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

University of Cambridge Wellcome Trust - MRC Institute of Metabolic Science
Erasmus MC
Netherlands Genomics Initiative
Kuopio University Hospital
German Research Center for Environmental Health
Imperial College London
University Hospital Center
Gothenburg University
deCODE genetics
Boston University School of Public Health
Icelandic Heart Association
Broad Institute
Boston Children's Hospital
Wellcome Trust Genome Campus
Cedars-Sinai Medical Center
University of Maryland School of Medicine
Washington University School of Medicine in St. Louis
University College London
Reykjavik University
University of Helsinki
Finnish Institute for Health and Welfare - THL
King's College London
MRC Human Genetics Unit
Karolinska Institutet
University of Washington
University of Edinburgh
Framingham Heart Study
University of Texas Southwestern Medical Center
Instituto de Salud Carlos III
National Institute on Aging (NIA)
University of Washington School of Medicine
Folkhälsan
Harvard Medical School
Lund University
Skane University Hospital
Cambridge Institute of Public Health
Wake Forest University School of Medicine
Uppsala University
GlaxoSmithKline, USA
and Newcastle University Institute for Ageing
Universidad Autónoma de Madrid
Group Health Cooperative
University of Cambridge
Institute for Anthropological Research
Landspitali - The National University Hospital of Iceland
University of Iceland
Leiden University
Pacific Biosciences
Sage Bionetworks
School of Medicine, University of Split
Gen Info Ltd.
Baltimore VA Medical Center
Uppsala University
Albert Einstein College of Medicine
Lund University Diabetes Centre
National Heart and Lung Institute
Ludwig-Maximilians-University
Massachusetts General Hospital

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

291 Citations (Scopus)

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
Publication status	Published - Aug 2011
Externally published	Yes

UN SDGs

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

SDG 3 Good Health and Well-being

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{051dcd5d3bd740828124c9d3666b59f2,

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 {\texttimes} 10-26) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 {\texttimes} 10-11) and one near SPRY2 (P = 3 {\texttimes} 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.\}",

year = "2011",

month = aug,

doi = "10.1038/ng.866",

language = "English",

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.

PY - 2011/8

Y1 - 2011/8

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 - 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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this