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

Authors:
Dr Anubha Mahajan, PhD
Dr Anubha Mahajan, PhD
Wellcome Trust Centre for Human Genetics, University of Oxford
UK
Tuomas O Kilpeläinen Jayne F Martin Carli Alicja A Skowronski Qi Sun Jennifer Kriebel Mary F Feitosa Åsa K Hedman Alexander W Drong James E Hayes Jinghua Zhao Tune H Pers Ursula Schick Niels Grarup Zoltán Kutalik Stella Trompet Massimo Mangino Kati Kristiansson Marian Beekman Leo-Pekka Lyytikäinen Joel Eriksson Peter Henneman Jari Lahti Toshiko Tanaka Jian'an Luan Fabiola Del Greco M Dorota Pasko Frida Renström Sara M Willems Lynda M Rose Xiuqing Guo Yongmei Liu Marcus E Kleber Louis Pérusse Tom Gaunt Tarunveer S Ahluwalia Yun Ju Sung Yolande F Ramos Najaf Amin Antoinette Amuzu Inês Barroso Claire Bellis John Blangero Brendan M Buckley Stefan Böhringer Yii-Der I Chen Anton J N de Craen David R Crosslin Caroline E Dale Zari Dastani Felix R Day Joris Deelen Graciela E Delgado Ayse Demirkan Francis M Finucane Ian Ford Melissa E Garcia Christian Gieger Stefan Gustafsson Göran Hallmans Susan E Hankinson Aki S Havulinna Christian Herder Dena Hernandez Andrew A Hicks David J Hunter Thomas Illig Erik Ingelsson Andreea Ioan-Facsinay John-Olov Jansson Nancy S Jenny Marit E Jørgensen Torben Jørgensen Magnus Karlsson Wolfgang Koenig Peter Kraft Joanneke Kwekkeboom Tiina Laatikainen Karl-Heinz Ladwig Charles A LeDuc Gordon Lowe Yingchang Lu Pedro Marques-Vidal Christa Meisinger Cristina Menni Andrew P Morris Richard H Myers Satu Männistö Mike A Nalls Lavinia Paternoster Annette Peters Aruna D Pradhan Tuomo Rankinen Laura J Rasmussen-Torvik Wolfgang Rathmann Treva K Rice J Brent Richards Paul M Ridker Naveed Sattar David B Savage Stefan Söderberg Nicholas J Timpson Liesbeth Vandenput Diana van Heemst Hae-Won Uh Marie-Claude Vohl Mark Walker Heinz-Erich Wichmann Elisabeth Widén Andrew R Wood Jie Yao Tanja Zeller Yiying Zhang Ingrid Meulenbelt Margreet Kloppenburg Arne Astrup Thorkild I A Sørensen Mark A Sarzynski D C Rao Pekka Jousilahti Erkki Vartiainen Albert Hofman Fernando Rivadeneira André G Uitterlinden Eero Kajantie Clive Osmond Aarno Palotie Johan G Eriksson Markku Heliövaara Paul B Knekt Seppo Koskinen Antti Jula Markus Perola Risto K Huupponen Jorma S Viikari Mika Kähönen Terho Lehtimäki Olli T Raitakari Dan Mellström Mattias Lorentzon Juan P Casas Stefanie Bandinelli Winfried März Aaron Isaacs Ko W van Dijk Cornelia M van Duijn Tamara B Harris Claude Bouchard Matthew A Allison Daniel I Chasman Claes Ohlsson Lars Lind Robert A Scott Claudia Langenberg Nicholas J Wareham Luigi Ferrucci Timothy M Frayling Peter P Pramstaller Ingrid B Borecki Dawn M Waterworth Sven Bergmann Gérard Waeber Peter Vollenweider Henrik Vestergaard Torben Hansen Oluf Pedersen Frank B Hu P Eline Slagboom Harald Grallert Tim D Spector J W Jukema Robert J Klein Erik E Schadt Paul W Franks Cecilia M Lindgren Rudolph L Leibel Ruth J F Loos

Nat Commun 2016 Feb 1;7:10494. Epub 2016 Feb 1.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.

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 × 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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http://dx.doi.org/10.1038/ncomms10494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740377PMC
February 2016
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References

(Supplied by CrossRef)
Article in Nature
RS Ahima et al.
Nature 1996
Article in Nature
CT Montague et al.
Nature 1997
Article in PLoS ONE
NR Shah et al.
PLoS ONE 2012
Article in N. Engl. J. Med.
RV Considine et al.
N. Engl. J. Med. 1996
Article in Clin. Endocrinol. (Oxf.)
J Liu et al.
Clin. Endocrinol. (Oxf.) 2010
Article in J. Hypertens.
K Narkiewicz et al.
J. Hypertens. 1999
Article in Obes. Res.
T Rice et al.
Obes. Res. 2002
Article in N. Engl. J. Med.
IS Farooqi et al.
N. Engl. J. Med. 1999
Article in J. Clin. Invest.
IS Farooqi et al.
J. Clin. Invest. 2002
Article in Nat. Genet.
A Strobel et al.
Nat. Genet. 1998
Article in Nature
IS Farooqi et al.
Nature 2001

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