4.8 Article

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

Journal

NATURE MEDICINE
Volume 27, Issue 6, Pages 1088-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01349-y

Keywords

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Funding

  1. Wellcome Trust [102215/2/13/2, 204813/Z/16/Z, 202802/Z/16/Z, 098497/Z/12/Z, WT 095515/Z/11/Z, 208363/Z/17/Z]
  2. MRC Metabolic Diseases Unit funding [MC_UU_00014/1]
  3. Elizabeth Blackwell Institute for Health Research, University of Bristol
  4. Cancer Research UK programme [C18281/A19169]
  5. BBSRC [BB/S017593/1]
  6. University of Cambridge Experimental Medicine Training Initiative programme
  7. AstraZeneca
  8. NIHR Cambridge Biomedical Research Centre
  9. Bernard Wolfe Health Neuroscience Endowment
  10. Wellcome Developing Concept Fund award
  11. MRC Metabolic Disease Unit [MC_UU_00014/1]
  12. National Institute for Health Research Cambridge Biomedical Research Centre
  13. Medical Research Council [MC_UU_00014/5]
  14. MRC Integrative Epidemiology Unit [MC_UU_00011]
  15. Botnar Fondation
  16. Wellcome Trust [098497/Z/12/Z] Funding Source: Wellcome Trust
  17. BBSRC [BB/S017593/1] Funding Source: UKRI
  18. MRC [MC_UU_00014/1, MC_UU_00014/5] Funding Source: UKRI

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Mutations in the MC4R gene are associated with obesity, with the frequency of LoF mutations being higher than previously estimated. Carriers of such mutations may enter adulthood with a significant burden of excess adiposity.
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 similar to 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.

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