A higher burden of multiple sclerosis genetic risk confers an earlier onset

Age at onset of multiple sclerosis (MS) is an objective, influential predictor of the evolution of MS independent of disease duration.

Determine the influence of MS genetic predisposition on age of onset.

We conducted a comprehensive investigation of MS risk variants and age at onset in 3495 non-Latinx white individuals, including for combinations of HLA-DRB1*15:01 alleles and quintiles of an unweighted genetic risk score (GRS) for 198 of 200 autosomal MS risk variants that reside outside the major histocompatibility complex.

The mean age at onset was 32 years, 29% were male, and 46% were HLA-DRB1*15:01 carriers. For those with the greatest genetic risk burden (the highest GRS quintile with two HLA-DRB1*15:01 alleles) were on average 5 years younger at onset (p = 0.002) than those with the lowest genetic risk burden (the lowest GRS quintile with no HLA-DRB1*15:01 alleles). There was a strong inverse relationship between the MS genetic risk burden and age at onset of MS (p < 5 × 10^-8).

We demonstrate a significant gradient between elevated MS genetic risk burden and an earlier onset of MS, suggesting that a higher MS genetic risk burden accelerates onset of the disease.