OUP accepted manuscript

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the central nervous system. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41,505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [UKBB, area under the curve (AUC) = 0.73, 95% CI: 0.72-0.74, P = 6.41e-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5e-53). Individuals within the top 10% of PRS were at greater than five-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8e-45) and fifteen-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7e-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS increased the risk discrimination by 13% to 26% over models based only on conventional multiple sclerosis risk factors, such as smoking and mononucleosis infection, in UKBB and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signaling cascades, nominated promising genetic candidate programs for functional characterization. These pathways include inflammatory signaling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multi-case families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.