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