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

Lookup NU author(s): Professor Mark Walker

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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 upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 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 similar to 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 systemin 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.


Publication metadata

Author(s): Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Felix R, Powell C, Vedantam S, Buchkovich ML, Yang J, Croteau-Chonka DC, Esko T, Fall T, Ferreira T, Gustafsson S, Kutalik Z, Luan JA, Magi R, Randall JC, Winkler TW, Wood AR, Workalemahu T, Faul JD, Smith JA, Zhao JH, Zhao W, Chen J, Fehrmann R, Hedman AK, Karjalainen J, Schmidt EM, Absher D, Amin N, Anderson D, Beekman M, Bolton JL, Bragg-Gresham L, Buyske S, Demirkan A, Deng GH, 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, Stancakova A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Settee J, Van Vliet-Ostaptchouk JV, Wang ZM, Yengo L, Zhang WH, Isaacs A, Albrecht E, Arnlov J, Arscott GM, Attwood AP, Bandinelli S, Barrett A, Bas IN, Bellis C, Bennett AJ, Berne C, Blagieva R, Bluher M, Bohringer S, Bonnycastle LL, Bottcher Y, Boyd HA, Bruinenberg M, Caspersen IH, Chen YD, 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, Grassler J, Gronberg 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 A, Jolley J, Juliusdottir T, Kinnunen L, Koenig W, Koskenvuo M, Kratzer W, Laitinen J, Lamina C, Leander K, Lee NR, Lichtner P, Lind L, Lindstrom J, Lo KS, Lobbens S, Lorbeer R, Lu YC, 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, Muller G, Muller-Nurasyid M, Musk AW, Nagaraja R, Nothen 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 JX, Smith AV, Smolonska J, Stanton AV, Steinthorsdottir V, Stirrups K, Stringham HM, Sundstrom J, Swertz MA, Swift AJ, Syvanen 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, Wrightl AF, Zhang QY, Brennan EP, Choi M, Dastani Z, Drong AW, Eriksson P, Franco-Cereceda A, Gadin JR, Gharavi AG, Goddard ME, Handsaker RE, Huang JY, Karpe F, Kathiresan S, Keildson S, Kiryluk K, Kubo M, Lee JY, Liang L, Lifton RP, Ma BS, 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, Bakker SJL, Beilby J, Bergman RN, Blangero J, Bovet P, Campbell H, Caulfield MJ, Cesana G, Chakravarti A, Chasman DI, Chines PS, Collins FS, Crawford DC, Cupples LA, Cusi D, Danesh J, de Faire U, den Ruijter HM, Dominiczak AF, Erbel R, Erdmann J, Eriksson JG, Farrall M, Felix SB, Ferrannini E, Ferrieres J, Ford I, Forouhi NG, Forrester T, Franco OH, Gansevoort RT, Gejman PV, Gieger C, Gottesman O, Gudnason V, Gyllensten U, Hall AS, Harris TB, Hattersley AT, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Homuth G, Hovingh GK, Humphries SE, Hunt SC, Hypponen E, Illig T, Jacobs KB, Jarvelin MR, Jockel KH, Johansen B, Jousilahti P, Jukema JW, Jula AM, Kaprio J, Kastelein JJP, Keinanen-Kiukaanniemi SM, Kiemeney LA, Knekt P, Kooner JS, Kooperberg C, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Le Marchand L, Lehtimaki T, Lyssenko V, Mannisto S, Marette A, Matise TC, McKenzie CA, McKnight B, Moll FL, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Madden PAF, Pasterkamp G, Peden JF, Peters A, Postma DS, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ridker PM, Rioux JD, Ritchie MD, Rudan I, Salomaa V, Samani NJ, Saramines J, Sarzynski MA, Schunkert H, Schwarz PEH, Sever P, Shuldiner AR, Sinisalo J, Stolk RP, Strauch K, Tonjes A, Tregouet DA, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Volker U, Waeber G, Willemsen G, Witteman JC, Zillikens MC, Adair LS, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bornstein SR, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PIW, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hui JN, Hunter DJ, Hveem K, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu YM, Martin NG, Marz W, Melbve M, Metspalu A, Moebus S, Munroe PB, Njolstad I, Oostra BA, Palmer CNA, Pedersen NL, Perola M, Perusse L, Peters U, Power C, Quertermous T, Rauramaa R, Rivadeneira F, Saaristo TE, Saleheen D, Sattar N, Schadt EE, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Thorsteinsdottir UR, Stumvoll M, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Weir DR, Wichmann HE, Wilson JF, Zanen P, Borecki IB, Deloukas P, Fox CS, Heid IM, O'Connell JR, Strachan DP, Stefansson K, van Duijri CM, Abecasis GR, Franke L, Frayling TM, McCarthy MI, Visscher PM, Scherag A, Willer CJ, Boehnke M, Mohlke KL, Lindgren CM, Beckmann JS, Barroso I, North KE, Ingelsson E, Hirschhorn JN, Loos RJF, Speliotes EK, LifeLines Cohort Study, ADIPOGen Consortium, AGEN-BMI Working Grp, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GLGC, ICBP, MAGIC Investigators, MuTHER Consortium, MIGen Consortium, PAGE Consortium, ReproGen Consortium, GENIE Consortium, Int Endogene Consortium

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2015

Volume: 518

Issue: 7538

Pages: 197-206

Print publication date: 12/02/2015

Online publication date: 11/02/2015

Acceptance date: 23/12/2014

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nature14177

DOI: 10.1038/nature14177


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Funding

Funder referenceFunder name
084766Wellcome Trust
097117Wellcome Trust
098381Wellcome Trust
085235Wellcome Trust
098017Wellcome Trust
100574Wellcome Trust
14136Cancer Research UK
CZB/4/672Chief Scientist Office
CZB/4/710Chief Scientist Office
G1000143Medical Research Council
G0601261Medical Research Council
K01 HL116770NHLBI NIH HHS
G1001799Medical Research Council
G9521010Medical Research Council
MC_U106179472Medical Research Council
MC_UU_12012/1Medical Research Council
MC_UU_12013/1Medical Research Council
MR/K006584/1Medical Research Council
MR/K013351/1Medical Research Council
MR/L003120/1Medical Research Council
K23 DK080145NIDDK NIH HHS
P20 MD006899NIMHD NIH HHS
P30 DK020541NIDDK NIH HHS
P30 DK020572NIDDK NIH HHS
P30 DK063491NIDDK NIH HHS
P30 DK072488NIDDK NIH HHS
P30 HL107251NHLBI NIH HHS
MC_PC_U127561128Medical Research Council
MC_U106179471Medical Research Council
MC_UP_A100_1003Medical Research Council
MC_UU_12015/1Medical Research Council
MC_UU_12015/2Medical Research Council
MC_UU_12015/5Medical Research Council
MC_UU_12019/1Medical Research Council
R01 AG025941NIA NIH HHS
R01 AG033193NIA NIH HHS
R01 AG041517NIA NIH HHS
R01 DK078150NIDDK NIH HHS
R01 NS017950NINDS NIH HHS
R21 DA027040NIDA NIH HHS
P30 GM103341NIGMS NIH HHS
P60 DK020541NIDDK NIH HHS
RG/10/12/28456British Heart Foundation
T32 GM080178NIGMS NIH HHS
T32 HL007055NHLBI NIH HHS
TL1 TR001066NCATS NIH HHS
R01 DK062370NIDDK NIH HHS
R01 DK072193NIDDK NIH HHS
R01 DK075787NIDDK NIH HHS
R01 DK089256NIDDK NIH HHS
R01 DK093757NIDDK NIH HHS
U01 AG049505NIA NIH HHS
U01 HG007376NHGRI NIH HHS
U01 HG007416NHGRI NIH HHS
UL1 TR000124NCATS NIH HHS
R01 HL109946NHLBI NIH HHS
R01 HL117078NHLBI NIH HHS
R01 HL117626NHLBI NIH HHS
UM1 CA182910NCI NIH HHS
UM1 CA182913NCI NIH HHS
RG/08/014/24067British Heart Foundation
T32 HL007824NHLBI NIH HHS
U01 AG009740NIA NIH HHS
U01 DK062370NIDDK NIH HHS
U01 HG007419NHGRI NIH HHS
UL1 TR001067NCATS NIH HHS

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