Severe obesity may be an oligogenic condition: evidence from 1,714 adults seeking treatment in the UK National Health Service

Severe (class III) obesity is a chronic, relapsing condition, with a high burden of co-morbidity and mortality. Previous evidence has established genetics as an important contributing factor. We therefore designed a custom genotyping array to screen a cohort of UK patients seeking treatment for severe obesity. 1,714 participants were genotyped using a custom AXIOM array, focusing on rare (minor allele frequency <0.01) variants, with CADD-PHRED ≥15 in 78 genes known/suspected to cause Mendelian forms of obesity. Concordance analyses of 22 duplicate samples and 66 samples with whole exome sequence data revealed good genotyping reliability. We identified the proportion of study participants who carried, or were homozygous for, rare, predicted-deleterious variants in genes with dominant and recessive modes of inheritance (MOI), respectively. 27% of patients carried relevant mutations consistent with the expected MOI, which was very similar to the rate observed in the UKB 50K whole exome sequencing dataset. However, the clinical obesity cohort were more likely to carry two or more such variants, in separate genes, than UK Biobank participants (p = 0.018). In conclusion, our results provide evidence: that (i) custom genotyping arrays, used with improved algorithms can allow reliable, cost-effective screening for rare genetic variants; (ii) rare mutations in “obesity genes” may be at high prevalence among bariatric patients, as well as in the general population; and (iii) that severe obesity may have an oligogenic pattern of inheritance in some cases. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Sumaya Almansoori was funded by the Ministry of Higher Education, United Arab Emirates. ### 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 collection and use of data for the PMMO study was given by the NRES Committee London Riverside (REC reference 11\LO\0935) and the research was performed in accordance with the principles of the Declaration of Helsinki. All participants gave informed consent. Also, This research was also approved by Brunel University London Ethics committee application number 26158. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors