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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Kilpeläinen, TO; Zillikens, MC; StanĨákova, 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, JF; 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

Published Date

  • June 26, 2011

Published In

Volume / Issue

  • 43 / 8

Start / End Page

  • 753 - 760

PubMed ID

  • 21706003

Pubmed Central ID

  • PMC3262230

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.866


  • eng

Conference Location

  • United States