Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile by Kilpeläinen Tuomas O, Zillikens M Carola, Stan¿ákova 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 Osten, 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 André 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 (2011). PubMed

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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