The genetics of multiple sclerosis: an updated perspective

Area of Science:

• Genetics
• Neuroimmunology
• Molecular Biology

Background:

• Multiple sclerosis (MS) is a complex autoimmune disease with a known polygenic susceptibility architecture.
• Previous research focused on genetic factors influencing MS susceptibility, primarily involving immune system pathways.
• Emerging research investigates the genetic underpinnings of MS disease progression and gene-environment interactions.

Purpose of the Study:

• To review recent advancements in understanding the genetics of multiple sclerosis (MS).
• To highlight the shift in focus from susceptibility genetics to genetics of disease progression.
• To explore the interplay between host genetics and environmental factors in MS pathogenesis.

Main Methods:

• Review of recent genetic studies in multiple sclerosis.
• Analysis of genome-wide association studies (GWAS) across diverse ancestries.
• Examination of evidence linking Epstein-Barr virus (EBV) and host genetics.

Main Results:

• Identification of the first locus (DYSF-ZNF638) associated with MS severity, indicating CNS-intrinsic progression mechanisms.
• Confirmation of known MS susceptibility loci and discovery of four new associations through multi-ancestry GWAS.
• Growing evidence supports critical gene-environment interactions, particularly involving EBV and host genetics, in MS development.

Conclusions:

• Genetic research is refining the understanding of MS pathogenesis, distinguishing immune-driven susceptibility from CNS-specific progression drivers.
• Future research directions include utilizing longitudinal cohorts and functional studies for translational applications.
• Advances promise improved prevention, prognostication, and treatment strategies for MS.