@article{Kilpeläinen2016, abstract = {AbstractLeptin 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.}, author = {Kilpeläinen, Tuomas O. (Tuomas) and Carli, Jayne F. Martin and Skowronski, Alicja A. (Alicja A.) and Sun, Qi and Kriebel, Jennifer and Hedman, Åsa K. and Feitosa, Mary F. (Mary Furlan) and Hedman, Asa K. (Asa) and Drong, Alexander W. and Hayes, James E. (James E.) and Zhao, Jinghua H. and Pers, Tune H. (Tune) and Schick, Ursula M. (Ursula) and Grarup, Niels and Kutalik, Zoltán and Trompet, Stella and Mangino, Massimo and Kristiansson, Kati and Beekman, Marian and Sung, Yun Ju and Lyytikäinen, Leo-Pekka and Eriksson, Joel and Henneman, Peter and Lahti, Jari and Tanaka, Toshiko and Luan, Jian’an and Del Greco M., Fabiola and Greco M., Fabiola Del and Martin Carli, Jayne F. and Pasko, Dorota and Renström, Frida and Willems, Sara M. (Sara) and Mahajan, Anubha and Rose, Lynda M. (Lynda) and Guo, Xiuqing and Liu, Yongmei and Kleber, Marcus E. (Marcus) and Pérusse, Louis and Gaunt, Tom R. (Tom) and Ahluwalia, Tarunveer S. (Tarunveer Singh) and Ju Sung, Yun and Perusse, L. (Louis) and Ramos, Yolande F. M. (Yolande) and Amin, Najaf and Amuzu, Antoinette and Barroso, Inês and Bellis, Claire and Blangero, John and Buckley, Brendan M. (Brendan M.) and Bohringer, Stefan and Böhringer, Stefan and I. Chen, Yii-Der and de Craen, Anton J. N. and Fabiola Del Greco, M. and Crosslin, David R. (David) and Dale, Caroline E. (Caroline E.) and Dastani, Zari and De Craen, A. J. N. (Anton J. N.) and Day, Felix R. (Felix) and Deelen, Joris and Delgado, Graciela E. and Demirkan, Ayse and Finucane, Francis M. (Francis) and Ford, Ian and Garcia, Melissa E. and Chen, Yii-Der I. and Gieger, Christian and Gustafsson, Stefan and Hallmans, Göran and Hankinson, Susan E. (Susan E.) and Havulinna, Aki S. (Aki) and Herder, Christian and Hernandez, Dena G. (Dena) and Hicks, Andrew A. (Andrew) and Hunter, David J. and Illig, Thomas and Ingelsson, Erik and Ioan-Facsinay, Andreea and Jansson, John-Olov and Jenny, Nancy S. (Nancy) and Jorgensen, Marit E. and Jorgensen, Torben and Jørgensen, Marit E. (Marit E.) and Jørgensen, Torben and Karlsson, Magnus and Koenig, Wolfgang and Jorgensen, T. (Torben) and Kraft, Peter and Kwekkeboom, Joanneke and Laatikainen, Tiina and Ladwig, Karl-Heinz and LeDuc, Charles A. (Charles A.) and Lowe, Gordon D. (Gordon D.) and Lu, Yingchang and Marques-Vidal, Pedro and Meisinger, Christa and Menni, Cristina and Morris, Andrew P. (Andrew) and Myers, Richard H. (Richard) and Mannisto, Satu and Männistö, Satu and Nalls, Mike A. (Michael) and Paternoster, Lavinia and Peters, Annette and Pradhan, Aruna D. (Aruna D.) and Rankinen, Tuomo and Rasmussen Torvik, Laura J. (Laura) and Rathmann, Wolfgang and Rice, Treva K. (Treva K.) and Brent Richards, J. and Ridker, Paul M. and Sattar, Naveed and Savage, David B. (David) and Soderberg, Stefan and Söderberg, Stefan and Timpson, Nicholas J. and Vandenput, Liesbeth and van Heemst, Diana and Uh, Hae-Won and Vohl, Marie-Claude and Richards, J. B. (J Brent) and Walker, Mark and Wichmann, Heinz-Erich and Widén, Elisabeth and Wood, Andrew R. (Andrew) and Yao, Jie and Zeller, Tanja and Zhang, Yiying and Meulenbelt, Ingrid and Heemst, D. (Diana) van and Kloppenburg, Margreet and Astrup, Arne and Sorensen, Thorkild I. A. and Sørensen, Thorkild I. A. (Thorkild) and Sarzynski, Mark A. (Mark A.) and Rao, D. C. (Dabeeru C.) and Jousilahti, Pekka and Vartiainen, Erkki and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, André G. (André) and Kajantie, Eero and Osmond, Clive and Palotie, Aarno and Hagen, K. (Knut) and Eriksson, Johan G. and Heliövaara, Markku and Knekt, Paul B. and Koskinen, Seppo and Jula, Antti and Perola, Markus and Huupponen, Risto K. (Risto K.) and Viikari, Jorma S. and Kahonen, Mika and Kähönen, Mika and Lehtimäki, Terho and Raitakari, Olli T. (Olli T.) and Mellström, Dan and Lorentzon, Mattias and Casas, Juan P. (Juan Pablo) and Bandinelli, Stefanie and März, Winfried and Maerz, Winfried and Isaacs, Aaron J. (Aaron) and van Dijk, Ko W. and van Duijn, Cornelia M. and Willems van Dijk, J. A. P. (Ko) and Harris, Tamara B. (Tamara) and Duijn, C. M. (Cock) van and Bouchard, Claude and Allison, Matthew A. (Matthew) and Chasman, Daniel I. (Daniel) and Ohlsson, Claes and Lind, Lars and Scott, Robert A. (Robert) and Langenberg, Claudia and Wareham, Nicholas J. (Nick) and Ferrucci, Luigi and Kao, W. H. L. (Wen) and Frayling, Timothy M. (Timothy) and Pramstaller, Peter P. (Peter Paul) and Borecki, Ingrid B. (Ingrid) and Waterworth, Dawn M. and Bergmann, Sven M. (Sven) and Waeber, Gérard and Vollenweider, Peter and Vestergaard, Henrik and Hansen, Torben and Pedersen, Oluf and Hu, Frank B. (Frank B.) and Slagboom, P. Eline and Eline Slagboom, P. and Grallert, Harald and Spector, Tim D. (Timothy) and Jukema, J. W. (Jan Wouter) and Klein, Robert J. (Robert J.) and Schadt, Erik E. (Eric) and Franks, Paul W. (Paul) and Lindgren, Cecilia M. (Cecilia M.) and Leibel, Rudolph L. (Rudolph L.) and Loos, Ruth J. F. (Ruth)}, doi = {10.1038/ncomms10494}, journal = {Nature Communications}, month = {feb}, title = {Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels}, url = {https://www.nature.com/articles/ncomms10494.pdf}, volume = {7}, year = {2016} }