Effects of Rare Coding Variants in Severe Early-Onset Obesity Genes in the Population-Based UK Biobank Study
Authors' conclusion
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. We also underscore the utility of population-based studies in supporting variant classifications.
Study context
- Population
- UK Biobank participants with whole-exome sequence data
- Participants
- 419,581 participants
- Exposure
- Heterozygous carriers of rare loss of function (LoF) variants in obesity genes vs noncarriers
- Outcome
- Population penetrance of obesity and associations with adult BMI and recalled childhood adiposity
Methodological detailswhole-exome sequence data, gene-based burden tests
- Whole-exome sequence data
- Gene-based burden tests
Main finding
As reported in the abstract
Obesity penetrance, experimentally characterized LoF variants (excluding MC4R): 22 heterozygous and 2 homozygous variants in POMC, PCSK1, LEPR, SH2B1, SIM1, KSR2
All P > .05
Observational data: associations, not effects.
Further findings
Adult body mass index (BMI), bioinformatically predicted rare heterozygous LoF variants in MC4R, PCSK1 and POMC (gene-based burden tests)
- Carriage associated with higher adult BMI; effect sizes ranged
- 0.5 to 2.5 kg/m², all P < .003
- No significant interaction with common variant polygenic risk of BMI
Original publication
Effects of Rare Coding Variants in Severe Early-Onset Obesity Genes in the Population-Based UK Biobank Study. J Clin Endocrinol Metab. Published 28 February 2025. doi:10.
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