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 journalArticle

192 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 languageEnglish (US)
Pages (from-to)753-760
Number of pages8
JournalNature Genetics
Volume43
Issue number8
DOIs
StatePublished - Aug 1 2011

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Metabolome
Adiposity
Adipose Tissue
Insulin Resistance
Genome-Wide Association Study
Subcutaneous Fat
Adiponectin
Dyslipidemias
Adipocytes
Single Nucleotide Polymorphism
Coronary Artery Disease
Body Mass Index
Fats
Alleles
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Kilpeläinen, T. O., Zillikens, M. C., Stančákova, A., Finucane, F. M., Ried, J. S., Langenberg, C., ... 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

Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. / Kilpeläinen, Tuomas O.; Zillikens, M. Carola; Stančákova, Alena; Finucane, Francis M.; Ried, Janina S.; Langenberg, Claudia; Zhang, Weihua; Beckmann, Jacques S.; Luan, Jian'An; Vandenput, Liesbeth; Styrkarsdottir, Unnur; Zhou, Yanhua; Smith, Albert Vernon; Zhao, Jing Hua; Amin, Najaf; Vedantam, Sailaja; Shin, So Youn; Haritunians, Talin; Fu, Mao; Feitosa, Mary F.; Kumari, Meena; Halldorsson, Bjarni V.; Tikkanen, Emmi; Mangino, Massimo; Hayward, Caroline; Song, Ci; Arnold, Alice M.; Aulchenko, Yurii S.; Oostra, Ben A.; Campbell, Harry; Cupples, L. Adrienne; Davis, Kathryn E.; Döring, Angela; Eiriksdottir, Gudny; Estrada, Karol; Fernández-Real, José Manuel; Garcia, Melissa; Gieger, Christian; Glazer, Nicole L.; Guiducci, Candace; Hofman, Albert; Humphries, Steve E.; Isomaa, Bo; Jacobs, Leonie C.; Jula, Antti; Karasik, David; Karlsson, Magnus K.; Khaw, Kay Tee; Kim, Lauren J.; Kivimäki, Mika; Klopp, Norman; Kühnel, Brigitte; Kuusisto, Johanna; Liu, Yongmei; Ljunggren, Östen; Lorentzon, Mattias; Luben, Robert N.; McKnight, Barbara; Mellström, Dan; Mitchell, Braxton D.; Mooser, Vincent; Moreno, José Maria; Männistö, Satu; O'Connell, Jeffery R.; Pascoe, Laura; Peltonen, Leena; Peral, Belén; Perola, Markus; Psaty, Bruce M.; Salomaa, Veikko; Savage, David B.; Semple, Robert K.; Skaric-Juric, Tatjana; Sigurdsson, Gunnar; Song, Kijoung S.; Spector, Timothy D.; Syvänen, Ann Christine; Talmud, Philippa J.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Uitterlinden, Andrá G.; Van Duijn, Cornelia M.; Vidal-Puig, Antonio; Wild, Sarah H.; Wright, Alan F.; Clegg, Deborah J.; Schadt, Eric; Wilson, James F.; Rudan, Igor; Ripatti, Samuli; Borecki, Ingrid B.; Shuldiner, Alan R.; Ingelsson, Erik; Jansson, John Olov; Kaplan, Robert C.; Gudnason, Vilmundur; Harris, Tamara B.; Groop, Leif; Kiel, Douglas P.; Rivadeneira, Fernando; Walker, Mark; Barroso, Inês; Vollenweider, Peter; Waeber, Gérard; Chambers, John C.; Kooner, Jaspal S.; Soranzo, Nicole; Hirschhorn, Joel N.; Stefansson, Kari; Wichmann, H. Erich; Ohlsson, Claes; O'Rahilly, Stephen; Wareham, Nicholas J.; Speliotes, Elizabeth K.; Fox, Caroline S.; Laakso, Markku; Loos, Ruth J.F.

In: Nature Genetics, Vol. 43, No. 8, 01.08.2011, p. 753-760.

Research output: Contribution to journalArticle

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
Kilpeläinen TO, Zillikens MC, Stančákova A, Finucane FM, Ried JS, Langenberg C et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nature Genetics. 2011 Aug 1;43(8):753-760. https://doi.org/10.1038/ng.866
Kilpeläinen, Tuomas O. ; Zillikens, M. Carola ; Stančákova, Alena ; Finucane, Francis M. ; Ried, Janina S. ; Langenberg, Claudia ; Zhang, Weihua ; Beckmann, Jacques S. ; Luan, Jian'An ; Vandenput, Liesbeth ; Styrkarsdottir, Unnur ; Zhou, Yanhua ; Smith, Albert Vernon ; Zhao, Jing Hua ; Amin, Najaf ; Vedantam, Sailaja ; Shin, So Youn ; Haritunians, Talin ; Fu, Mao ; Feitosa, Mary F. ; Kumari, Meena ; Halldorsson, Bjarni V. ; Tikkanen, Emmi ; Mangino, Massimo ; Hayward, Caroline ; Song, Ci ; Arnold, Alice M. ; Aulchenko, Yurii S. ; Oostra, Ben A. ; Campbell, Harry ; Cupples, L. Adrienne ; Davis, Kathryn E. ; Döring, Angela ; Eiriksdottir, Gudny ; Estrada, Karol ; Fernández-Real, José Manuel ; Garcia, Melissa ; Gieger, Christian ; Glazer, Nicole L. ; Guiducci, Candace ; Hofman, Albert ; Humphries, Steve E. ; Isomaa, Bo ; Jacobs, Leonie C. ; Jula, Antti ; Karasik, David ; Karlsson, Magnus K. ; Khaw, Kay Tee ; Kim, Lauren J. ; Kivimäki, Mika ; Klopp, Norman ; Kühnel, Brigitte ; Kuusisto, Johanna ; Liu, Yongmei ; Ljunggren, Östen ; Lorentzon, Mattias ; Luben, Robert N. ; McKnight, Barbara ; Mellström, Dan ; Mitchell, Braxton D. ; Mooser, Vincent ; Moreno, José Maria ; Männistö, Satu ; O'Connell, Jeffery R. ; Pascoe, Laura ; Peltonen, Leena ; Peral, Belén ; Perola, Markus ; Psaty, Bruce M. ; Salomaa, Veikko ; Savage, David B. ; Semple, Robert K. ; Skaric-Juric, Tatjana ; Sigurdsson, Gunnar ; Song, Kijoung S. ; Spector, Timothy D. ; Syvänen, Ann Christine ; Talmud, Philippa J. ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnur ; Uitterlinden, Andrá G. ; Van Duijn, Cornelia M. ; Vidal-Puig, Antonio ; Wild, Sarah H. ; Wright, Alan F. ; Clegg, Deborah J. ; Schadt, Eric ; Wilson, James F. ; Rudan, Igor ; Ripatti, Samuli ; Borecki, Ingrid B. ; Shuldiner, Alan R. ; Ingelsson, Erik ; Jansson, John Olov ; Kaplan, Robert C. ; Gudnason, Vilmundur ; Harris, Tamara B. ; Groop, Leif ; Kiel, Douglas P. ; Rivadeneira, Fernando ; Walker, Mark ; Barroso, Inês ; Vollenweider, Peter ; Waeber, Gérard ; Chambers, John C. ; Kooner, Jaspal S. ; Soranzo, Nicole ; Hirschhorn, Joel N. ; Stefansson, Kari ; Wichmann, H. Erich ; Ohlsson, Claes ; O'Rahilly, Stephen ; Wareham, Nicholas J. ; Speliotes, Elizabeth K. ; Fox, Caroline S. ; Laakso, Markku ; Loos, Ruth J.F. / Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. In: Nature Genetics. 2011 ; Vol. 43, No. 8. pp. 753-760.
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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.",
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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 - 2011/8/1

Y1 - 2011/8/1

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.

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