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

K H Wade, B Y H Lam, A Melvin, W Pan, L J Corbin, D A Hughes, K Rainbow, J H Chen, K Duckett, X Liu, J Mokrosińsk, Alexander Mörseburg, S Neaves, A Williamson, C Zhang, I S Farooqi, G S H Yeo, N J Timpson*, S O'Rahilly*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

51 Downloads (Pure)


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.
Original languageEnglish
Pages (from-to)1088-1096
Number of pages9
JournalNature Medicine
Issue number6
Publication statusPublished - 27 May 2021

Bibliographical note

Funding Information:
We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. We acknowledge the technical support of Tolulope Osunnuyi and the NIHR BRC-MRC BioRepository at Cambridge Biomedical Research Centre. We also thank staff members of the Wellcome Trust-MRC Institute of Metabolic Science Genomics and Transcriptomic core and the Genomics Core at the CRUK Cambridge Institute for their experimental support for next-generation sequencing. WES was obtained from ALSPAC (under proposal no. B2680) for comparison to the current study and we thank E. Robinson and B. Neale from the BROAD Institute for their contribution to exome sequencing. The UK MRC and Wellcome Trust (grant ref. 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Genome-wide association data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Mutational screening, sequencing and functional analyses were supported by MRC Metabolic Diseases Unit funding (MC_UU_00014/1). This publication is the work of all authors and K.H.W., N.J.T. and S.O. serve as guarantors for the contents of this paper. K.H.W. was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). N.J.T. is a Wellcome Trust Investigator (202802/Z/16/Z), a workpackage lead in the Integrative Cancer Epidemiology Programme that is supported by a Cancer Research UK programme grant (C18281/A19169) and works within the University of Bristol National Institute for Health Research Biomedical Research Centre. D.A.H. and L.J.C. are supported by N.J.T.’s Wellcome Trust Investigator grant (202802/Z/16/Z) and work within the MRC Integrative Epidemiology Unit (MC_UU_00011). B.Y.H.L. is supported by a BBSRC Project Grant (BB/S017593/1). A. Melvin holds a PhD studentship supported jointly by the University of Cambridge Experimental Medicine Training Initiative programme in partnership with AstraZeneca. I.S.F. was supported by the Wellcome Trust (098497/Z/12/Z), the NIHR Cambridge Biomedical Research Centre, the Botnar Fondation and the Bernard Wolfe Health Neuroscience Endowment and a Wellcome Developing Concept Fund award (with J.M.). S.O.R. and G.S.H.Y. is supported by the MRC Metabolic Disease Unit (MC_UU_00014/1) and S.O.R. by a Wellcome Trust Investigator award (WT 095515/Z/11/Z) and National Institute for Health Research Cambridge Biomedical Research Centre. The Wellcome-MRC Institute of Metabolic Science Genomics and transcriptomics core facility is supported by the Medical Research Council (MC_UU_00014/5) and the Wellcome Trust (208363/Z/17/Z).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Structured keywords

  • ICEP


  • MC4R
  • mutation
  • prevalence
  • obesity


Dive into the research topics of 'Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort'. Together they form a unique fingerprint.

Cite this