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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Lookup NU author(s): Professor Mark Walker

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Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P < 10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P < 5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

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Author(s): Kilpelainen TO, Carli JFM, Skowronski AA, Sun Q, Kriebel J, Feitosa MF, Hedman AK, Drong AW, Hayes JE, Zhao JH, Pers TH, Schick U, Grarup N, Kutalik Z, Trompet S, Mangino M, Kristiansson K, Beekman M, Lyytikainen LP, Eriksson J, Henneman P, Lahti J, Tanaka T, Luan JA, Del Greco F, Pasko D, Renstrom F, Willems SM, Mahajan A, Rose LM, Guo XQ, Liu YM, Kleber ME, Perusse L, Gaunt T, Ahluwalia TS, Sung YJ, Ramos YF, Amin N, Amuzu A, Barroso I, Bellis C, Blangero J, Buckley BM, Bohringer S, Chen YDI, de Craen AJN, Crosslin DR, Dale CE, Dastani Z, Day FR, Deelen J, Delgado GE, Demirkan A, Finucane FM, Ford I, Garcia ME, Gieger C, Gustafsson S, Hallmans G, Hankinson SE, Havulinna AS, Herder C, Hernandez D, Hicks AA, Hunter DJ, Illig T, Ingelsson E, Ioan-Facsinay A, Jansson JO, Jenny NS, Jorgensen ME, Jorgensen T, Karlsson M, Koenig W, Kraft P, Kwekkeboom J, Laatikainen T, Ladwig KH, LeDuc CA, Lowe G, Lu YC, Marques-Vidal P, Meisinger C, Menni C, Morris AP, Myers RH, Mannisto S, Nalls MA, Paternoster L, Peters A, Pradhan AD, Rankinen T, Rasmussen-Torvik LJ, Rathmann W, Rice TK, Richards JB, Ridker PM, Sattar N, Savage DB, Soderberg S, Timpson NJ, Vandenput L, van Heemst D, Uh HW, Vohl MC, Walker M, Wichmann HE, Widen E, Wood AR, Yao J, Zeller T, Zhang YY, Meulenbelt I, Kloppenburg M, Astrup A, Sorensen TIA, Sarzynski MA, Rao DC, Jousilahti P, Vartiainen E, Hofman A, Rivadeneira F, Uitterlinden AG, Kajantie E, Osmond C, Palotie A, Eriksson JG, Heliovaara M, Knekt PB, Koskinen S, Jula A, Perola M, Huupponen RK, Viikari JS, Kahonen M, Lehtimaki T, Raitakari OT, Mellstrom D, Lorentzon M, Casas JP, Bandinelli S, Marz W, Isaacs A, van Dijk KW, van Duijn CM, Harris TB, Bouchard C, Allison MA, Chasman DI, Ohlsson C, Lind L, Scott RA, Langenberg C, Wareham NJ, Ferrucci L, Frayling TM, Pramstaller PP, Borecki IB, Waterworth DM, Bergmann S, Waeber G, Vollenweider P, Vestergaard H, Hansen T, Pedersen O, Hu FB, Slagboom PE, Grallert H, Spector TD, Jukema JW, Klein RJ, Schadt EE, Franks PW, Lindgren CM, Leibel RL, Loos RJF

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2016

Volume: 7

Print publication date: 01/02/2016

Online publication date: 01/02/2016

Acceptance date: 16/12/2015

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ncomms10494

DOI: 10.1038/ncomms10494

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