Genetic and Epigenetic Mechanisms in Multiple Sclerosis

Multiple sclerosis (MS) arises from a complex interplay between inherited genetic variants and dynamic epigenetic marks that collectively shape immune function and central nervous system integrity. The strongest genetic risk factor resides in the human leukocyte antigen (HLA) region, notably the HLA-DRB1*15:01 allele, but genome-wide association studies have revealed over 200 additional non-HLA loci involved in immune regulation, cell signalling and neural maintenance. These genetic variants influence antigen presentation, T and B lymphocyte activation, cytokine expression and blood–brain barrier permeability. Epigenetic mechanisms—primarily DNA methylation, histone modifications and non-coding RNAs—act as a reversible interface between genes and environment, modulating expression profiles in distinct cell types. Altered methylation patterns in immune cells and resident glia contribute to inflammatory demyelination, remyelination failure and neurodegeneration. Moreover, epigenetic age acceleration in lymphocyte subtypes suggests premature immunosenescence in MS. Elucidating the nexus of genetic predisposition and epigenetic regulation has opened avenues for precision risk profiling and novel therapies that target specific molecular mechanisms to attenuate immune-mediated damage and promote neural repair.

Research from Nature Portfolio

In a cross-tissue, multi-omic analysis of primary progressive MS, hypermethylation of the 1q21.1 locus was shown to be under genetic control and to regulate expression of CHD1L and PRKAB2 in the brain and blood. Functional assays, including CRISPR-mediated modulation, confirmed that methylation changes causally affect gene expression and neuronal functions, revealing a locus-specific genetic–epigenetic–transcriptional interplay in progressive disease.

An integrative study of the HLA-DRB1 region demonstrated that the DRB1*15:01 risk allele is hypomethylated in monocytes, leading to elevated gene expression. Mendelian randomisation provided evidence that methylation at an exon-2 differentially methylated region mediates genetic risk, while a protective variant was identified that increases methylation and reduces expression, suggesting epigenetic modulation as a therapeutic strategy.

Genetic and Epigenetic Mechanisms in Multiple Sclerosis publication trend

The graph below shows the total number of articles in genetic and epigenetic mechanisms in multiple sclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Single Nucleotide Polymorphism: A DNA sequence variation affecting a single base pair, often influencing disease susceptibility.

DNA Methylation: Addition of methyl groups to cytosine bases, modulating gene expression without altering the sequence.

Differentially Methylated Region (DMR): A genomic segment showing altered methylation patterns between conditions.

Epigenetic Age Acceleration: A discrepancy between biological and chronological age estimated from DNA methylation.

HLA-DRB1*15:01: A major allele in the human leukocyte antigen region conferring increased risk of MS.

References

1. A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis. Nature Communications (2024).
2. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nature Communications (2018).
3. Shared aetiology underlying multiple sclerosis and other immune mediated inflammatory diseases: Swedish familial co-aggregation and large-scale genetic correlation analyses. Journal of Autoimmunity (2024).
4. Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis. Frontiers in Immunology (2023).
5. Evaluation of Cell-Specific Epigenetic Age Acceleration in People With Multiple Sclerosis. Neurology (2023).