Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Laura Pascoe, Professor Mark Walker


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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 similar to 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 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 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.

Publication metadata

Author(s): Kilpelainen TO, Zillikens MC, Stancakova A, Finucane FM, Ried JS, Langenberg C, Zhang WH, Beckmann JS, Luan JA, Vandenput L, Styrkarsdottir U, Zhou YH, Smith AV, Zhao JH, Amin N, Vedantam S, Shin SY, Haritunians T, Fu M, Feitosa MF, Kumari M, Halldorsson BV, Tikkanen E, Mangino M, Hayward C, Song C, Arnold AM, Aulchenko YS, Oostra BA, Campbell H, Cupples LA, Davis KE, Doring A, Eiriksdottir G, Estrada K, Fernandez-Real JM, Garcia M, Gieger C, Glazer NL, Guiducci C, Hofman A, Humphries SE, Isomaa B, Jacobs LC, Jula A, Karasik D, Karlsson MK, Khaw KT, Kim LJ, Kivimaki M, Klopp N, Kuhnel B, Kuusisto J, Liu YM, Ljunggren O, Lorentzon M, Luben RN, McKnight B, Mellstrom D, Mitchell BD, Mooser V, Moreno JM, Mannisto S, O'Connell JR, Pascoe L, Peltonen L, Peral B, Perola M, Psaty BM, Salomaa V, Savage DB, Semple RK, Skaric-Juric T, Sigurdsson G, Song KS, Spector TD, Syvanen AC, Talmud PJ, Thorleifsson G, Thorsteinsdottir U, Uitterlinden AG, van Duijn CM, Vidal-Puig A, Wild SH, Wright AF, Clegg DJ, Schadt E, Wilson JF, Rudan I, Ripatti S, Borecki IB, Shuldiner AR, Ingelsson E, Jansson JO, Kaplan RC, Gudnason V, Harris TB, Groop L, Kiel DP, Rivadeneira F, Walker M, Barroso I, Vollenweider P, Waeber G, Chambers JC, Kooner JS, Soranzo N, Hirschhorn JN, Stefansson K, Wichmann HE, Ohlsson C, O'Rahilly S, Wareham NJ, Speliotes EK, Fox CS, Laakso M, Loos RJF

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2011

Volume: 43

Issue: 8

Pages: 753-U58

Print publication date: 26/06/2011

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group


DOI: 10.1038/ng.866


Altmetrics provided by Altmetric


Funder referenceFunder name
Baltimore Geriatric Research Education and Clinical Centers
Cedars-Sinai Board of Governors' Chair in Medical Genetics
Centre for Medical Systems Biology (The Netherlands)
Department of Health (UK)
Department of Veterans Affairs (USA)
Emil and Vera Cornell Foundation
Erasmus Medical Center (Rotterdam)
Erasmus University (Rotterdam)
Finnish Diabetes Foundation
Finnish Diabetes Research Foundation
Finnish Heart Foundation
Finnish Medical Society
Folkhalsan Research Foundation
Food Standards Agency (UK)
Goteborg Medical Society
Gyllenberg Foundation
Health and Safety Executive (UK)
Health Care Center in Vasa
John D. and Catherine T. MacArthur Foundation
Knut and Alice Wallenberg Foundation
Ludwig-Maximilians Universitat Munchen
Men's Associates of Hebrew SeniorLife
Ministry for Health, Welfare and Sports (The Netherlands)
Municipal Health Care Center and Hospital in Jakobstad
Municipality of Rotterdam
Narpes Health Care Foundation
National Institute for Health Research (UK)
Ollqvist Foundation
Robert Dawson Evans Endowment
Royal Society (UK)
Scottish Executive Health Department
State of Bavaria
Stroke Association (UK)
Swedish Strategic Foundation
Uppsala University
Althingi (the Icelandic Parliament)
Biocentrum Helsinki Foundation
Cancer Research UK
Centre Hospitalier Universitaire Vaudois (Lausanne)
Finnish Foundation for Cardiovascular Research
Foundation for Life and Health in Finland
German Federal Ministry of Education and Research
Giorgi-Cavaglieri Foundation
Health Care Center in Korsholm
Health Care Center in Narpes
Hjartavernd (the Icelandic Heart Association)
Leenaards Foundation
Lundberg Foundation
Medical Research Council (UK)
Ministry of Education (Finland)
Ministry of Education, Culture and Science (The Netherlands)
Netherlands Organization for the Health Research and Development
Nordic Center of Excellence in Disease Genetics
Novo Nordisk Foundation
Paavo Nurmi Foundation
Perklen Foundation
Petrus and Augusta Hedlunds Foundation
Sahlgrenska University Hospital Foundation (ALF/LUA)
Science Funding programme (UK)
Sigrid Juselius Foundation
Swedish Cultural Foundation in Finland
Swedish Foundation for Strategic Research
Swiss Institute of Bioinformatics
Torsten and Ragnar Soderberg's Foundation
United Kingdom NIHR Cambridge Biomedical Research Centre
University of Lausanne
014-93-015Research Institute for Diseases in the Elderly
01AK803A-HGerman Bundesministerium fur Forschung und Technology
01IG07015GGerman Bundesministerium fur Forschung und Technology
050-060-810Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging
10404Academy of Finland
124243Academy of Finland
2006-3832Swedish Research Council
10SDG269004American Heart Association
129494Academy of Finland
129680Academy of Finland
141005Academy of Finland
3100AO-116323/1Swiss National Science Foundation
33CSCO-122661Swiss National Science Foundation
175.010.2005.011Netherlands Organisation for Scientific Research
196-1962766-2747Croatian Ministry of Science, Education and Sport
911-03-012Netherlands Organisation for Scientific Research
A305:188Sahlgrenska Center for Cardiovascular and Metabolic Research
213506Academy of Finland
216-1080315-0302Croatian Ministry of Science, Education and Sport
309-0061194-2023Croatian Ministry of Science, Education and Sport
310000-112552Swiss National Science Foundation
FP7/2007-2013European Commission
FP7-KBBE-2010-4-266408European Commission
HEALTH-F4-2007-201413European Commission
HEALTH-F4-2007-201550European Commission
HS06516Agency for Health Care Policy Research
LSHG-CT-2006-018947European Commission
LSHM-CT-2003-503041European Commission
G20234Biotechnology and Biological Sciences Research Council
HEALTH-F2-2007-201681European Commission
HEALTH-F2-2008-201865-GEFOSEuropean Commission
NGFNPlus: 01GS0823German National Genome Research Network
K2010-52X-20229-05-3Swedish Research Council
K2010-54X-09894-19-3Swedish Research Council
LSHG-CT-2006-01947European Commission
LSHM-CT-2004-512013European Commission
M01 RR 16500University of Maryland General Clinical Research Center
NGFN-2German National Genome Research Network
RIDE2Research Institute for Diseases in the Elderly
PG/07/133/24260British Heart Foundation
SAF-2009Ministerio de Ciencia e Innovacion (Spain)
QLG1-CT-2001-01252European Commission
QLG2-CT-2002-01254European Commission
RG/08/008British Heart Foundation
SAF-2008-02073Ministerio de Ciencia e Innovacion (Spain)
SP/04/002British Heart Foundation
SP/07/007/23671British Heart Foundation