Mutations in the melanocortin 4 receptor gene (MC4R) have frequently been reported to be associated with human obesity but there is little information on the prevalence and extent of longitudinal phenotypic impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5724 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC), functionally characterised all non-synonymous MC4R variants and examined the relationship between carriage of loss of function (LoF) mutations and anthropometric variables from childhood to early adulthood. The frequency of heterozygous LoF mutations in MC4R in this unselected birth cohort was ~1/337 (0.30%), which is considerably higher than previous estimates that, unlike this study, may have been affected by known healthy participant bias of studies based in adult volunteers. At age 18 years, the mean difference in body weight, body mass index (BMI) and fat mass was 17.76kg (95% CI:9.41, 26.10), 4.84kg/m2 52 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively, in carriers of LoF mutations compared to non-LoF carriers. Carriage of LoF mutations increased adiposity from as early as 5 years. MC4R LoF was associated with an impact on BMI at age 18 years that was approximately double that of a genome-wide polygenic risk score (comparing the upper 10th 56 and lower 90th percentile). Our findings suggest that heterozygous LoF mutations in MC4R may be more common than has previously been suggested and that those carrying such variants may enter adult life with a substantial burden of excess adiposity.
|Publication status||Accepted/In press - 3 Mar 2021|