Genetic and Epigenetic Links Between DNA and Brain Function in Multiple Sclerosis

Multiple sclerosis (MS) is a complex immune*mediated neurodegenerative disease where genetic, epigenetic, and environmental factors converge to trigger immune attacks on the central nervous system. While prior research has identified more than 100 susceptibility variants, including the well-known HLA-DRB1 locus in the major histocompatibility complex (MHC) region, much of MS's genetic architecture remains elusive. The study conducted by Andlauer et al. (2016) advances our understanding of MS susceptibility by uncovering novel genetic loci linked to the disease and offering new insights into the epigenetic mechanisms involved in MS pathogenesis.

The Power of a Homogeneous Population
In this genome-wide association study (GWAS), the researchers conducted an extensive analysis of 4,888 MS cases and 10,395 controls from German cohorts. This focus on a relatively homogeneous population—a key factor in minimizing genetic substructure—enabled them to detect associations that might be obscured in more diverse populations. By using a well-controlled and large sample size, they had the statistical power to detect significant genetic associations with moderate effect sizes, ultimately identifying 15 loci outside the MHC region that reached genome-wide significance, with four being novel susceptibility loci.

Novel Loci and Their Role in MS
Among the novel loci identified, genes such as L3MBTL3, MAZ, ERG, and SHMT1 emerged as promising candidates for MS susceptibility:
L3MBTL3: This gene encodes a Polycomb group protein, which plays a key role in maintaining the transcriptionally repressive state of genes. It is frequently deleted in acute leukemia, and its connection to transcriptional regulation positions it as a possible player in the immune dysfunction seen in MS.

MAZ: The MYC-associated zinc finger protein is a transcription factor involved in inflammation and is upregulated during chronic myeloid leukemia. Given its role in regulating the proto-oncogene MYC, which is implicated in immune regulation, MAZ could be an important factor in MS-related immune pathways.

ERG: A transcription factor essential for hematopoiesis, ERG has been linked to both acute myeloid leukemia and acute T-cell lymphoblastic leukemia. Its regulation of NF-κB, a critical mediator of inflammation, points to a potential mechanism by which ERG could influence MS development.

SHMT1: This serine hydroxymethyltransferase is involved in the folate cycle, a metabolic pathway essential for DNA methylation and one-carbon metabolism. The identification of SHMT1 as a novel MS susceptibility locus suggests that disturbances in methylation homeostasis might contribute to MS pathogenesis. Interestingly, the researchers found that the SHMT1 gene showed strong eQTL (expression quantitative trait locus) and mQTL (methylation quantitative trait locus) associations with MS, further emphasizing its potential role in epigenetic regulation.

Epigenetic Regulation and MS
The findings of this study highlight the importance of epigenetic regulation in MS susceptibility, particularly through DNA methylation. SHMT1's involvement in the generation of S-adenosylmethionine, a key methyl donor for DNA and protein methylation, suggests that alterations in methylation homeostasis could disrupt gene expression patterns critical for immune regulation. The mediation analysis conducted in the study supports the hypothesis that DNA methylation at specific CpG sites within SHMT1 partially explains the effect of genetic variation on gene expression.

These results align with growing evidence from other studies showing that epigenetic changes, such as DNA methylation and histone modifications, are associated with MS. Differential methylation patterns have been observed in various immune cell types, including CD8+ T cells and brain tissue from MS patients, further linking epigenetic mechanisms to MS pathogenesis.

Implications for Future Research
The discovery of novel MS susceptibility loci with potential roles in epigenetic regulation opens new avenues for research. Future studies should explore how these genetic variants interact with environmental risk factors, such as vitamin D deficiency or viral infections, to influence MS onset and progression. Additionally, investigating the role of DNA methylation in different cell types and tissues could provide further insights into the mechanisms by which genetic and environmental factors contribute to MS.

Moreover, replication of these findings in other populations, including genetically distinct cohorts like Sardinians, will be critical for validating the significance of these loci across diverse populations. The replication of the SHMT1 locus in the Sardinian cohort, as noted in the study, underscores the robustness of this association.

Conclusion
Andlauer et al. (2016) offer significant contributions to our understanding of MS genetics by identifying new susceptibility loci and highlighting the role of epigenetic regulation in disease pathogenesis. Their findings provide a more nuanced view of how genetic variants influence immune cell regulation and epigenetic mechanisms, reinforcing the importance of continued research into the genetic and environmental factors that drive MS. As we move forward, integrating genetic, epigenetic, and environmental data will be crucial for developing personalized therapeutic approaches to combat this debilitating disease.

References:
Andlauer, T. F., Buck, D., Antony, G., Bayas, A., Bechmann, L., Berthele, A., ... & Müller-Myhsok, B. (2016). Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation. Science advances, 2(6), e1501678.