Genetics

This blog post critically examines the UK Biobank case–control study by Jacobs and colleagues, which tests whether polygenic susceptibility to multiple sclerosis (MS) modifies the impact of established early-life environmental risk factors. Using externally weighted polygenic risk scores (constructed with and without the major histocompatibility complex) and multivariable logistic regression, the study confirms associations of MS with childhood body size (as a proxy for childhood obesity), smoking before age 20, and earlier age at menarche, and then evaluates interaction on both additive and multiplicative scales. The principal finding is robust additive interaction between childhood obesity proxy and genome-wide genetic risk (attributable proportion ≈ 0.17), suggesting that the effect of childhood adiposity on MS risk is amplified among individuals with higher inherited burden—an observation with direct implications for mechanistic hypotheses and genetically informed prevention strategies.