학술논문
Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort
Document Type
Article
Author
Wade, Kaitlin H.; Lam, Brian Y. H.; Melvin, Audrey; Pan, Warren; Corbin, Laura J.; Hughes, David A.; Rainbow, Kara; Chen, Jian-Hua; Duckett, Katie; Liu, Xiaoming; Mokrosiński, Jacek; Mörseburg, Alexander; Neaves, Sam; Williamson, Alice; Zhang, Chen; Farooqi, I. Sadaf; Yeo, Giles S. H.; Timpson, Nicholas J.; O’Rahilly, Stephen
Source
Nature Medicine; 20210101, Issue: Preprints p1-9, 9p
Subject
Language
ISSN
10788956; 1546170X
Abstract
Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4Rcoding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4Rvariants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4Rwas ~1 in 337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and noncarriers of LoF mutations were 17.76 kg (95% CI 9.41, 26.10), 4.84 kg m−2(95% CI 2.19, 7.49) and 14.78 kg (95% CI 8.56, 20.99), respectively. MC4RLoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.