Contribution of Polygenic Scores to Progression Independent of Relapse Activity in Multiple Sclerosis

Area of Science:

• Neuroimmunology
• Genetics of Neurological Disorders
• Multiple Sclerosis Pathogenesis

Background:

• Multiple sclerosis (MS) patients often experience disability accrual independent of relapse activity (PIRA), even early in the disease.
• Understanding the genetic contribution to PIRA is crucial for predicting disease trajectory and developing targeted therapies.
• This study investigates the genetic underpinnings of PIRA in a cohort of Italian MS patients.

Purpose of the Study:

• To evaluate the genetic contribution to progression independent of relapse activity (PIRA) in multiple sclerosis (MS).
• To assess the association between polygenic risk scores (PRS) and the rate of PIRA events.
• To explore potential interactions between genetic risk and age at onset (AAO) in MS disability progression.

Main Methods:

• Polygenic risk scores (PRS) were derived from a large genome-wide association study on MS severity (>20,000 patients).
• PRS were computed at five p-value thresholds following a clumping procedure.
• Negative binomial regression models were used to test the association between PRS and the rate of PIRA events.

Main Results:

• A trend for association was observed between PRS and the rate of PIRA events in the overall cohort.
• This association was significant in patients with an age at onset (AAO) ≤ 50 years (Rate Ratio = 1.148, p = 0.0328).
• A significant mild antagonistic interaction effect was identified between PRS and AAO (p = 0.033).

Conclusions:

• Genetic factors, specifically severity-related genetic load, appear to influence the rate of PIRA events in MS.
• The impact of genetic risk on PIRA is more pronounced in individuals with an earlier disease onset (≤ 50 years).
• Findings suggest an age-dependent influence of genetic risk scores on MS disability accumulation, potentially due to less prominent aging effects in younger patients.