MC4R and obesity due to melanocortin 4 receptor deficiency: 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 < .003), with no significant interaction effects with common variant polygenic risk of BMI.<h4>Conclusion</h4>This study provides the population-specific report of variant penetrance of known obesity genes and confirmed the heterozygous rare variant effects in MC4R, POMC, and PCSK1.