Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity

Leptin influences food intake by informing the brain about the status of body fat stores. Rare <i>LEP</i> 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 <i>LEP</i>, <i>ZNF800</i>, <i>KLHL31</i>, and <i>ACTL9</i>, and one intergenic variant near <i>KLF14.</i> The missense variant Val94Met (rs17151919) in <i>LEP</i> was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (<i>P</i> = 2 × 10^-16, <i>n</i> = 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.