Prevalence and expressivity of loss of function mutations in the Melanocortin 4 Receptor (MC4R) in a UK birth cohort

Abstract

Mutations in the melanocortin 4 receptor gene (MC4R) have frequently been reported in severe early-onset human obesity but the prevalence and extent of phenotypic impact of such mutations are unclear. In a large UK birth cohort, we found that 17 of 5724 unrelated participants (~1/337; 0.30%) were heterozygous for functionally deleterious mutations. 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 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively, in carriers of loss of function (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 and lower 90th percentile). An extrapolation of incidence for MC4R LoF mutations from this birth cohort suggests that up to ~200,000 people in the UK are likely to carry such mutations. This frequency, combined with the substantial impact of these variants on adiposity, has implications for public health, and drug development.

The genetics of obesity: from discovery to biology

“…Mutations in MC4R in particular, are the most common single-gene defect leading to hyperphagia and obesity. Pathogenic mutations in MC4R are found in up to 5% of cases of severe childhood obesity 101 and up to 0.3% of the general population 101,102 . Of note, the degree of receptor dysfunction, as measured by in vitro assays, can predict the amount of food eaten at a test meal by an individual harbouring that particular mutation 101 .…”