Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
Authors: Kilpeläinen Tuomas O. , Carli Jayne F. Martin , Skowronski Alicja A. , Sun Qi , Kriebel Jennifer , Feitosa Mary F , Hedman Åsa K. , Drong Alexander W. , Hayes James E. , Zhao Jinghua , Pers Tune H. , Schick Ursula , Grarup Niels , Kutalik Zoltán , Trompet Stella , Mangino Massimo , Kristiansson Kati , Beekman Marian , Lyytikäinen Leo-Pekka , Eriksson Joel , Henneman Peter , Lahti Jari , Tanaka Toshiko , Luan Jian’an , Greco M Fabiola Del , Pasko Dorota , Renström Frida , Willems Sara M. , Mahajan Anubha , Rose Lynda M. , Guo Xiuqing , Liu Yongmei , Kleber Marcus E. , Pérusse Louis , Gaunt Tom , Ahluwalia Tarunveer S. , Ju Sung Yun , Ramos Yolande F. , Amin Najaf , Amuzu Antoinette , Barroso Inês , Bellis Claire , Blangero John , Buckley Brendan M. , Böhringer Stefan , I Chen Yii-Der , de Craen Anton J. N. , Crosslin David R. , Dale Caroline E. , Dastani Zari , Day Felix R. , Deelen Joris , Delgado Graciela E. , Demirkan Ayse , Finucane Francis M. , Ford Ian , Garcia Melissa E. , Gieger Christian , Gustafsson Stefan , Hallmans Göran , Hankinson Susan E. , Havulinna Aki S , Herder Christian , Hernandez Dena , Hicks Andrew A. , Hunter David J. , Illig Thomas , Ingelsson Erik , Ioan-Facsinay Andreea , Jansson John-Olov , Jenny Nancy S. , Jørgensen Marit E. , Jørgensen Torben , Karlsson Magnus , Koenig Wolfgang , Kraft Peter , Kwekkeboom Joanneke , Laatikainen Tiina , Ladwig Karl-Heinz , LeDuc Charles A. , Lowe Gordon , Lu Yingchang , Marques-Vidal Pedro , Meisinger Christa , Menni Cristina , Morris Andrew P. , Myers Richard H. , Männistö Satu , Nalls Mike A. , Paternoster Lavinia , Peters Annette , Pradhan Aruna D. , Rankinen Tuomo , Rasmussen-Torvik Laura J. , Rathmann Wolfgang , Rice Treva K. , Brent Richards J , Ridker Paul M. , Sattar Naveed , Savage David B. , Söderberg Stefan , Timpson Nicholas J. , Vandenput Liesbeth , van Heemst Diana , Uh Hae-Won , Vohl Marie-Claude , Walker Mark , Wichmann Heinz-Erich , Widén Elisabeth , Wood Andrew R. , Yao Jie , Zeller Tanja , Zhang Yiying , Meulenbelt Ingrid , Kloppenburg Margreet , Astrup Arne , Sørensen Thorkild I. A. , Sarzynski Mark A. , Rao D. C. , Jousilahti Pekka , Vartiainen Erkki , Hofman Albert , Rivadeneira Fernando , Uitterlinden André G. , Kajantie Eero , Osmond Clive , Palotie Aarno , Eriksson Johan G. , Heliövaara Markku , Knekt Paul B. , Koskinen Seppo , Jula Antti , Perola Markus , Huupponen Risto K. , Viikari Jorma S. , Kähönen Mika , Lehtimäki Terho , Raitakari Olli T. , Mellström Dan , Lorentzon Mattias , Casas Juan P. , Bandinelli Stefanie , März Winfried , Isaacs Aaron , van Dijk Ko W. , van Duijn Cornelia M. , Harris Tamara B. , Bouchard Claude , Allison Matthew A. , Chasman Daniel I. , Ohlsson Claes , Lind Lars , Scott Robert A. , Langenberg Claudia , Wareham Nicholas J. , Ferrucci Luigi , Frayling Timothy M. , Pramstaller Peter P. , Borecki Ingrid B. , Waterworth Dawn M. , Bergmann Sven , Waeber Gérard , Vollenweider Peter , Vestergaard Henrik , Hansen Torben , Pedersen Oluf , Hu Frank B. , Eline Slagboom P , Grallert Harald , Spector Tim D. , Jukema J.W. , Klein Robert J. , Schadt Erik E , Franks Paul W. , Lindgren Cecilia M. , Leibel Rudolph L. , Loos Ruth J. F. 
Published: February 2016

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.