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

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.

Transcriptome profiling from adipose tissue during a low-calorie diet reveals predictors of weight and glycemic outcomes in obese, nondiabetic subjects

“…Remarkably, within this list, 7 of the 10 most differentially expressed genes [ME1, secreted protein acidic and cysteine rich (SPARC), MTCH2, LOX, ELOVL5, CAV2, and LEP] are well established in the context of obesity, T2D onset, or adipocyte regulation. ME1 is a known causal obesity gene (45), SPARC is involved with adipocyte differentiation and strongly associated with both obesity and diabetes (46), MTCH2 is a known obesity risk factor gene (47), LOX levels were found altered on bariatric surgery (48), ELOVL5 plays a key role in regulating triglycerides and MUFA/PUFA synthesis (49), genetic polymorphisms in CAV2, in interaction with fat intake, are associated with T2D (50), and LEP is a major hallmark gene in weight loss and obesity (51)(52)(53). Such enrichment in obesity biomarkers lends further credibility to our results.…”

LEPR Gene Polymorphism and Plasma Soluble Leptin Receptor Levels are Associated with Polycystic Ovary Syndrome in Han Chinese Women

“…However, whether the serum leptin receptor levels had a correlation with the quantity of the total fat mass has not been confirmed. In the previous studies, researchers demonstrated the significant correlation between serum sOB-R and BMI in a cohort of healthy children and adolescents [26]; and Sun and colleagues showed that the two nonsynonymous SNPs in the LEPR gene were associated with plasma sOB-R levels at the genome-wide significance level, which highlighted and confirmed the role of LEPR as a candidate gene for regulating sOB-R levels [27]. The above conflicting data might reflect variations in the study design and population stratification.…”

Examining the Causal Role of Leptin in Alzheimer Disease: A Mendelian Randomization Study

“…Single nucleotide polymorphisms (SNPs) were identified by first identifying all published genome-wide association studies (GWASs) for leptin and sOB-R. We identified 1 GWAS for circulating leptin (log-transformed ng/mL) [24] and 1 GWAS for sOB-R (log-transformed ng/mL) [25] . All SNPs reported by the authors as having a p value of <5 × 10 -5 after adjusting for age, sex (if applicable), and body mass index (BMI) were considered for inclusion.…”

“…The GWAS for leptin identified 5 SNPs predictive of leptin levels in 32,161 individuals of European descent from 23 different studies with men ( n = 13,363) and women ( n = 18,698) analyzed separately because of sex differences in circulating leptin [24] . Loci from this first stage were then examined in a sample of 19,979 individuals of European descent from 13 studies.…”