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Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort.

Accepted version
Peer-reviewed

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Authors

Wade, Kaitlin H 
Melvin, Audrey 
Pan, Warren 

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 MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~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. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity.

Description

Keywords

Adolescent, Adult, Body Weight, Child, Child, Preschool, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Infant, Newborn, Loss of Function Mutation, Male, Obesity, Phenotype, Receptor, Melanocortin, Type 4, United Kingdom, Young Adult

Journal Title

Nat Med

Conference Name

Journal ISSN

1078-8956
1546-170X

Volume Title

27

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
MRC (Unknown)
Wellcome Trust (208363/Z/17/Z)
Wellcome Trust (095515/Z/11/Z)
Wellcome Trust (098497/Z/12/Z)
Biotechnology and Biological Sciences Research Council (BB/S017593/1)
MRC (MC_UU_00014/1)
MRC (MC_UU_00014/5)
Medical Research Council (MC_UU_12012/1)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (214274/Z/18/Z)
Medical Research Council (MC_PC_12012)
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