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

Artikel i vetenskaplig tidskrift
Författare Tuomas O. Kilpeläinen
Jayne F. Martin Carli
Alicja A. Skowronski
Qi Sun
Joel Eriksson
Liesbeth Vandenput
Dan Mellström
Mattias Lorentzon
Claes Ohlsson
John-Olov Jansson
Publicerad i Nature Communications
Volym 7
ISSN 2041-1723
Publiceringsår 2016
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Centre for Bone and Arthritis Research
Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition
Språk en
Länkar dx.doi.org/10.1038/ncomms10494
Ämnesord adipose tissue; animal tissue; Article; birth weight; body mass; controlled study; explant; female; follow up; gene locus; genetic association; genetic trait; human; major clinical study; male; meta analysis (topic); mouse; nonhuman; obesity
Ämneskategorier Medicinsk genetik, Genetik, Endokrinologi och diabetes

Sammanfattning

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.

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