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

Tuomas Oskari 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; Osten 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; André G Uitterlinden; Cornelia M van Duijn; Antonio Vidal-Puig; Sarah H Wild; Alan F Wright; Deborah J Clegg; Eric Schadt; James 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 Oskari 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, Osten 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, André G Uitterlinden, Cornelia M van Duijn, Antonio Vidal-Puig, Sarah H Wild, Alan F Wright, Deborah J Clegg, Eric Schadt, James 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

215 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	43
Udgave nummer	8
Sider (fra-til)	753-60
Antal sider	8
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.866
Status	Udgivet - aug. 2011

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Oskari Kilpeläinen, T., Zillikens, M. C., Stančákova, A., Finucane, F. M., Ried, J. S., Langenberg, C., Zhang, W., Beckmann, J. S., Luan, J., 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), 753-60. https://doi.org/10.1038/ng.866

Oskari Kilpeläinen, T, Zillikens, MC, Stančákova, A, Finucane, FM, Ried, JS, Langenberg, C, Zhang, W, Beckmann, JS, Luan, J, Vandenput, L, Styrkarsdottir, U, Zhou, Y, Smith, AV, Zhao, J-H, Amin, N, Vedantam, S, Shin, S-Y, 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, K-T, Kim, LJ, Kivimäki, M, Klopp, N, Kühnel, B, Kuusisto, J, Liu, Y, Ljunggren, O, 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, A-C, Talmud, PJ, Thorleifsson, G, Thorsteinsdottir, U, Uitterlinden, AG, van Duijn, CM, Vidal-Puig, A, Wild, SH, Wright, AF, Clegg, DJ, Schadt, E, Wilson, J, Rudan, I, Ripatti, S, Borecki, IB, Shuldiner, AR, Ingelsson, E, Jansson, J-O, 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, H-E, 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, bind 43, nr. 8, s. 753-60. https://doi.org/10.1038/ng.866

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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.",

keywords = "Adiponectin, Adiposity, Alleles, Body Fat Distribution, Body Mass Index, Body Weight, Female, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Male, Meta-Analysis as Topic, Metabolome, Obesity, Polymorphism, Single Nucleotide, Subcutaneous Fat",

author = "{Oskari Kilpel{\"a}inen}, Tuomas 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 Jing-Hua Zhao and Najaf Amin and Sailaja Vedantam and So-Youn Shin 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 Kay-Tee Khaw and Kim, {Lauren J} and Mika Kivim{\"a}ki and Norman Klopp and Brigitte K{\"u}hnel and Johanna Kuusisto and Yongmei Liu and Osten 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 Ann-Christine Syv{\"a}nen and Talmud, {Philippa J} and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Uitterlinden, {Andr{\'e} 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 James Wilson and Igor Rudan and Samuli Ripatti and Borecki, {Ingrid B} and Shuldiner, {Alan R} and Erik Ingelsson and John-Olov Jansson 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 H-Erich Wichmann 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--60",

journal = "Nature: New biology",

issn = "1061-4036",

publisher = "nature publishing group",

number = "8",

}

TY - JOUR

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

AU - Oskari Kilpeläinen, Tuomas

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, Osten

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, André 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

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.

KW - Adiponectin

KW - Adiposity

KW - Alleles

KW - Body Fat Distribution

KW - Body Mass Index

KW - Body Weight

KW - Female

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Insulin Receptor Substrate Proteins

KW - Intracellular Signaling Peptides and Proteins

KW - Male

KW - Meta-Analysis as Topic

KW - Metabolome

KW - Obesity

KW - Polymorphism, Single Nucleotide

KW - Subcutaneous Fat

U2 - 10.1038/ng.866

DO - 10.1038/ng.866

M3 - Journal article

C2 - 21706003

SN - 1061-4036

VL - 43

SP - 753

EP - 760

JO - Nature: New biology

JF - Nature: New biology

IS - 8

ER -

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

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