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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, 10494Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 7, 10494
National Category
Medical and Health Sciences Medical Genetics
URN: urn:nbn:se:uu:diva-275673DOI: 10.1038/ncomms10494PubMedID: 26833098OAI: diva2:900718
EU, FP7, Seventh Framework Programme, FP7-201668 FP7-223004 FP7-259679 FP7-305739 FP7-IDEAS-ERC-323195GlaxoSmithKline (GSK)Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyKnut and Alice Wallenberg FoundationNIH (National Institute of Health), DK52431 HG004399 HG004446 CA087969 CA055075 DK058845 CA65725 CA49449 CA67262 CA50385 UO1CA098233Novo NordiskSwedish Diabetes AssociationSwedish Foundation for Strategic Research Swedish Heart Lung Foundation, 20140422Swedish Research Council, 2012-1397Ragnar Söderbergs stiftelseTorsten Söderbergs stiftelseWellcome trust, WT064890 WT089062 WT090532 WT098017 WT098051 WT091551 081917/Z/07/Z 086596/Z/08/Z
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2016-04-05Bibliographically approved

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Hedman, Åsa KGustafsson, StefanIngelsson, ErikLind, Lars
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