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

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Kilpelainen , T O , Carli , J F M , Skowronski , A A , Sun , Q , Kriebel , J , Feitosa , M F , Hedman , A K , Drong , A W , Hayes , J E , Zhao , J , Pers , T H , Schick , U , Grarup , N , Kutalik , Z , Trompet , S , Mangino , M , Kristiansson , K , Beekman , M , Lyytikainen , L-P , Eriksson , J , Henneman , P , Lahti , J , Tanaka , T , Luan , J , Del Greco M , F , Pasko , D , Renstrom , F , Willems , S M , Mahajan , A , Rose , L M , Guo , X , Liu , Y , Kleber , M E , Perusse , L , Gaunt , T , Ahluwalia , T S , Sung , Y J , Ramos , Y F , Amin , N , Amuzu , A , Barroso , I , Bellis , C , Blangero , J , Buckley , B M , Boehringer , S , Chen , Y-D I , de Craen , A J N , Crosslin , D R , Dale , C E , Dastani , Z , Day , F R , Deelen , J , Delgado , G E , Demirkan , A , Finucane , F M , Ford , I , Garcia , M E , Gieger , C , Gustafsson , S , Hallmans , G , Hankinson , S E , Havulinna , A S , Herder , C , Hernandez , D , Hicks , A A , Hunter , D J , Illig , T , Ingelsson , E , Ioan-Facsinay , A , Jansson , J-O , Jenny , N S , Jorgensen , M E , Jorgensen , T , Karlsson , M , Koenig , W , Kraft , P , Kwekkeboom , J , Laatikainen , T , Ladwig , K-H , LeDuc , C A , Lowe , G , Lu , Y , Marques-Vidal , P , Meisinger , C , Menni , C , Morris , A P , Myers , R H , Mannisto , S , Nalls , M A , Paternoster , L , Peters , A , Pradhan , A D , Rankinen , T , Rasmussen-Torvik , L J , Rathmann , W , Rice , T K , Richards , J B , Ridker , P M , Sattar , N , Savage , D B , Soderberg , S , Timpson , N J , Vandenput , L , van Heemst , D , Uh , H-W , Vohl , M-C , Walker , M , Wichmann , H-E , Widen , E , Wood , A R , Yao , J , Zeller , T , Zhang , Y , Meulenbelt , I , Kloppenburg , M , Astrup , A , Sorensen , T I A , Sarzynski , M A , Rao , D C , Jousilahti , P , Vartiainen , E , Hofman , A , Rivadeneira , F , Uitterlinden , A G , Kajantie , E , Osmond , C , Palotie , A , Eriksson , J G , Heliovaara , M , Knekt , P B , Koskinen , S , Jula , A , Perola , M , Huupponen , R K , Viikari , J S , Kahonen , M , Lehtimaki , T , Raitakari , O T , Mellstrom , D , Lorentzon , M , Casas , J P , Bandinelli , S , Maerz , W , Isaacs , A , van Dijk , K W , van Duijn , C M , Harris , T B , Bouchard , C , Allison , M A , Chasman , D I , Ohlsson , C , Lind , L , Scott , R A , Langenberg , C , Wareham , N J , Ferrucci , L , Frayling , T M , Pramstaller , P P , Borecki , I B , Waterworth , D M , Bergmann , S , Waeber , G , Vollenweider , P , Vestergaard , H , Hansen , T , Pedersen , O , Hu , F B , Slagboom , P E , Grallert , H , Spector , T D , Jukema , J W , Klein , R J , Schadt , E E , Franks , P W , Lindgren , C M , Leibel , R L & Loos , R J F 2016 , ' Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels ' , Nature Communications , vol. 7 , 10494 . https://doi.org/10.1038/ncomms10494

Title: Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
Author: Kilpelainen, Tuomas O.; Carli, Jayne F. Martin; Skowronski, Alicja A.; 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, Zoltan; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikainen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Del Greco M, Fabiola; Pasko, Dorota; Renstrom, Frida; Willems, Sara M.; Mahajan, Anubha; Rose, Lynda M.; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E.; Perusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S.; Sung, Yun Ju; Ramos, Yolande F.; Amin, Najaf; Amuzu, Antoinette; Barroso, Ines; Bellis, Claire; Blangero, John; Buckley, Brendan M.; Boehringer, 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, Goran; 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.; Jorgensen, Marit E.; Jorgensen, 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.; Mannisto, 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.; Soderberg, Stefan; Timpson, Nicholas J.; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widen, Elisabeth; Wood, Andrew R.; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sorensen, Thorkild I. A.; Sarzynski, Mark A.; Rao, D. C.; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G.; Heliovaara, Markku; Knekt, Paul B.; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K.; Viikari, Jorma S.; Kahonen, Mika; Lehtimaki, Terho; Raitakari, Olli T.; Mellstrom, Dan; Lorentzon, Mattias; Casas, Juan P.; Bandinelli, Stefanie; Maerz, 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, Gerard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B.; Slagboom, P. Eline; 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.
Contributor: University of Helsinki, Helsinki Collegium for Advanced Studies
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, University of Helsinki
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2016-02
Language: eng
Number of pages: 14
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/160840
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 x 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.
Subject: EARLY-ONSET OBESITY
GENE-EXPRESSION
PLASMA LEPTIN
ADIPOSE-TISSUE
SERUM LEPTIN
RECOMBINANT LEPTIN
INSULIN-RESISTANCE
PROVIDES INSIGHTS
WEIGHT-LOSS
FAT MASS
3111 Biomedicine
515 Psychology
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