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. Feitosa; Meena 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

doi:10.1038/ng.866

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. Feitosa

Meena 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 journal › Article › peer-review

286 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 language	English
Pages (from-to)	753-760
Number of pages	8
Journal	Nature Genetics
Volume	43
Issue number	8
DOIs	https://doi.org/10.1038/ng.866
State	Published - 26 Jun 2011
Externally published	Yes

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

Funding

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). 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

Funders	Funder number
Biocentrum Helsinki Foundation
CedarsSinai Board
Erasmus University
Finnish Diabetes Foundation
Finnish Heart Foundation
Foundation for Life and Health in Finland
German National Genome Research Network	01GS0823
GiorgiCavaglieri Foundation
Municipal Health Care Center and Hospital in Jakobstad
Municipality of Rotterdam
Ollqvist Foundation
Perklén Foundation
RIDE2
Research Institute for Diseases in the Elderly	01493015
Robert Dawson Evans Endowment
Sahlgrenska Center for Cardiovascular and Metabolic Research	A305:188
Sahlgrenska University Hospital Foundation
Scottish Executive Health Department
State of Bavaria
Swedish Strategic Foundation
University of Maryland General Clinical Research Center	M01 RR 16500
National Institutes of Health	R01AR/AG41398, R01AG18728, M01RR00425, P30DK072488, R01AR046838, N01HC35129, K23DK080145, U01HL080295, R01HL08770003, N01HC85086, N01AG62106, R01DK06833603, N01AG62101, N01HC25195, R01AG03209801A1, N01AG62103, N01HC75150, AG13196, U01HL72515, R01HL088119, N01HC15103, R01DK075787, R01AG03189001, U01HL84756, 050060810, R01HL03631020A2, N01HC55222, R01DK07568102, N01HC85079, DK063491, R01HL087652, N01HC45133
National Institute on Aging	N01AG012100
U.S. Department of Veterans Affairs
John D. and Catherine T. MacArthur Foundation
American Heart Association	10SDG269004
AstraZeneca
GlaxoSmithKline
Västra Götalandsregionen
Torsten Söderbergs Stiftelse
Agency for Health Care Policy and Research	HS06516
Finska Läkaresällskapet
Wellcome Trust	084723/Z/08/Z, 091746/Z/10/Z, 077016/Z/05/Z
Petrus och Augusta Hedlunds Stiftelse
Nash Health Care Foundation
Folkhälsanin Tutkimussäätiö
Geriatric Research Education and Clinical Center
Medical Research Council
Biotechnology and Biological Sciences Research Council	G20234
National Institute for Health and Care Research
British Heart Foundation	PG/07/133/24260, SP/04/002, RG/08/008, SP/07/007/23671
Department of Health and Social Care
Royal Society
Cancer Research UK
Food Standards Agency
Stroke Association
European Commission	QLG1CT200101252, FP7KBBE20104266408, LSHMCT2004512013, LSHMCT2003503041, FP7/20072013, QLG2CT200201254, HEALTHF22007201681, HEALTHF42007201413, LSHGCT2006018947
Health and Safety Executive
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	310000112552, 3100AO116323/1, 33CSCO-122661
Stiftelsen för Strategisk Forskning
ZonMw
Academy of Finland	10404, 141005, 124243, 213506, 129680, 129494
Bundesministerium für Bildung und Forschung
Ministry of Education
Ministerie van Volksgezondheid, Welzijn en Sport
Erasmus Medisch Centrum
Ministerie van Onderwijs, Cultuur en Wetenschap
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	175.010.2005.011, 91103012
Tekes	1510/31/06
Knut och Alice Wallenbergs Stiftelse
Lars Erik Lundbergs Stiftelse för Forskning och Utbildning
Signe ja Ane Gyllenbergin Säätiö
Vetenskapsrådet	K201054X09894193, 2006-3832, K201052X20229053
Ministerio de Ciencia e Innovación	SAF200802073, SAF2009
Bundesministerium für Forschung und Technologie	01AK803AH, 01IG07015G
Sydäntutkimussäätiö
Göteborgs Läkaresällskap
Ludwig-Maximilians-Universität München
Sigrid Juséliuksen Säätiö
Fondation Leenaards
Université de Lausanne
Centre Hospitalier Universitaire Vaudois
Ministarstvo Znanosti, Obrazovanja i Sporta	30900611942023, 21610803150302, 19619627662747
Uppsala Universitet
Svenska Kulturfonden
Paavo Nurmen Säätiö
Novo Nordisk Fonden
Emil och Wera Cornells Stiftelse
Hjartavernd
Diabetestutkimussäätiö
Centre for Medical Systems Biology
Swiss Institute of Bioinformatics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng.866

Cite this

Kilpeläinen, T. O., Zillikens, M. C., Stančákova, A., Finucane, F. M., Ried, J. S., Langenberg, C., Zhang, W., Beckmann, J. S., Luan, JA., Vandenput, L., Styrkarsdottir, U., Zhou, Y., Smith, A. V., Zhao, J. H., Amin, N., Vedantam, S., Shin, S. Y., Haritunians, T., Fu, M., ... Loos, R. J. F. (2011). Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nature Genetics, 43(8), 753-760. https://doi.org/10.1038/ng.866

@article{797577a0eb0540feb3a2810d5ba01a33,

title = "Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile",

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.",

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

note = "Funding Information: of Governors{\textquoteright} 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; Folkh{\"a}lsan Research Foundation; Food Standards Agency (UK); Foundation for Life and Health in Finland; German B{\"u}ndesministerium f{\"u}r 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; G{\"o}teborg Medical Society; Gyllenberg Foundation; Health and Safety Executive (UK); Health Care Centers in Vasa, N{\"a}rpes and Korsholm; Hjartavernd (the Icelandic Heart Association); John D. and Catherine T. MacArthur Foundation; Knut and Alice Wallenberg Foundation; Leenaards Foundation; LudwigMaximilians Universit{\"a}t M{\"u}nchen; Lundberg Foundation; Medical Research Council (UK); Men{\textquoteright}s Associates of Hebrew SeniorLife; Ministerio de Ciencia e Innovaci{\'o}n (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; N{\"a}rpes 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; Perkl{\'e}n 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 S{\"o}derberg{\textquoteright}s Foundation; United Kingdom NIHR Cambridge Biomedical Research Centre; University of Lausanne; University of Maryland General Clinical Research Center (M01 RR 16500); Uppsala University; V{\"a}stra G{\"o}taland 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",

year = "2011",

month = jun,

day = "26",

doi = "10.1038/ng.866",

language = "אנגלית",

volume = "43",

pages = "753--760",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "8",

}

Kilpeläinen, TO, Zillikens, MC, Stančákova, A, Finucane, FM, Ried, JS, Langenberg, C, Zhang, W, Beckmann, JS, Luan, JA, Vandenput, L, Styrkarsdottir, U, Zhou, Y, 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, Döring, A, Eiriksdottir, G, Estrada, K, Fernández-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, Kivimäki, M, Klopp, N, Kühnel, B, Kuusisto, J, Liu, Y, Ljunggren, Ö, Lorentzon, M, Luben, RN, McKnight, B, Mellström, D, Mitchell, BD, Mooser, V, Moreno, JM, Männistö, 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, Syvänen, 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 2011, 'Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile', Nature Genetics, vol. 43, no. 8, pp. 753-760. https://doi.org/10.1038/ng.866

TY - JOUR

T1 - Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile

AU - Kilpeläinen, Tuomas O.

AU - Zillikens, M. Carola

AU - Stančákova, Alena

AU - Finucane, Francis M.

AU - Ried, Janina S.

AU - Langenberg, Claudia

AU - Zhang, Weihua

AU - Beckmann, Jacques S.

AU - Luan, Jian'An

AU - Vandenput, Liesbeth

AU - Styrkarsdottir, Unnur

AU - Zhou, Yanhua

AU - Smith, Albert Vernon

AU - Zhao, Jing Hua

AU - Amin, Najaf

AU - Vedantam, Sailaja

AU - Shin, So Youn

AU - Haritunians, Talin

AU - Fu, Mao

AU - Feitosa, Mary F.

AU - Kumari, Meena

AU - Halldorsson, Bjarni V.

AU - Tikkanen, Emmi

AU - Mangino, Massimo

AU - Hayward, Caroline

AU - Song, Ci

AU - Arnold, Alice M.

AU - Aulchenko, Yurii S.

AU - Oostra, Ben A.

AU - Campbell, Harry

AU - Cupples, L. Adrienne

AU - Davis, Kathryn E.

AU - Döring, Angela

AU - Eiriksdottir, Gudny

AU - Estrada, Karol

AU - Fernández-Real, José Manuel

AU - Garcia, Melissa

AU - Gieger, Christian

AU - Glazer, Nicole L.

AU - Guiducci, Candace

AU - Hofman, Albert

AU - Humphries, Steve E.

AU - Isomaa, Bo

AU - Jacobs, Leonie C.

AU - Jula, Antti

AU - Karasik, David

AU - Karlsson, Magnus K.

AU - Khaw, Kay Tee

AU - Kim, Lauren J.

AU - Kivimäki, Mika

AU - Klopp, Norman

AU - Kühnel, Brigitte

AU - Kuusisto, Johanna

AU - Liu, Yongmei

AU - Ljunggren, Östen

AU - Lorentzon, Mattias

AU - Luben, Robert N.

AU - McKnight, Barbara

AU - Mellström, Dan

AU - Mitchell, Braxton D.

AU - Mooser, Vincent

AU - Moreno, José Maria

AU - Männistö, Satu

AU - O'Connell, Jeffery R.

AU - Pascoe, Laura

AU - Peltonen, Leena

AU - Peral, Belén

AU - Perola, Markus

AU - Psaty, Bruce M.

AU - Salomaa, Veikko

AU - Savage, David B.

AU - Semple, Robert K.

AU - Skaric-Juric, Tatjana

AU - Sigurdsson, Gunnar

AU - Song, Kijoung S.

AU - Spector, Timothy D.

AU - Syvänen, Ann Christine

AU - Talmud, Philippa J.

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Uitterlinden, Andrá G.

AU - Van Duijn, Cornelia M.

AU - Vidal-Puig, Antonio

AU - Wild, Sarah H.

AU - Wright, Alan F.

AU - Clegg, Deborah J.

AU - Schadt, Eric

AU - Wilson, James F.

AU - Rudan, Igor

AU - Ripatti, Samuli

AU - Borecki, Ingrid B.

AU - Shuldiner, Alan R.

AU - Ingelsson, Erik

AU - Jansson, John Olov

AU - Kaplan, Robert C.

AU - Gudnason, Vilmundur

AU - Harris, Tamara B.

AU - Groop, Leif

AU - Kiel, Douglas P.

AU - Rivadeneira, Fernando

AU - Walker, Mark

AU - Barroso, Inês

AU - Vollenweider, Peter

AU - Waeber, Gérard

AU - Chambers, John C.

AU - Kooner, Jaspal S.

AU - Soranzo, Nicole

AU - Hirschhorn, Joel N.

AU - Stefansson, Kari

AU - Wichmann, H. Erich

AU - Ohlsson, Claes

AU - O'Rahilly, Stephen

AU - Wareham, Nicholas J.

AU - Speliotes, Elizabeth K.

AU - Fox, Caroline S.

AU - Laakso, Markku

AU - Loos, Ruth J.F.

N1 - 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

PY - 2011/6/26

Y1 - 2011/6/26

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/79960895140

U2 - 10.1038/ng.866

DO - 10.1038/ng.866

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 21706003

AN - SCOPUS:79960895140

SN - 1061-4036

VL - 43

SP - 753

EP - 760

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

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