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

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

doi:10.1038/ng.866

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

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

Research output: Contribution to journal › Article › Academic › peer-review

267 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 similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

Original language	Undefined/Unknown
Pages (from-to)	753-U58
Journal	Nature Genetics
Volume	43
Issue number	8
DOIs	https://doi.org/10.1038/ng.866
Publication status	Published - 2011

Research programs

EMC MGC-02-96-01
EMC MM-01-25-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC NIHES-01-64-02

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

Access to Document

10.1038/ng.866

http://hdl.handle.net/1765/34179

Cite this

Kilpelainen, TO., Zillikens, M. C., Stancakova, A., Finucane, FM., Ried, JS., Langenberg, C., Zhang, WH., Beckmann, JS., Luan, JA., Vandenput, L., Styrkarsdottir, U., Zhou, YH., Smith, AV., Zhao, JH., Amin, N., Vedantam, S., Shin, SY., Haritunians, T., Fu, M., ... Loos, RJF. (2011). Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nature Genetics, 43(8), 753-U58. https://doi.org/10.1038/ng.866

@article{8ff6cec8e7814de780aae5aa1fc58eca,

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 similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.",

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

year = "2011",

doi = "10.1038/ng.866",

language = "Undefined/Unknown",

volume = "43",

pages = "753--U58",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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Kilpelainen, TO, Zillikens, MC, Stancakova, A, Finucane, FM, Ried, JS, Langenberg, C, Zhang, WH, Beckmann, JS, Luan, JA, Vandenput, L, Styrkarsdottir, U, Zhou, YH, Smith, AV, Zhao, JH, Amin, N, Vedantam, S, Shin, SY, Haritunians, T, Fu, M, Feitosa, MF, Kumari, M, Halldorsson, BV, Tikkanen, E, Mangino, M, Hayward, C, Song, C, Arnold, AM, Aulchenko, YS, Oostra, B, Campbell, H, Cupples, LA, Davis, KE, Doring, A, Eiriksdottir, G, Estrada Gil, K, Fernandez-Real, JM, Garcia, M, Gieger, C, Glazer, NL, Guiducci, C, Hofman, B, Humphries, SE, Isomaa, B, Jacobs, L, Jula, A, Karasik, D, Karlsson, MK, Khaw, KT, Kim, LJ, Kivimaki, M, Klopp, N, Kuhnel, B, Kuusisto, J, Liu, YM, Ljunggren, O, Lorentzon, M, Luben, RN, McKnight, B, Mellstrom, D, Mitchell, BD, Mooser, V, Moreno, JM, Mannisto, S, O'Connell, JR, Pascoe, L, Peltonen, L, Peral, B, Perola, M, Psaty, BM, Salomaa, V, Savage, DB, Semple, RK, Skaric-Juric, T, Sigurdsson, G, Song, KS, Spector, TD, Syvanen, AC, Talmud, PJ, Thorleifsson, G, Thorsteinsdottir, U, Uitterlinden, A, Duijn, C, 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-U58. https://doi.org/10.1038/ng.866

TY - JOUR

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

AU - Kilpelainen, TO

AU - Zillikens, M.C.

AU - Stancakova, A

AU - Finucane, FM

AU - Ried, JS

AU - Langenberg, C

AU - Zhang, WH

AU - Beckmann, JS

AU - Luan, JA

AU - Vandenput, L

AU - Styrkarsdottir, U

AU - Zhou, YH

AU - Smith, AV

AU - Zhao, JH

AU - Amin, Najaf

AU - Vedantam, S

AU - Shin, SY

AU - Haritunians, T

AU - Fu, M

AU - Feitosa, MF

AU - Kumari, M

AU - Halldorsson, BV

AU - Tikkanen, E

AU - Mangino, M

AU - Hayward, C

AU - Song, C

AU - Arnold, AM

AU - Aulchenko, YS

AU - Oostra, Ben

AU - Campbell, H

AU - Cupples, LA

AU - Davis, KE

AU - Doring, A

AU - Eiriksdottir, G

AU - Estrada Gil, Karol

AU - Fernandez-Real, JM

AU - Garcia, M

AU - Gieger, C

AU - Glazer, NL

AU - Guiducci, C

AU - Hofman, Bert

AU - Humphries, SE

AU - Isomaa, B

AU - Jacobs, Leonie

AU - Jula, A

AU - Karasik, D

AU - Karlsson, MK

AU - Khaw, KT

AU - Kim, LJ

AU - Kivimaki, M

AU - Klopp, N

AU - Kuhnel, B

AU - Kuusisto, J

AU - Liu, YM

AU - Ljunggren, O

AU - Lorentzon, M

AU - Luben, RN

AU - McKnight, B

AU - Mellstrom, D

AU - Mitchell, BD

AU - Mooser, V

AU - Moreno, JM

AU - Mannisto, S

AU - O'Connell, JR

AU - Pascoe, L

AU - Peltonen, L

AU - Peral, B

AU - Perola, M

AU - Psaty, BM

AU - Salomaa, V

AU - Savage, DB

AU - Semple, RK

AU - Skaric-Juric, T

AU - Sigurdsson, G

AU - Song, KS

AU - Spector, TD

AU - Syvanen, AC

AU - Talmud, PJ

AU - Thorleifsson, G

AU - Thorsteinsdottir, U

AU - Uitterlinden, André

AU - Duijn, Cornelia

AU - Vidal-Puig, A

AU - Wild, SH

AU - Wright, AF

AU - Clegg, DJ

AU - Schadt, E

AU - Wilson, JF

AU - Rudan, I

AU - Ripatti, S

AU - Borecki, IB

AU - Shuldiner, AR

AU - Ingelsson, E

AU - Jansson, JO

AU - Kaplan, RC

AU - Gudnason, V

AU - Harris, TB

AU - Groop, L

AU - Kiel, DP

AU - Rivadeneira, Fernando

AU - Walker, M

AU - Barroso, I

AU - Vollenweider, P

AU - Waeber, G

AU - Chambers, JC

AU - Kooner, JS

AU - Soranzo, N

AU - Hirschhorn, JN

AU - Stefansson, K

AU - Wichmann, HE

AU - Ohlsson, C

AU - O'Rahilly, S

AU - Wareham, NJ

AU - Speliotes, EK

AU - Fox, CS

AU - Laakso, M

AU - Loos, RJF

PY - 2011

Y1 - 2011

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 similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

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 similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

U2 - 10.1038/ng.866

DO - 10.1038/ng.866

M3 - Article

C2 - 21706003

SN - 1061-4036

VL - 43

SP - 753-U58

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -