Abstract
Background: Melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor involved in appetite regulation. Mutations in the MC4R gene are the most common cause of monogenic obesity. More than 200 sequence variants in the MC4R gene have been associated with obesity, although the vast majority of these data have been obtained from populations of European ancestry. The prevalence and mutation profile of MC4R is thus poorly characterized in other ancestries/ethnicities. Materials and Methods: We surveyed the allele frequencies of the MC4R variants of multiple racial/ethnic populations represented in the Genome Aggregation Database (gnomAD) and sequenced the MC4R gene in a diverse population of 60 individuals with extreme obesity. Results: Allele frequencies were similar for most classes of variants except for a higher rate of synonymous substitutions in the African gnomAD population. We also identified two apparently novel MC4R variants and two variants with much higher allele frequencies in African populations whose functional impacts are not yet known. Conclusion: These results highlight the need for characterizing MC4R variants in diverse populations with extreme obesity.