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. Bis; Michael 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 Dube; Tapani Ebeling; Gudny Eiriksdottir; Tonu 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. Jorgensen; 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. M. Liewald; Li An Lin; Allan Linneberg; Ruth J. F. Loos; Yingchang Lu; Xiangfeng Lu; Reedik Magi; Anders Malarstig; Ani Manichaikul; Alisa K. Manning; Pekka Mantyselka; Eirini Marouli; Nicholas G. D. Masca; Andrea Maschio; James B. Meigs; Olle Melander; Andres Metspalu; Andrew P. Morris; Alanna C. Morrison; Antonella Mulas; Martina Mueller-Nurasyid; Patricia B. Munroe; Matt J. Neville; Jonas B. Nielsen; Sune F. Nielsen; Borge 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 Renstrom; 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; VA Million Veteran Program

doi:10.1038/ng.3977

Back

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

Journal article

Peer reviewed

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, …

Nature genetics, Vol.49(12), pp.1758-1766

01/12/2017

DOI: https://doi.org/10.1038/ng.3977

PMID: 29083408

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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 TG-rich 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.

Metrics

1 Record Views

See more details

Details

Title: Exome-wide association study of plasma lipids in > 300,000 individuals
Creators - without role: Dajiang J. Liu - Pennsylvania State University
Gina M. Peloso - Boston University
Haojie Yu - Harvard University
Adam S. Butterworth - University of Cambridge
Xiao Wang - Supreme Council Of Health
Anubha Mahajan - University of Oxford
Danish Saleheen - Supreme Council Of Health
Connor Emdin - Broad Institute
Dewan Alam - International Centre for Diarrhoeal Disease Research
Alexessander Couto Alves - Imperial Coll London, London, England
Philippe Amouyel - Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,Risk Factors & Mol Determinant, Lille, France
Emanuele Di Angelantonio - University of Cambridge
Dominique Arveiler - University of Strasbourg
Themistocles L. Assimes - VA Palo Alto Hlth Care Syst, Palo Alto, CA USA
Paul L. Auer - University of Wisconsin–Milwaukee
Usman Baber - Supreme Council Of Health
Christie M. Ballantyne - College Station Medical Center
Lia E. Bang - Copenhagen Univ Hosp, Dept Cardiol, Rigshosp, Copenhagen, Denmark
Marianne Benn - Rigshosp, Dept Clin Biochem, Copenhagen, Denmark
Joshua C. Bis - University of Washington
Michael Boehnke - Biostat
Eric Boerwinkle - Supreme Council Of Health
Jette Bork-Jensen - University of Copenhagen
Erwin P. Bottinger - Supreme Council Of Health
Ivan Brandslund - Lillebaelt Hosp, Dept Clin Biochem, Vejle, Denmark
Morris Brown - Queen Mary University of London
Fabio Busonero
Mark J. Caulfield - Queen Mary University of London
John C. Chambers - Supreme Council Of Health
Daniel I. Chasman - Brigham and Women's Hospital
Y. Eugene Chen - College Station Medical Center
Yii-Der Ida Chen - College Station Medical Center
Rajiv Chowdhury
Cramer Christensen - College Station Medical Center
Audrey Y. Chu - Brigham and Women's Hospital
John M. Connell - University of Dundee
Francesco Cucca - University of Sassari
L. Adrienne Cupples - Boston University
Scott M. Damrauer - College Station Medical Center
Gail Davies - University of Edinburgh
Ian J. Deary - University of Edinburgh
George Dedoussis - Harokopio University of Athens
Joshua C. Denny - Vanderbilt University
Anna Dominiczak - University of Glasgow
Marie-Pierre Dube - Montreal Heart Institute
Tapani Ebeling - College Station Medical Center
Gudny Eiriksdottir - Iceland Heart Assoc, Kopavogur, Iceland
Tonu Esko - Broad Institute
Aliki-Eleni Farmaki - Harokopio University of Athens
Mary F. Feitosa - Supreme Council Of Health
Marco Ferrario - University of Insubria
Jean Ferrieres - University of Toulouse
Ian Ford - University of Glasgow
Myriam Fornage - College Station Medical Center
Paul W. Franks - Lund University
Timothy M. Frayling - University of Exeter
Ruth Frikke-Schmidt - Rigshosp, Dept Clin Biochem, Copenhagen, Denmark
Lars G. Fritsche - Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA
Philippe Frossard - Ctr Noncommunicable Dis, Karachi, Pakistan
Valentin Fuster - Supreme Council Of Health
Santhi K. Ganesh - College Station Medical Center
Wei Gao - Peking University
Melissa E. Garcia - NHLBI, Bldg 10, Bethesda, MD 20892 USA
Christian Gieger - German Ctr Diabet Res DZD & V, Neuherberg, Germany
Franco Giulianini - Brigham and Women's Hospital
Mark O. Goodarzi - College Station Medical Center
Harald Grallert - German Ctr Diabet Res DZD & V, Neuherberg, Germany
Niels Grarup - University of Copenhagen
Leif Groop - Lund University
Megan L. Grove - Supreme Council Of Health
Vilmundur Gudnason - Iceland Heart Assoc, Kopavogur, Iceland
Torben Hansen - University of Copenhagen
Tamara B. Harris - Institute of Aging
Caroline Hayward - University of Edinburgh
Joel N. Hirschhorn - Broad Institute
Oddgeir L. Holmen - Norwegian Univ Sci & Technol, HUNT Res Ctr, Dept Publ Hlth & Gen Practice, Levanger, Norway
Jennifer Huffman - University of Edinburgh
Yong Huo - Peking University
Kristian Hveem - College Station Medical Center
Sehrish Jabeen - Ctr Noncommunicable Dis, Karachi, Pakistan
Anne U. Jackson - Biostat
Johanna Jakobsdottir - Iceland Heart Assoc, Kopavogur, Iceland
Marjo-Riitta Jarvelin - Imperial Coll London, London, England
Gorm B. Jensen - Frederiksberg Univ Hosp, Copenhagen City Heart Study, Copenhagen, Denmark
Marit E. Jorgensen - Steno Diabet Ctr, Gentofte, Denmark
J. Wouter Jukema - Leiden University
Johanne M. Justesen - University of Copenhagen
Pia R. Kamstrup - Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Copenhagen, Denmark
Stavroula Kanoni - Queen Mary University of London
Fredrik Karpe - University of Oxford
Frank Kee - Queens University
Amit V. Khera - Broad Institute
Derek Klarin - Broad Institute
Heikki A. Koistinen - University of Helsinki
Jaspal S. Kooner - Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England
Charles Kooperberg - Hutchinson
Kari Kuulasmaa
Johanna Kuusisto - University of Eastern Finland
Markku Laakso - University of Eastern Finland
Timo Lakka - University of Eastern Finland
Claudia Langenberg - University of Cambridge
Anne Langsted - Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Copenhagen, Denmark
Lenore J. Launer - Institute of Aging
Torsten Lauritzen - Univ Aarhus, Sect Gen Practice, Dept Publ Hlth, Aarhus, Denmark
David C. M. Liewald - University of Edinburgh
Li An Lin - College Station Medical Center
Allan Linneberg - Rigshosp, Dept Clin Expt Res, Glostrup, Denmark
Ruth J. F. Loos - Supreme Council Of Health
Yingchang Lu - Supreme Council Of Health
Xiangfeng Lu - College Station Medical Center
Reedik Magi - University of Tartu
Anders Malarstig - Karolinska Institutet
Ani Manichaikul - University of Virginia
Alisa K. Manning - Broad Institute
Pekka Mantyselka - University of Eastern Finland
Eirini Marouli - Queen Mary University of London
Nicholas G. D. Masca - University of Leicester
Andrea Maschio
James B. Meigs - Broad Institute
Olle Melander - Lund University
Andres Metspalu - University of Tartu
Andrew P. Morris - University of Oxford
Alanna C. Morrison - Supreme Council Of Health
Antonella Mulas
Martina Mueller-Nurasyid - Helmholtz Zentrum München
Patricia B. Munroe - Queen Mary University of London
Matt J. Neville - University of Oxford
Jonas B. Nielsen - College Station Medical Center
Sune F. Nielsen - Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Copenhagen, Denmark
Borge G. Nordestgaard - Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Copenhagen, Denmark
Jose M. Ordovas - Natl Ctr Cardiovasc Invest, Dept Cardiovasc Epidemiol & Populat Genet, Madrid, Spain
Roxana Mehran - Supreme Council Of Health
Christoper J. O'Donnell - VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA
Marju Orho-Melander - Lund University
Cliona M. Molony - Merck Sharp & Dohme Corp, Genet, Kenilworth, NJ USA
Pieter Muntendam - G3 Pharmaceut, Lexington, MA USA
Sandosh Padmanabhan - University of Glasgow
Colin N. A. Palmer - University of Dundee
Dorota Pasko - University of Exeter
Aniruddh P. Patel - Broad Institute
Oluf Pedersen - University of Copenhagen
Markus Perola - University of Helsinki
Annette Peters - German Ctr Diabet Res DZD & V, Neuherberg, Germany
Charlotta Pisinger - Res Ctr Prevent & Hlth, Copenhagen, Denmark
Giorgio Pistis - CNR, Ist Ric Genet & Biomed, Cagliari, Italy
Ozren Polasek - University of Split
Neil Poulter - Imperial Coll London, Internat Ctr Circulatory Hlth, London, England
Bruce M. Psaty - University of Washington
Daniel J. Rader - Supreme Council Of Health
Asif Rasheed - Ctr Noncommunicable Dis, Karachi, Pakistan
Rainer Rauramaa - College Station Medical Center
Dermot F. Reilly - Merck Sharp & Dohme Corp, Genet, Kenilworth, NJ USA
Alex P. Reiner - Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA
Frida Renstrom - Lund University
Stephen S. Rich - University of Virginia
Paul M. Ridker - Brigham and Women's Hospital
John D. Rioux - Montreal Heart Institute
Neil R. Robertson - University of Oxford
Dan M. Roden - Vanderbilt University
Jerome I. Rotter - College Station Medical Center
Igor Rudan - University of Edinburgh
Veikko Salomaa
Nilesh J. Samani - University of Leicester
Serena Sanna - CNR, Ist Ric Genet & Biomed, Cagliari, Italy
Naveed Sattar - University of Glasgow
Ellen M. Schmidt - College Station Medical Center
Robert A. Scott - University of Cambridge
Peter Sever - Imperial Coll London, Internat Ctr Circulatory Hlth, London, England
Raquel S. Sevilla - Merck Sharp & Dohme Corp, Imaging, Kenilworth, NJ USA
Christian M. Shaffer - Vanderbilt University
Xueling Sim - Supreme Council Of Health
Suthesh Sivapalaratnam - University of Amsterdam
Kerrin S. Small - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Albert V. Smith - Iceland Heart Assoc, Kopavogur, Iceland
Blair H. Smith - University of Dundee
Sangeetha Somayajula - Merck Sharp & Dohme Corp, Sci Informat, Kenilworth, NJ USA
Lorraine Southam - University of Oxford
Timothy D. Spector - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Elizabeth K. Speliotes - College Station Medical Center
John M. Starr - University of Edinburgh
Kathleen E. Stirrups - Queen Mary University of London
Nathan Stitziel - Supreme Council Of Health
Konstantin Strauch - IBE
Heather M. Stringham - Biostat
Praveen Surendran
Hayato Tada - Kanazawa University
Alan R. Tall - Columbia University
Hua Tang - Stanford University
Jean-Claude Tardif - Montreal Heart Institute
Kent D. Taylor - College Station Medical Center
Stella Trompet - Leiden University
Philip S. Tsao - VA Palo Alto Hlth Care Syst, Palo Alto, CA USA
Jaakko Tuomilehto - Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland
Anne Tybjaerg-Hansen - Rigshosp, Dept Clin Biochem, Copenhagen, Denmark
Natalie R. van Zuydam - University of Oxford
Anette Varbo - Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Copenhagen, Denmark
Tibor V. Varga - Lund University
Jarmo Virtamo - Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland
Melanie Waldenberger - Helmholtz Zentrum München
Nan Wang - Columbia University
Nick J. Wareham - University of Cambridge
Helen R. Warren - Queen Mary University of London
Peter E. Weeke - Vanderbilt University
Joshua Weinstock - Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA
Jennifer Wessel - Indiana University
James G. Wilson - University of Mississippi
Peter W. F. Wilson - College Station Medical Center
Ming Xu - Peking University
Hanieh Yaghootkar - University of Exeter
Robin Young
Eleftheria Zeggini - Wellcome Sanger Institute
He Zhang - College Station Medical Center
Neil S. Zheng - Yale University
Weihua Zhang - Supreme Council Of Health
Yan Zhang - Peking University
Wei Zhou - College Station Medical Center
Yanhua Zhou - Boston University
Magdalena Zoledziewska - CNR, Ist Ric Genet & Biomed, Cagliari, Italy
Joanna M. M. Howson
John Danesh - University of Cambridge
Mark I. McCarthy - University of Oxford
Chad A. Cowan - Harvard University
Goncalo Abecasis - Biostat
Panos Deloukas - Queen Mary University of London
Kiran Musunuru - Supreme Council Of Health
Cristen J. Willer - College Station Medical Center
Sekar Kathiresan - Broad Institute
VA Million Veteran Program
Publication Details: Nature genetics, Vol.49(12), pp.1758-1766
Publisher: NATURE PORTFOLIO
Number of pages: 14
Grant note: SDCC 3.A Complications / Steno Diabetes Center Copenhagen (SDCC) R01HG008983 / National Human Genome Research Institute of the National Institute of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) National Institute for Health Research (NIHR) Senior Investigator; National Institutes of Health Research (NIHR) British Heart Foundation European Research Council Senior Investigator; European Research Council (ERC) University of Michigan Department of Internal Medicine NNF14OC0009819 / Novo Nordisk Fonden; Novo Nordisk Foundation National Institute for Health Research (NIHR) Exeter Clinical Research Facility R01 DK106621; R01 DK107904; HL117491; HL129778; HL122684; HL094535; HL109946; R01 HL127564; R33 HL120781 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA G0601261; MC_UU_12015/1; MR/P013880/1; MR/N005813/1; MC_PC_14089; MR/K006584/1; MC_PC_U127561128; MC_PC_13048; MR/L003120/1; G0600237; MR/M009203/1; MC_PC_13046; MR/P02811X/1; MC_EX_MR/M009203/1; G9521010; MR/K026992/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) RG/14/5/30893; RG/08/014/24067; RG/16/4/32218 / British Heart Foundation ERC Advanced Principal Investigator award; European Research Council (ERC) MC_UU_12015/1 / Medical Research Council, UK; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) K01HL125751 / National Heart, Lung, and Blood Institute of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) MC_PC_14089; MC_EX_MR/M009203/1; MR/M009203/1; G9521010; MR/L003120/1; MR/P02811X/1; MC_PC_U127561128; MR/N005813/1; MC_UU_12015/1; G0600237; G0601261; MR/P013880/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) R21DA040177; R01DA037904 / National Institute of Drug Abuse of the National Institute of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA) University of Michigan Biological Sciences Scholars Program; University of Michigan System Stanley J. Sarnoff Cardiovascular Research Foundation WT098017 / Wellcome Trust Senior Fellow in Basic Biomedical Science; Wellcome Trust 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC / ERC; European Research Council (ERC); European Commission Donovan Family Foundation HL121422-02 / NHLBI R21 from the NIH NF-SI-0611-10099; NF-SI-0512-10113; NF-SI-0512-10165; NF-SI-0513-10059; NF-SI-0512-10135 / National Institute for Health Research; National Institutes of Health Research (NIHR) Massachusetts General Hospital; General Electric Japanese Circulation Society Grarup Group / NNF Center for Basic Metabolic Research; Novo Nordisk Foundation
Identifiers: 9937380008331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article