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

Kilpeläinen, T.O.; Carli, J.F.; Skowronski, A.A.; Sun, Q.; Kriebel, J.; Feitosa, M.F.; Hedman, Å.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.; Lyytikäinen, L.P.; Eriksson, J.; Henneman, P.; Lahti, J.; Tanaka, T.; Luan, J.; Del Greco M, F.; Pasko, D.; Renström, F.; Willems, S.M.; Mahajan, A.; Rose, L.M.; Guo, X.; Liu, Y.; Kleber, M.E.; Pérusse, L.; Gaunt, T.; Ahluwalia, T.S.; Ju Sung, Y.; Ramos, Y.F.; Amin, N.; Amuzu, A.; Barroso, I.; Bellis, C.; Blangero, J.; Buckley, B.M.; Böhringer, S.; I Chen, Y.D.; de Craen, A.J.; 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.; Jørgensen, M.E.; Jørgensen, 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.; Männistö, S.; Nalls, M.A.; Paternoster, L.; Peters, A.; Pradhan, A.D.; Rankinen, T.; Rasmussen-Torvik, L.J.; Rathmann, W.; Rice, T.K.; Brent Richards, J.; Ridker, P.M.; Sattar, N.; Savage, D.B.; Söderberg, S.; Timpson, N.J.; Vandenput, L.; van Heemst, D.; Uh, H.W.; Vohl, M.C.; Walker, M.; Wichmann, H.E.; Widén, E.; Wood, A.R.; Yao, J.; Zeller, T.; Zhang, Y.; Meulenbelt, I.; Kloppenburg, M.; Astrup, A.; Sørensen, T.I.; 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.; Heliövaara, M.; Knekt, P.B.; Koskinen, S.; Jula, A.; Perola, M.; Huupponen, R.K.; Viikari, J.S.; Kähönen, M.; Lehtimäki, T.; Raitakari, O.T.; Mellström, D.; Lorentzon, M.; Casas, J.P.; Bandinelli, S.; März, 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.; Eline Slagboom, P.; 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.

doi:10.1038/ncomms10494

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

Details

Download: BIB_35AFF34A673F.P001.pdf (851.19 [Ko])
State: Public
Version: Final published version

Serval ID

serval:BIB_35AFF34A673F

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

Nature Communications

Author(s)

Kilpeläinen T.O., Carli J.F., Skowronski A.A., Sun Q., Kriebel J., Feitosa M.F., Hedman Å.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., Lyytikäinen L.P., Eriksson J., Henneman P., Lahti J., Tanaka T., Luan J., Del Greco M F., Pasko D., Renström F., Willems S.M., Mahajan A., Rose L.M., Guo X., Liu Y., Kleber M.E., Pérusse L., Gaunt T., Ahluwalia T.S., Ju Sung Y., Ramos Y.F., Amin N., Amuzu A., Barroso I., Bellis C., Blangero J., Buckley B.M., Böhringer S., I Chen Y.D., de Craen A.J., 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., Jørgensen M.E., Jørgensen 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., Männistö S., Nalls M.A., Paternoster L., Peters A., Pradhan A.D., Rankinen T., Rasmussen-Torvik L.J., Rathmann W., Rice T.K., Brent Richards J., Ridker P.M., Sattar N., Savage D.B., Söderberg S., Timpson N.J., Vandenput L., van Heemst D., Uh H.W., Vohl M.C., Walker M., Wichmann H.E., Widén E., Wood A.R., Yao J., Zeller T., Zhang Y., Meulenbelt I., Kloppenburg M., Astrup A., Sørensen T.I., 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., Heliövaara M., Knekt P.B., Koskinen S., Jula A., Perola M., Huupponen R.K., Viikari J.S., Kähönen M., Lehtimäki T., Raitakari O.T., Mellström D., Lorentzon M., Casas J.P., Bandinelli S., März 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., Eline Slagboom P., 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.

ISSN

2041-1723 (Electronic)

ISSN-L

2041-1723

Publication state

Published

Issued date

2016

Peer-reviewed

Oui

Volume

Pages

10494

Language

english

Notes

Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish

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.

Keywords

Adipose Tissue/metabolism, Animals, Gene Expression Regulation/physiology, Gene Knockdown Techniques, Genome-Wide Association Study, Leptin/blood, Leptin/genetics, Male, Mice, RNA, Messenger/genetics, RNA, Messenger/metabolism, Tissue Culture Techniques

URN

urn:nbn:ch:serval-BIB_35AFF34A673F0

OAI-PMH

oai:serval.unil.ch:BIB_35AFF34A673F

DOI

10.1038/ncomms10494

Pubmed

26833098

Web of science

000371012200001

Open Access

Yes