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 organization: Helsinki Collegium for Advanced Studies
Behavioural Sciences
Institute for Molecular Medicine Finland
Elisabeth Ingrid Maria Widen / Principal Investigator
University of Helsinki
Children's Hospital
Lastentautien yksikkö
Aarno Palotie / Principal Investigator
Clinicum
Johan Eriksson / Principal Investigator
Department of General Practice and Primary Health Care
Quantitative Genetics
Developmental Psychology Research Group
Genomics of Neurological and Neuropsychiatric Disorders
Genomic Discoveries and Clinical Translation
Date: 2016-02
Language: eng
Number of pages: 14
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/ncomms10494
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
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion


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