Genetic Risk in Multiple Sclerosis: Susceptibility, Modifiers and Unresolved Questions

Area of Science:

• Neurology
• Immunology
• Genetics

Background:

• Multiple sclerosis (MS) is a chronic, immune-mediated central nervous system disorder.
• Its etiology involves complex interactions between genetic susceptibility, environmental factors, and immune processes.
• Recent genomic studies have significantly advanced understanding of MS pathogenesis.

Purpose of the Study:

• To synthesize current evidence on the genetic architecture of MS.
• To explore biological mechanisms linking genetic risk to disease susceptibility.
• To review gene-environment interactions and their impact on clinical outcomes, prognosis, and treatment response.

Main Methods:

• Review of large-scale genomic studies, including genome-wide association studies (GWAS).
• Analysis of family-based studies to identify rare susceptibility variants.
• Synthesis of evidence on gene-environment interactions (e.g., Epstein-Barr virus, vitamin D, obesity, smoking).

Main Results:

• MS risk is highly polygenic, driven by immune regulatory mechanisms.
• 233 common susceptibility variants identified, with strongest effects in the Major Histocompatibility Complex (MHC), particularly HLA-DRB1*15:01.
• Genetic risk alone is insufficient; gene-environment interactions are critical for disease manifestation.

Conclusions:

• Genetic factors and their interplay with environmental exposures significantly shape MS susceptibility and clinical outcomes.
• Further research, including ancestry-diverse studies and multi-omics integration, is needed.
• Translating genetic insights into clinical care remains a key future direction.