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

Abstract

Background:

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

Objectives:

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

Methods:

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.

Results:

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).

Conclusion:

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.

Keywords

Epidemiology genetics multiple sclerosis age at onset genetic risk score

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