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

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 × 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.

• Authors: 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, Anubha Mahajan, 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
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 10494 (Feb 01 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 26833098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Leptin
• RNA, Messenger

Topics

• Adipose Tissue (metabolism)
• Animals
• Gene Expression Regulation (physiology)
• Gene Knockdown Techniques
• Genome-Wide Association Study
• Leptin (blood, genetics, metabolism)
• Male
• Mice
• RNA, Messenger (genetics, metabolism)
• Tissue Culture Techniques