CoChat
Sign Up
Cited by 133Regulation of Appetite and ObesityGenetic Associations and EpidemiologyHypothalamic control of reproductive hormones

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

Open access
Wade, Kaitlin H., Lam, Brian Y. H., Melvin, Audrey, Pan, Warren, Corbin, Laura J., Hughes, David A., Rainbow, Kara, Chen, Jian-Hua +11 more·2021·Nature Medicine
DOI 10.1038/s41591-021-01349-yPMC PMC7611835

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41591-021-01349-y

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MC4R is the most commonly mutated gene in monogenic obesity.

    “MC4R is the most commonly mutated gene in monogenic obesity (110).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [110]

    The Introduction describes MC4R mutations in people with obesity and says obesity-associated mutations in leptin and its receptor are very rare. The Discussion estimates MC4R deficiency at about 1 in 340, but the paper does not compare MC4R with all other monogenic obesity genes or establish that it is the most commonly mutated. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 35

  1. [1]Zhang Y Positional cloning of the mouse obese gene and its human homologue Nature 1994 372 425 432 7984236
  2. [2]Huszar D Targeted disruption of the melanocortin-4 receptor results in obesity in mice Cell 1997 88 131 141 9019399
  3. [3]Montague CT Congenital leptin deficiency is associated with severe early-onset obesity in humans Nature 1997 387 903 908 9202122
  4. [4]Yeo GS A frameshift mutation in MC4R associated with dominantly inherited human obesity Nature genetics 1998 20 111 112 9771698
  5. [5]Clément K A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction Nature 1998 392 398 401 9537324
  6. [6]Gantz I Molecular cloning, expression, and gene localization of a fourth melanocortin receptor The Journal of biological chemistry 1993 268 15174 15179 8392067
  7. [7]Mountjoy KG Mortrud MT Low MJ Simerly RB Cone RD Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain Molecular endocrinology (Baltimore, Md) 1994 8 1298 1308 7854347
  8. [8]Cowley MA Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat Neuron 1999 24 155 163 10677034
  9. [9]Cowley MA Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus Nature 2001 411 480 484 11373681
  10. [11]Fan W Boston BA Kesterson RA Hruby VJ Cone RD Role of melanocortinergic neurons in feeding and the agouti obesity syndrome Nature 1997 385 165 168 8990120
  11. [12]Vaisse C Clement K Guy-Grand B Froguel P A frameshift mutation in human MC4R is associated with a dominant form of obesity Nature genetics 1998 20 113 114 9771699
  12. [13]Farooqi IS Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency J Clin Invest 2000 106 271 279 10903343 PMC314308
  13. [15]Hinney A Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany The Journal of clinical endocrinology and metabolism 2006 91 1761 1769 16492696
  14. [16]Dempfle A Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index J Med Genet 2004 41 795 800 15466016 PMC1735595
  15. [17]Farooqi IS Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene New England Journal of Medicine 2003 348 1085 1095 12646665
  16. [19]Stutzmann F Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees Diabetes 2008 57 2511 2518 18559663 PMC2518504
  17. [20]Turcot V Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity Nature genetics 2018 50 26 41 29273807 PMC5945951
  18. [21]Gonçalves JPL Palmer D Meldal M MC4R Agonists: Structural Overview on Antiobesity Therapeutics Trends in pharmacological sciences 2018 39 402 423 29478721
  19. [22]Apovian CM The Obesity Epidemic--Understanding the Disease and the Treatment The New England journal of medicine 2016 374 177 179 26760089
  20. [23]Boyd AGJ Macleod J Lawlor DA Fraser A Henderson J Molloy L Ness A Ring S Davey Smith G Cohort Profile: the ‘children of the 90s’--the index offspring of the Avon Longitudinal Study of Parents and Children International Journal of Epidemiology 2013 42 111 127 22507743 PMC3600618
  21. [24]Fraser A Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort International Journal of Epidemiology 2012 42 97 110 22507742 PMC3600619
  22. [25]Cornish RP Macleod J Boyd A Tilling K Factors associated with participation over time in the Avon Longitudinal Study of Parents and Children: a study using linked education and primary care data Int J Epidemiol 2020 PMC7938505 33057662
  23. [26]Lotta LA Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity Cell 2019 177 597 607 e599 31002796 PMC6476272
  24. [28]Khera AV Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood Cell 2019 177 587 596 e589 31002795 PMC6661115
  25. [29]Krakoff J Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant Diabetes 2008 57 3267 3272 18835933 PMC2584132
  26. [30]Thearle MS Greater impact of melanocortin-4 receptor deficiency on rates of growth and risk of type 2 diabetes during childhood compared with adulthood in Pima Indians Diabetes 2012 61 250 257 22106157 PMC3237672
  27. [31]Tunç S Melanocortin-4 Receptor Gene Mutations in a Group of Turkish Obese Children and Adolescents J Clin Res Pediatr Endocrinol 2017 9 216 221 28218067 PMC5596802
  28. [33]Fry A Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population American journal of epidemiology 2017 186 1026 1034 28641372 PMC5860371
  29. [34]Majithia AR Prospective functional classification of all possible missense variants in PPARG Nature genetics 2016 48 1570 1575 27749844 PMC5131844
  30. [35]Chami N Preuss M Walker RW Moscati A Loos RJF The role of polygenic susceptibility to obesity among carriers of pathogenic mutations in MC4R in the UK Biobank population PLOS Medicine 2020 17 e1003196 32692746 PMC7373259
  31. [38]Richardson TG Sanderson E Elsworth B Tilling K Davey Smith G Use of genetic variation to separate the effects of early and later life adiposity on disease risk: mendelian randomisation study BMJ (Clinical research ed) 2020 369 m1203 PMC7201936 32376654
  32. [39]Northstone K The Avon Longitudinal Study of Parents and Children (ALSPAC): an update on the enrolled sample of index children in 2019 Wellcome Open Res 2019 4 51 51 31020050 PMC6464058
  33. [40]Howe LD Changes in ponderal index and body mass index across childhood and their associations with fat mass and cardiovascular risk factors at age 15 PLoS One 2010 5 e15186 21170348 PMC2999567
  34. [41]Wade KH Assessing the Causal Role of Body Mass Index on Cardiovascular Health in Young Adults Circulation 2018 138 2187 2201 30524135 PMC6250296
  35. [43]Leckie G Charlton C runmlwin: A Program to Run the MLwiN Multilevel Modeling Software from within Stata J Journal of Statistical Software 2013 52 40 2013

Cited by

Sorted by citations

Authors
Wade, K. H., Lam, B. Y. H., Melvin, A., Pan, W., Corbin, L. J., Hughes, D. A., Rainbow, K., Chen, J.-H., Duckett, K., Liu, X., Mokrosiński, J., Mörseburg, A., Neaves, S., Williamson, A., Zhang, C., Farooqi, I. S., Yeo, G. S. H., Timpson, N. J., & O’Rahilly, S.
Affiliations
  • University of Bristol (GB)
  • University of Cambridge (GB)
Corresponding author
  • Timpson, Nicholas J.
  • O’Rahilly, Stephen
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2021-05-27
Volume
27
Issue
6
Pages
1088-1096
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-021-01349-y
PMC
PMC7611835
OpenAlex
W3164363802
Cited by
133
References
8
Citations by year
2026: 19 · 2025: 35 · 2024: 26 · 2023: 17 · 2022: 23 · 2021: 13
FWCI
10.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • Explore Bristol Research (acceptedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (202802/Z/16/Z, 095515/Z/11/Z, 208363/Z/17/Z, 204813/Z/16/Z, 098497/Z/12/Z)
  • RCUK | Medical Research Council (MC_UU_00014/1, MC_UU_00014/5)
  • RCUK | Biotechnology and Biological Sciences Research Council (BB/S017593/1)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
melanocortin-4 receptor, obesity, adiposity, body mass index, fat mass, non-synonymous mutations, mutation prevalence, early adulthood, Avon Longitudinal Study of Parents and Children
MeSH terms
Loss of Function Mutation, Adolescent, Adult, Body Weight, Child, Child, Preschool, United Kingdom, Heterozygote, Humans, Infant, Infant, Newborn, Male, Obesity, Phenotype, Genetic Predisposition to Disease, Receptor, Melanocortin, Type 4, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review