Effects of rare coding variants in severe early-onset obesity genes in the population-based UK Biobank study

Objectives: Clinical case-based studies have identified rare pathogenic variants in several genes as causes of severe early-onset obesity, but their penetrance and interaction with polygenic susceptibility in the general population remain unclear. We analysed the UK Biobank (UKBB) whole exome sequence data to assess the effects of heterozygous variants in nine previously reported genes on adult BMI and recalled childhood adiposity. Methods: Among 419,581 UKBB participants, we identified heterozygous carriers of coding variants that were i) experimentally-characterised as loss-of-function (LoF), or ii) bioinformatically-predicted as rare (minor allele frequency 0.05). For bioinformatically-predicted rare LoF variants, gene-based burden tests showed that carriage of heterozygous variants in MC4R, PCSK1, and POMC was associated with higher adult BMI (effect sizes ranged from 0.5 to 2.5 kg/m2, all P