sandosh Padmanabhan, Colin N.A. Palmer, Dorota Pasko, Aniruddh P. Patel, Oluf Pedersen, Markus Perola, Annette Peters, Charlotta Pisinger, Giorgio Pistis, Ozren Polasek, Neil Poulter, Bruce M. Psaty, Daniel J. Rader, Asif Rasheed, Rainer Rauramaa, Dermot F. Reilly, Alex P. Reiner, Frida Renström, Stephen S. Rich, Paul M. Ridker, John D. Rioux, Neil R. Robertson, Dan M. Roden, Jerome I. Rotter, Igor Rudan, Veikko Salomaa, Nilesh J. Samani, Serena Sanna, Naveed Sattar, Ellen M. Schmidt, Robert A. Scott, Peter Sever, Raquel S. Sevilla, Christian M. Shaffer, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S. Small, Albert V. Smith, Blair H. Smith, Sangeetha Somayajula, Lorraine Southam, Timothy D. Spector, Elizabeth K. Speliotes, John M. Starr, Kathleen E. Stirrups, Nathan Stitziel, Konstantin Strauch, Heather M. Stringham, Praveen Surendran, Hayato Tada, Alan R. Tall, Hua Tang, Jean Claude Tardif, Kent D. Taylor, Stella Trompet, Philip S. Tsao, Jaakko Tuomilehto, Anne Tybjaerg-Hansen, Natalie R.Van Zuydam, Anette Varbo, Tibor V. Varga, Jarmo Virtamo, Melanie Waldenberger, Nan Wang, Nick J. Wareham, Helen R. Warren, Peter E. Weeke, Joshua Weinstock, Jennifer Wessel, James G. Wilson, Peter W.F. Wilson, Ming Xu, Hanieh Yaghootkar, Robin Young, Eleftheria Zeggini, He Zhang, Neil S. Zheng, Weihua Zhang, Yan Zhang, Wei Zhou, Yanhua Zhou, Magdalena Zoledziewska, Joanna M.M. Howson, John Danesh, Mark I. McCarthy, Chad A. Cowan, Goncalo Abecasis, Panos Deloukas, Kiran Musunuru, Cristen J. Willer*, Sekar Kathiresan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

228 Citations (Scopus)

Abstract

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TGrich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

Original languageEnglish
Pages (from-to)1758-1766
Number of pages9
JournalNature Genetics
Volume49
Issue number12
DOIs
Publication statusPublished - 1 Dec 2017

Bibliographical note

Funding Information:
of Health. G.M.P. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health award K01HL125751. A.P.P. is supported by a research fellowship from the Stanley J. Sarnoff Cardiovascular Research Foundation. H. Tada is supported by a grant from the Japanese Circulation Society to study in the United States. The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F. E.K.S. is supported by NIH grants R01 DK106621 and R01 DK107904, the University of Michigan Biological Sciences Scholars Program, and the University of Michigan Department of Internal Medicine. T.D.S. is supported by an ERC Advanced Principal Investigator award. A.P.M. is supported as a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant no. WT098017). Y.E.C. is supported by HL117491 and HL129778 from the NIH. S.K.G. is supported by HL122684 from the NIH. P.L.A. is supported by NHLBI R21 HL121422-02 from the NIH. C.L., N.J.W., and R.A.S. acknowledge funding from the Medical Research Council, UK (MC_UU_12015/1). J.D. is supported as a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. C.J.W. is supported by HL094535 and HL109946 from the NIH. S. Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564 and R33 HL120781 from the NIH. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health or the US Department of Health and Human Services.

Funding Information:
D.J.L. is partially supported by R01HG008983 from the National Human Genome Research Institute of the National Institute of Health, and R21DA040177 and R01DA037904 from the National Institute of Drug Abuse of the National Institute

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