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

Summary, in English

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: Tuomas O. Kilpelainen; M. Carola Zillikens; Alena Stancakova; 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 Doering; Gudny Eiriksdottir; Karol Estrada; Jose Manuel Fernandez-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 Kivimaeki; Norman Klopp; Brigitte Kuehnel; Johanna Kuusisto; Yongmei Liu; Osten Ljunggren; Mattias Lorentzon; Robert N. Luben; Barbara McKnight; Dan Mellstrom; Braxton D. Mitchell; Vincent Mooser; Jose Maria Moreno; Satu Mannisto; Jeffery R. O'Connell; Laura Pascoe; Leena Peltonen; Belen 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 Syvanen; Philippa J. Talmud; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Andre 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; Ines Barroso; Peter Vollenweider; Gerard 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
• Department/s: EXODIAB: Excellence of Diabetes Research in Sweden; Department of Clinical Sciences, Malmö; Translational Muscle Research
• Publishing year: 2011
• Language: English
• Pages: 58-753
• Publication/Series: Nature Genetics
• Volume: 43
• Issue: 8
• Links: http://dx.doi.org/10.1038/ng.866
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Endocrinology and Diabetes
• Status: Published
• Research group: Genomics, Diabetes and Endocrinology
• ISBN/ISSN/Other: ISSN: 1546-1718