Genetic Susceptibility in Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system characterised by demyelination, neuroinflammation and varying degrees of neurodegeneration. Genetic factors account for a substantial proportion of disease risk and contribute to the wide heterogeneity observed in clinical presentation and progression. The HLA region on chromosome 6 remains the strongest susceptibility locus, with HLA-DRB1*15:01 conferring the highest individual risk. Beyond this, genome-wide studies have uncovered over 200 additional loci, implicating pathways involved in immune regulation, cytokine signalling and antigen presentation. Both common variants of modest effect size and rarer coding changes combine to influence disease susceptibility, while epigenetic mechanisms and cell-type specificity modulate the functional impact of these variants. Understanding this genetic architecture is pivotal for personalised risk prediction, mechanistic insight and the development of targeted interventions.

Research from Nature Portfolio

Recent studies have integrated genetic association data with cell-specific regulatory maps to reveal the principal contexts in which MS risk variants operate. Analyses of chromatin accessibility and histone modifications in immune and nervous-system cells demonstrate significant enrichment of susceptibility loci within regulatory regions of microglia, B cells and monocytes. Cell-specific polygenic risk scores have been shown to correlate with clinical phenotypes such as brain white-matter volume, underlining the relevance of particular cell types in disease pathogenesis. A complementary systems biology framework has further dissected genome-wide association signals into cell-specific susceptibility pathways, identifying distinct gene networks in T cells, B cells and monocytes that explain individual genetic risk profiles and offer avenues for precision therapeutics.

Genetic Susceptibility in Multiple Sclerosis publication trend

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

Technical terms

Genome-wide association study (GWAS): A high-throughput method to scan the genome for common variants associated with disease risk.

Polygenic risk score (PRS): A quantitative measure of cumulative genetic risk, calculated from multiple risk alleles.

Major histocompatibility complex (MHC): A genomic region encoding antigen-presentation molecules critical for immune recognition.

Microglia: Resident immune cells of the central nervous system that mediate inflammation and tissue homeostasis.

Rare-coding variant: An infrequent change in the protein-coding sequence that can have large effects on gene function.

Epigenetic regulation: Modifications of DNA or chromatin that influence gene expression without altering the underlying sequence.

References

1. Analysis of CNS autoimmunity in genetically diverse mice reveals unique phenotypes and mechanisms. JCI Insight (2024).
2. Integration of epigenetic and genetic profiles identifies multiple sclerosis disease-critical cell types and genes. Communications Biology (2023).
3. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell (2018).
4. Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects. PLOS Genetics (2013).
5. Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation. Science Advances (2016).
6. A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis. Nature Communications (2019).
7. Genome‐wide association studies of multiple sclerosis. Clinical & Translational Immunology (2018).