Multiple Sclerosis (MS) is a common neuro-inflammatory disorder caused by a combination of environmental exposures and genetic risk factors.
To determine which environmental risk factors are associated with MS in UK Biobank, to validate an autosomal polygenic risk score for MS , and to determine whether genetic risk modifies the effect of environmental MS risk factors.
People with MS were identified within UK Biobank using ICD10-coded MS or self-report. Associations between environmental risk factors, HLA alleles, and MS risk were quantified using multivariable logistic regression. Interaction between environmental and genetic risk factors was quantified using the Attributable Proportion due to interaction (AP). Model fits were quantified using Nagelkerke’s pseudo-R2 metric.
Phenotype data were available for 2151 pwMS and 486,125 controls. Exposures associated with MS risk were childhood obesity (OR=1.39, 95%CI 1.22-1.58), smoking (OR=1.19, 95%CI 1.07-1.33), earlier menarche 0.95, 95%CI 0.92-0.98), HLA-DRB1*15 (ORHomozygote 5.05, 95%CI 4.22-6.05) and lack of the HLA-A*02allele (ORHomozygote=0.57, 95%CI 0.46-0.70). The autosomal polygenic risk score (PRS) was associated with MS disease status (ORTop-vs-bottom-decile=3.96, 95%CI 3.11-5.04). There was evidence of positive (synergistic) interaction between elevated childhood body size and the PRS (AP 0.11, 95% CI 0.008 to 0.202, p = 0.036), and weaker evidence suggesting a possible interaction between smoking status prior to age 20 and the PRS (AP 0.098, 95% CI -0.013 to 0.194, p = 0.082).
This study provides novel evidence for an interaction between childhood obesity and a high burden of autosomal genetic risk. These findings have significant implications for our understanding of MS biology, and inform targeted planning of prevention strategies.