Prevalence and expressivity of loss of function mutations in the Melanocortin 4 Receptor (MC4R) in a UK birth cohort

Mutations in the melanocortin 4 receptor gene ( MC4R ) have frequently been reported in severe early-onset human obesity but the prevalence and extent of phenotypic impact of such mutations are unclear. In a large UK birth cohort, we found that 17 of 5724 unrelated participants (∼1/337; 0.30%) were heterozygous for functionally deleterious mutations. At age 18 years, the mean difference in body weight, body mass index (BMI) and fat mass was 17.76kg (95% CI: 9.41, 26.10), 4.84kg/m2 (95% CI: 2.19, 7.49) and 14.78kg (95% CI: 8.56, 20.99), respectively, in carriers of loss of function (LoF) mutations compared to non-LoF carriers. Carriage of LoF mutations increased adiposity from as early as 5 years. MC4R LoF was associated with an impact on BMI at age 18 years that was approximately double that of a genome-wide polygenic risk score (comparing the upper 10th and lower 90th percentile). An extrapolation of incidence for MC4R LoF mutations from this birth cohort suggests that up to ∼200,000 people in the UK are likely to carry such mutations. This frequency, combined with the substantial impact of these variants on adiposity, has implications for public health, and drug development. ### Competing Interest Statement SOR has undertaken remunerated consultancy work for Pfizer, AstraZeneca, GSK, and ERX Pharmaceuticals. All other authors have declared no competing interests. ### Funding Statement The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Genome-wide association data was 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 KHW, NJT and SO serve as guarantors for the contents of this paper. KHW 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]. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), a work-package lead in the Integrative Cancer Epidemiology Programme (ICEP) that is supported by a Cancer Research UK programme grant (C18281/A19169) and works within the University of Bristol NIHR Biomedical Research Centre (BRC). DAH and LJC are supported by NJT's Wellcome Trust Investigator grant (202802/Z/16/Z) and work within the Medical Research Council Integrative Epidemiology Unit [MC\_UU\_00011]. BYHL is supported by a BBSRC Project Grant (BB/S017593/1). AM holds a PhD studentship supported jointly by the University of Cambridge Experimental Medicine Training Initiative (EMI) programme in partnership with AstraZeneca (EMI-AZ). ISF 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 JM). SOR and GSHY is supported by the MRC Metabolic Disease Unit (MC\_UU\_00014/1) and SOR by a Wellcome Trust Investigator award (WT 095515/Z/11/Z) and NIHR 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]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004) and Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Full details of the cohort and study design have been described previously and are available at http://www.alspac.bris.ac.uk. Please note that the study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool (http://www.bristol.ac.uk/alspac/researchers/our-data/). ALSPAC data are available through a system of managed open access. Data for this project was accessed under the project number B2891. 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