Severe obesity as an oligogenic condition: evidence from 1714 adults seeking treatment in the UK National Health Service.

UNLABELLED: Previous evidence has established genetics as an important contributing factor to severe (class III) obesity, which is a chronic, relapsing condition, with a high burden of comorbidity and mortality. We therefore designed a custom genotyping array to screen a cohort of UK patients seeking treatment for severe obesity in a cost-effective way. A total of 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 50 K whole exome sequencing dataset. However, the clinical obesity cohort was more likely to carry two or more such variants, in separate genes, than UK Biobank participants (17.1% vs. 13%, p = 0 0.018), which strongly indicates the possibility of oligogenic inheritance. 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-025-00895-7.