Genetic studies of body mass index yield new insights for obesity biology.

Pubmed ID: 25673413

Pubmed Central ID: PMC4382211

Journal: Nature

Publication Date: Feb. 12, 2015

Affiliation: Department of Internal Medicine, Division of Gastroenterology, and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.

MeSH Terms: Humans, Male, Female, Age Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Body Mass Index, Genome-Wide Association Study, Obesity, Europe, Adiposity, Energy Metabolism, Insulin, Adipogenesis, Glutamic Acid, Quantitative Trait Loci, Synapses, Insulin Secretion, Racial Groups

Grants: G0401527, RG/08/008/25291, RG/08/014/24067, MR/K013351/1, G1000143, MC_U106179472, P30 DK072488, MC_U106179471, MC_UU_12015/1, UL1 TR000124, P20 MD006899, MR/L003120/1, P30 DK063491, R01 AG033193, U01 AG049505, R01 NS017950, R01 HL105756, P30 AG010129, UM1 CA182913, R01 HL117078, T32 HL007055, CZB/4/710, MC_PC_U127561128, R01 DK089256, MC_UU_12013/1, P30 DK020572, P30 DK020541, P60 DK020541, G19/35, G0100222, G8802774, G0902037, G1000616, RG/07/008/23674, R01 DK093757, U01 HG007417, MC_UU_12012/1, G9521010, G1001799, CZB/4/672, K23 DK080145, 098017, R21 DA027040, U01 HG007419, MRC_MC_UU_12013/1, BHF_FS/14/55/30806, T32 GM007814, WT098017, MRC_G9521010, MRC_MR/K013351/1, MRC_MC_UU_12015/5, R01 HL109946, MC_UP_A100_1003, WT098381, T32 GM080178, U01 AG009740, 085235, MRC_MR/N01104X/1, U01 HG007416, MRC_MC_UU_12015/2, R01 DK072193, MC_UU_12019/1, U01 HG007376, BHF_RG/10/12/28456, U01 CA164930, R01 DK075787, MRC_MC_UP_A100_1003, R01 AG025941, R01 AG041517, R01 DK062370, MRC_G1000143, MRC_MC_UU_12019/1, MR/N01104X/1, R25 GM062459, 097117, MC_UU_12015/2, TL1 TR001066, T32 HL007824, WT084766, K01 HL116770, 14136, WT100574, CSO_CZB/4/672, CSO_CZB/4/710, MRC_MC_PC_U127561128, CRUK_14136, U01 DK062370, G0600717, P30 HL107251, MRC_MR/K006584/1, 084766, 100574, P30 GM103341, FS/14/55/30806, MRC_G0401527, MR/K006584/1, MRC_MC_UU_12015/1, MC_UU_12015/5, BHF_RG/08/014/24067, R01 HL117626, MRC_MC_U106179471, BHF_RG/08/008/25291, 098381, MRC_MR/L003120/1, WT085235, UM1 CA182910, MRC_G0601261, G0601261, P30 CA071789, WT097117, MRC_G1001799, R01 DK078150, MRC_MC_U106179472, MRC_MC_UU_12012/1, UL1 TR001067, RG/10/12/28456, P2C HD050924, MR/K002414/1, P30 DK056341, MC_UU_12013/4

Authors: Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, Croteau-Chonka DC, Esko T, Fall T, Ferreira T, Gustafsson S, Kutalik Z, Luan J, Mägi R, Randall JC, Winkler TW, Wood AR, Workalemahu T, Faul JD, Smith JA, Zhao JH, Zhao W, Chen J, Fehrmann R, Hedman ÅK, Karjalainen J, Schmidt EM, Absher D, Amin N, Anderson D, Beekman M, Bolton JL, Bragg-Gresham JL, Buyske S, Demirkan A, Deng G, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Goel A, Gong J, Jackson AU, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Mangino M, Leach IM, Medina-Gomez C, Medland SE, Nalls MA, Palmer CD, Pasko D, Pechlivanis S, Peters MJ, Prokopenko I, Shungin D, Stančáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet-Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Isaacs A, Albrecht E, Ärnlöv J, Arscott GM, Attwood AP, Bandinelli S, Barrett A, Bas IN, Bellis C, Bennett AJ, Berne C, Blagieva R, Blüher M, Böhringer S, Bonnycastle LL, Böttcher Y, Boyd HA, Bruinenberg M, Caspersen IH, Chen YI, Clarke R, Daw EW, de Craen AJM, Delgado G, Dimitriou M, Doney ASF, Eklund N, Estrada K, Eury E, Folkersen L, Fraser RM, Garcia ME, Geller F, Giedraitis V, Gigante B, Go AS, Golay A, Goodall AH, Gordon SD, Gorski M, Grabe HJ, Grallert H, Grammer TB, Gräßler J, Grönberg H, Groves CJ, Gusto G, Haessler J, Hall P, Haller T, Hallmans G, Hartman CA, Hassinen M, Hayward C, Heard-Costa NL, Helmer Q, Hengstenberg C, Holmen O, Hottenga JJ, James AL, Jeff JM, Johansson Å, Jolley J, Juliusdottir T, Kinnunen L, Koenig W, Koskenvuo M, Kratzer W, Laitinen J, Lamina C, Leander K, Lee NR, Lichtner P, Lind L, Lindström J, Lo KS, Lobbens S, Lorbeer R, Lu Y, Mach F, Magnusson PKE, Mahajan A, McArdle WL, McLachlan S, Menni C, Merger S, Mihailov E, Milani L, Moayyeri A, Monda KL, Morken MA, Mulas A, Müller G, Müller-Nurasyid M, Musk AW, Nagaraja R, Nöthen MM, Nolte IM, Pilz S, Rayner NW, Renstrom F, Rettig R, Ried JS, Ripke S, Robertson NR, Rose LM, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Scott WR, Seufferlein T, Shi J, Smith AV, Smolonska J, Stanton AV, Steinthorsdottir V, Stirrups K, Stringham HM, Sundström J, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Tayo BO, Thorand B, Thorleifsson G, Tyrer JP, Uh HW, Vandenput L, Verhulst FC, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Warren HR, Waterworth D, Weedon MN, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q, Brennan EP, Choi M, Dastani Z, Drong AW, Eriksson P, Franco-Cereceda A, Gådin JR, Gharavi AG, Goddard ME, Handsaker RE, Huang J, Karpe F, Kathiresan S, Keildson S, Kiryluk K, Kubo M, Lee JY, Liang L, Lifton RP, Ma B, McCarroll SA, McKnight AJ, Min JL, Moffatt MF, Montgomery GW, Murabito JM, Nicholson G, Nyholt DR, Okada Y, Perry JRB, Dorajoo R, Reinmaa E, Salem RM, Sandholm N, Scott RA, Stolk L, Takahashi A, Tanaka T, van 't Hooft FM, Vinkhuyzen AAE, Westra HJ, Zheng W, Zondervan KT, Heath AC, Arveiler D, 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Studies:

Abstract

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.