Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile

Tuomas O. Kilpeläinen, M. Carola Zillikens, Alena Stančákova, Francis M. Finucane, Janina S. Ried, Claudia Langenberg, Weihua Zhang, Jacques S. Beckmann, Jian'An Luan, Liesbeth Vandenput, Unnur Styrkarsdottir, Yanhua Zhou, Albert Vernon Smith, Jing Hua Zhao, Najaf Amin, Sailaja Vedantam, So Youn Shin, Talin Haritunians, Mao Fu, Mary F. FeitosaMeena Kumari, Bjarni V. Halldorsson, Emmi Tikkanen, Massimo Mangino, Caroline Hayward, Ci Song, Alice M. Arnold, Yurii S. Aulchenko, Ben A. Oostra, Harry Campbell, L. Adrienne Cupples, Kathryn E. Davis, Angela Döring, Gudny Eiriksdottir, Karol Estrada, José Manuel Fernández-Real, Melissa Garcia, Christian Gieger, Nicole L. Glazer, Candace Guiducci, Albert Hofman, Steve E. Humphries, Bo Isomaa, Leonie C. Jacobs, Antti Jula, David Karasik, Magnus K. Karlsson, Kay Tee Khaw, Lauren J. Kim, Mika Kivimäki, Norman Klopp, Brigitte Kühnel, Johanna Kuusisto, Yongmei Liu, Östen Ljunggren, Mattias Lorentzon, Robert N. Luben, Barbara McKnight, Dan Mellström, Braxton D. Mitchell, Vincent Mooser, José Maria Moreno, Satu Männistö, Jeffery R. O'Connell, Laura Pascoe, Leena Peltonen, Belén Peral, Markus Perola, Bruce M. Psaty, Veikko Salomaa, David B. Savage, Robert K. Semple, Tatjana Skaric-Juric, Gunnar Sigurdsson, Kijoung S. Song, Timothy D. Spector, Ann Christine Syvänen, Philippa J. Talmud, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Andrá G. Uitterlinden, Cornelia M. Van Duijn, Antonio Vidal-Puig, Sarah H. Wild, Alan F. Wright, Deborah J. Clegg, Eric Schadt, James F. Wilson, Igor Rudan, Samuli Ripatti, Ingrid B. Borecki, Alan R. Shuldiner, Erik Ingelsson, John Olov Jansson, Robert C. Kaplan, Vilmundur Gudnason, Tamara B. Harris, Leif Groop, Douglas P. Kiel, Fernando Rivadeneira, Mark Walker, Inês Barroso, Peter Vollenweider, Gérard Waeber, John C. Chambers, Jaspal S. Kooner, Nicole Soranzo, Joel N. Hirschhorn, Kari Stefansson, H. Erich Wichmann, Claes Ohlsson, Stephen O'Rahilly, Nicholas J. Wareham, Elizabeth K. Speliotes, Caroline S. Fox, Markku Laakso, Ruth J.F. Loos

Research output: Contribution to journalArticlepeer-review

263 Scopus citations

Abstract

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10-6) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10-26) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10-11) and one near SPRY2 (P = 3 × 10-8). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

Original languageEnglish
Pages (from-to)753-760
Number of pages8
JournalNature Genetics
Volume43
Issue number8
DOIs
StatePublished - 26 Jun 2011
Externally publishedYes

Bibliographical note

Funding Information:
of Governors’ Chair in Medical Genetics; Centre for Medical Systems Biology (The Netherlands); Centre Hospitalier Universitaire Vaudois (Lausanne); Croatian Ministry of Science, Education and Sport (19619627662747, 21610803150302 and 30900611942023); Department of Health (UK); Department of Veterans Affairs (USA); Emil and Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus University (Rotterdam); European Commission (DG XII, FP7/20072013, FP7KBBE20104266408, HEALTHF22007201681, HEALTHF22008201865GEFOS, HEALTHF42007201413, HEALTHF42007201550, LSHGCT2006018947, LSHGCT200601947, LSHMCT2003503041, LSHMCT2004512013, QLG1CT200101252 and QLG2CT200201254); Finnish Diabetes Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Heart Foundation; Finnish Medical Society; Folkhälsan Research Foundation; Food Standards Agency (UK); Foundation for Life and Health in Finland; German Bündesministerium für Forschung und Technology (01AK803AH and 01IG07015G); German Federal Ministry of Education and Research; German National Genome Research Network (NGFN2 and NGFNPlus: 01GS0823); GiorgiCavaglieri Foundation; GlaxoSmithKline; Göteborg Medical Society; Gyllenberg Foundation; Health and Safety Executive (UK); Health Care Centers in Vasa, Närpes and Korsholm; Hjartavernd (the Icelandic Heart Association); John D. and Catherine T. MacArthur Foundation; Knut and Alice Wallenberg Foundation; Leenaards Foundation; LudwigMaximilians Universität München; Lundberg Foundation; Medical Research Council (UK); Men’s Associates of Hebrew SeniorLife; Ministerio de Ciencia e Innovación (Spain) (SAF2009 and SAF200802073); Ministry for Health, Welfare and Sports (The Netherlands); Ministry of Education (Finland); Ministry of Education, Culture and Science (The Netherlands); Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Närpes Health Care Foundation; National Institute for Health Research (UK); US National Institutes of Health (USA) (AG13196, DK063491, K23DK080145, M01RR00425, N01AG12100, N01AG62101, N01AG62103, N01AG62106, N01HC15103, N01HC25195, N01HC35129, N01HC45133, N01HC55222, N01HC75150, N01HC85079 through N01HC85086, P30DK072488, R01AG03189001, R01AG18728, R01AG03209801A1, R01AR/AG41398, R01AR046838, R01DK06833603, R01DK075787, R01DK07568102, R01HL03631020A2, R01HL087652, R01HL08770003, R01HL088119, U01HL080295, U01HL72515 and U01HL84756); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050060810); Netherlands Organisation for Scientific Research (175.010.2005.011 and 91103012); Netherlands Organization for the Health Research and Development; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklén Foundation; Petrus and Augusta Hedlunds Foundation; Research Institute for Diseases in the Elderly (01493015; RIDE2); Robert Dawson Evans Endowment; Royal Society (UK); Sahlgrenska Center for Cardiovascular and Metabolic Research (A305:188); Sahlgrenska University Hospital Foundation (ALF/LUA); Science Funding programme (UK); Scottish Executive Health Department; Sigrid Juselius Foundation; State of Bavaria; Stroke Association (UK); Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Research Council (K201054X09894193, K201052X20229053 and 2006-3832); Swedish Strategic Foundation; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO116323/1, 310000112552 and 33CSCO-122661); TEKES (1510/31/06); Torsten and Ragnar Söderberg’s Foundation; United Kingdom NIHR Cambridge Biomedical Research Centre; University of Lausanne; University of Maryland General Clinical Research Center (M01 RR 16500); Uppsala University; Västra Götaland Foundation; and Wellcome Trust (077016/Z/05/Z, 084723/Z/08/Z and 091746/Z/10/Z).

Funding Information:
A full list of Acknowledgments appears in the Supplementary Note. Funding was provided by Academy of Finland (10404, 124243, 129680, 129494, 141005 and 213506); Agency for Health Care Policy Research (HS06516); Althingi (the Icelandic Parliament); American Heart Association (10SDG269004); AstraZeneca; Baltimore Geriatric Research Education and Clinical Centers; Biocentrum Helsinki Foundation; Biotechnology and Biological Sciences Research Council (G20234); British Heart Foundation (PG/07/133/24260, RG/08/008, SP/04/002, SP/07/007/23671); CamStrad; Cancer Research UK; CedarsSinai Board

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