TY - JOUR

T1 - Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

AU - Kilpeläinen, Tuomas O

AU - Carli, Jayne F Martin

AU - Skowronski, Alicja A

AU - Sun, Qi

AU - Kriebel, Jennifer

AU - Feitosa, Mary F

AU - Hedman, Åsa K

AU - Drong, Alexander W

AU - Hayes, James E

AU - Zhao, Jinghua

AU - Pers, Tune H

AU - Schick, Ursula

AU - Grarup, Niels

AU - Kutalik, Zoltán

AU - Trompet, Stella

AU - Mangino, Massimo

AU - Kristiansson, Kati

AU - Beekman, Marian

AU - Lyytikäinen, Leo-Pekka

AU - Eriksson, Joel

AU - Henneman, Peter

AU - Lahti, Jari

AU - Tanaka, Toshiko

AU - Luan, Jian'an

AU - Greco M, Fabiola Del

AU - Pasko, Dorota

AU - Renström, Frida

AU - Willems, Sara M

AU - Mahajan, Anubha

AU - Rose, Lynda M

AU - Guo, Xiuqing

AU - Liu, Yongmei

AU - Kleber, Marcus E

AU - Pérusse, Louis

AU - Gaunt, Tom

AU - Ahluwalia, Tarun Veer Singh

AU - Ju Sung, Yun

AU - Ramos, Yolande F

AU - Amin, Najaf

AU - Amuzu, Antoinette

AU - Barroso, Inês

AU - Bellis, Claire

AU - Blangero, John

AU - Buckley, Brendan M

AU - Böhringer, Stefan

AU - I Chen, Yii-Der

AU - de Craen, Anton J N

AU - Crosslin, David R

AU - Dale, Caroline E

AU - Dastani, Zari

AU - Day, Felix R

AU - Deelen, Joris

AU - Delgado, Graciela E

AU - Demirkan, Ayse

AU - Finucane, Francis M

AU - Ford, Ian

AU - Garcia, Melissa E

AU - Gieger, Christian

AU - Gustafsson, Stefan

AU - Hallmans, Göran

AU - Hankinson, Susan E

AU - Havulinna, Aki S

AU - Herder, Christian

AU - Hernandez, Dena

AU - Hicks, Andrew A

AU - Hunter, David J

AU - Illig, Thomas

AU - Ingelsson, Erik

AU - Ioan-Facsinay, Andreea

AU - Jansson, John-Olov

AU - Jenny, Nancy S

AU - Jørgensen, Marit E

AU - Jørgensen, Torben

AU - Karlsson, Magnus

AU - Koenig, Wolfgang

AU - Kraft, Peter

AU - Kwekkeboom, Joanneke

AU - Laatikainen, Tiina

AU - Ladwig, Karl-Heinz

AU - LeDuc, Charles A

AU - Lowe, Gordon

AU - Lu, Yingchang

AU - Marques-Vidal, Pedro

AU - Meisinger, Christa

AU - Menni, Cristina

AU - Morris, Andrew P

AU - Myers, Richard H

AU - Männistö, Satu

AU - Nalls, Mike A

AU - Paternoster, Lavinia

AU - Peters, Annette

AU - Pradhan, Aruna D

AU - Rankinen, Tuomo

AU - Rasmussen-Torvik, Laura J

AU - Rathmann, Wolfgang

AU - Rice, Treva K

AU - Brent Richards, J

AU - Ridker, Paul M

AU - Sattar, Naveed

AU - Savage, David B

AU - Söderberg, Stefan

AU - Timpson, Nicholas J

AU - Vandenput, Liesbeth

AU - van Heemst, Diana

AU - Uh, Hae-Won

AU - Vohl, Marie-Claude

AU - Walker, Mark

AU - Wichmann, Heinz-Erich

AU - Widén, Elisabeth

AU - Wood, Andrew R

AU - Yao, Jie

AU - Zeller, Tanja

AU - Zhang, Yiying

AU - Meulenbelt, Ingrid

AU - Kloppenburg, Margreet

AU - Astrup, Arne

AU - Sørensen, Thorkild I A

AU - Sarzynski, Mark A

AU - Rao, D C

AU - Jousilahti, Pekka

AU - Vartiainen, Erkki

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G

AU - Kajantie, Eero

AU - Osmond, Clive

AU - Palotie, Aarno

AU - Eriksson, Johan G

AU - Heliövaara, Markku

AU - Knekt, Paul B

AU - Koskinen, Seppo

AU - Jula, Antti

AU - Perola, Markus

AU - Huupponen, Risto K

AU - Viikari, Jorma S

AU - Kähönen, Mika

AU - Lehtimäki, Terho

AU - Raitakari, Olli T

AU - Mellström, Dan

AU - Lorentzon, Mattias

AU - Casas, Juan P

AU - Bandinelli, Stefanie

AU - März, Winfried

AU - Isaacs, Aaron

AU - van Dijk, Ko W

AU - van Duijn, Cornelia M

AU - Harris, Tamara B

AU - Bouchard, Claude

AU - Allison, Matthew A

AU - Chasman, Daniel I

AU - Ohlsson, Claes

AU - Lind, Lars

AU - Scott, Robert A

AU - Langenberg, Claudia

AU - Wareham, Nicholas J

AU - Ferrucci, Luigi

AU - Frayling, Timothy M

AU - Pramstaller, Peter P

AU - Borecki, Ingrid B

AU - Waterworth, Dawn M

AU - Bergmann, Sven

AU - Waeber, Gérard

AU - Vollenweider, Peter

AU - Vestergaard, Henrik

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Hu, Frank B

AU - Eline Slagboom, P

AU - Grallert, Harald

AU - Spector, Tim D

AU - Jukema, J W

AU - Klein, Robert J

AU - Schadt, Erik E

AU - Franks, Paul W

AU - Lindgren, Cecilia M

AU - Leibel, Rudolph L

AU - Loos, Ruth J F

N1 - CURIS 2016 NEXS 411

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms10494

DO - 10.1038/ncomms10494

M3 - Journal article

C2 - 26833098

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 10494

ER -