Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
Creators: Kilpelainen, Tuomas O.
Martin-Carli, Jayne Frances
Skowronski, Alicja Anna
Sun, Qi
Kriebel, Jennifer
Feitosa, Mary F.
Hedman, Asa 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
Del Greco M, Fabiola
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.
Sung, Yun Ju
Ramos, Yolande F.
Amin, Najaf
Amuzu, Antoinette
Barroso, Inês
Bellis, Claire
Blangero, John
Buckley, Brendan M.
Böhringer, Stefan
Chen, Yii-Der I.
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.
Richards, J. Brent
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
Publisher: name: Columbia University
Year: 2016
Subjects: subject: Meta-analysis
subject: Leptin
subject: Molecular biology
subject: Genetics
subject: FOS: Biological sciences

description: 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&lt;10−6 in 19,979 additional individuals. We identify five loci robustly associated (P&lt;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.