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 × 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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 10494 |
| Tidsskrift | Nature Communications |
| Vol/bind | 7 |
| Antal sider | 14 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2016 |
Bibliografisk note
CURIS 2016 NEXS 411Adgang til dokumentet
- 10.1038/ncomms10494Licens: CC BY
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. / Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K; Drong, Alexander W; Hayes, James E; Zhao, Jinghua; Pers, Tune H; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Greco M, Fabiola Del; Pasko, Dorota; Renström, Frida; Willems, Sara M; Mahajan, Anubha; Rose, Lynda M; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarun Veer Singh; Ju Sung, Yun; Ramos, Yolande F; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M; Böhringer, Stefan; I Chen, Yii-Der; 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, Göran; 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; Jørgensen, Marit E; Jørgensen, 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; Männistö, Satu; Nalls, Mike A; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rice, Treva K; Brent Richards, J; Ridker, Paul M; Sattar, Naveed; Savage, David B; Söderberg, Stefan; Timpson, Nicholas J; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I A; Sarzynski, Mark A; Rao, D C; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G; Heliövaara, Markku; Knekt, Paul B; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K; Viikari, Jorma S; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P; Bandinelli, Stefanie; März, 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, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B; Eline Slagboom, P; 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.
I: Nature Communications, Bind 7, 10494, 2016.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
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 -