Journal
DIABETES
Volume 69, Issue 12, Pages 2806-2818Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db20-0070
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Funding
- Data Tecnica International
- National Institute on Aging, National Institutes of Health
- Johnson Johnson
- NHGRI NIH [F31HG009850]
- MRC [MC_UU_12015/1, MR/T002239/1] Funding Source: UKRI
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Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 x 10(-16), n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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