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

Publication

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

Journal Paper/Review - Feb 1, 2016

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

Units

PubMed

26833098

Doi

10.1038/ncomms10494

Citation

Perola M, Vartiainen E, Jousilahti P, Rao D, Sarzynski M, Sørensen T, Astrup A, Kloppenburg M, Meulenbelt I, Zhang Y, Hofman A, Rivadeneira F, Jula A, Koskinen S, Knekt P, Heliövaara M, Eriksson J, Palotie A, Osmond C, Kajantie E, Uitterlinden A, Zeller T, Yao J, Sattar N, Ridker P, Brent Richards J, Rice T, Rathmann W, Rasmussen-Torvik L, Rankinen T, Pradhan A, Peters A, Savage D, Söderberg S, Wood A, Widén E, Wichmann H, Walker M, Vohl M, Uh H, van Heemst D, Vandenput L, Timpson N, Paternoster L, Loos R, Hansen T, Vestergaard H, Vollenweider P, Waeber G, Bergmann S, Waterworth D, Borecki I, Pramstaller P, Frayling T, Pedersen O, Hu F, Leibel R, Lindgren C, Franks P, Schadt E, Klein R, Jukema J, Spector T, Grallert H, Eline Slagboom P, Ferrucci L, Wareham N, März W, Bandinelli S, Casas J, Lorentzon M, Mellström D, Raitakari O, Lehtimäki T, Kähönen M, Viikari J, Isaacs A, van Dijk K, Langenberg C, Scott R, Lind L, Ohlsson C, Chasman D, Allison M, Bouchard C, Harris T, van Duijn C, Huupponen R, Nalls M, Buckley B, Liu Y, Guo X, Rose L, Mahajan A, Willems S, Renström F, Pasko D, Del Greco M F, Luan J, Kleber M, Pérusse L, Blangero J, Bellis C, Barroso I, Amuzu A, Amin N, Ramos Y, Ju Sung Y, Ahluwalia T, Gaunt T, Tanaka T, Lahti J, Zhao J, Hayes J, Drong A, Hedman Å, Feitosa M, Kriebel J, Sun Q, Skowronski A, Carli J, Pers T, Schick U, Henneman P, Eriksson J, Lyytikäinen L, Beekman M, Kristiansson K, Mangino M, Trompet S, Kutalik Z, Grarup N, Kilpeläinen T, Männistö S, Kraft P, Koenig W, Karlsson M, Jørgensen T, Jørgensen M, Jenny N, Jansson J, Ioan-Facsinay A, Ingelsson E, Kwekkeboom J, Laatikainen T, Myers R, Morris A, Menni C, Meisinger C, Marques-Vidal P, Lu Y, Lowe G, LeDuc C, Ladwig K, Illig T, Hunter D, Demirkan A, Delgado G, Deelen J, Day F, Dastani Z, Dale C, Crosslin D, de Craen A, I Chen Y, Finucane F, Ford I, Hicks A, Hernandez D, Herder C, Havulinna A, Hankinson S, Hallmans G, Gustafsson S, Gieger C, Garcia M, Böhringer S. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat Commun 2016; 7:10494.

Type

Journal Paper/Review (English)

Journal

Nat Commun 2016; 7

Publication Date

Feb 1, 2016

Issn Electronic

2041-1723

Pages

10494

Brief description/objective

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.