Decoding the Genetic Landscape of Multiple Sclerosis: Insights from Low-Frequency and Rare Variants

Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease that primarily affects the central nervous system, leading to neurological disabilities in young adults. Despite extensive research, the genetic underpinnings of MS remain only partially understood, with common genetic variants identified by genome-wide association studies (GWAS) explaining approximately 20% of the disease’s heritability. A significant portion of MS heritability remains unexplained, sparking interest in the role of low-frequency and rare genetic variants in contributing to disease risk.

In a pivotal study published in Cell by the International Multiple Sclerosis Genetics Consortium (IMSGC), researchers embarked on a large-scale, multi-cohort analysis to uncover the contributions of low-frequency and rare-coding variants to MS risk. Their findings provide crucial insights into the genetic architecture of MS, revealing that these variants, often overlooked in GWAS, play a substantial role in disease heritability.

A Massive Effort to Uncover MS Susceptibility Genes
The study analyzed genetic data from an impressive cohort of 47,429 individuals with MS and 68,374 controls. This large-scale analysis allowed the researchers to identify 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), a key region already known for its involvement in MS. Additionally, they identified one variant on the X chromosome and 32 variants within the extended MHC. This extensive mapping effort led to the prioritization of 551 putative susceptibility genes, significantly expanding our understanding of the genetic factors involved in MS.

The Genetic Puzzle of MS Heritability
MS is characterized by a high heritability, with studies indicating that siblings of MS patients have a sevenfold increased risk of developing the disease. However, the common genetic variants identified so far explain only a fraction of this heritability, leaving researchers to explore other genetic factors that might contribute to the disease.

The IMSGC study utilized data from over 68,000 individuals, including 32,367 MS cases and 36,012 controls, across 14 different cohorts. By focusing on 120,991 low-frequency coding variants across the autosomal genome, the researchers aimed to assess their contribution to MS risk. These variants, including both non-synonymous (affecting protein structure) and synonymous (not affecting protein structure) variants, are less common in the population, making them challenging to detect in traditional GWAS.

Key Findings: Rare Variants and MS Risk
One of the most significant findings of this study is that low-frequency coding variants explain up to 5% of MS heritability, a substantial increase in the understanding of the genetic basis of the disease. The study identified seven low-frequency coding variants in six genes that are significantly associated with MS risk. These genes include:

PRF1 (Perforin 1): This gene plays a critical role in the immune response, particularly in the function of cytotoxic T cells and natural killer cells. The MS-associated variant in PRF1, p.Ala91Val, has been linked to decreased cytotoxicity, potentially leading to prolonged immune cell interactions and aberrant immune responses in MS.

HDAC7 (Histone Deacetylase 7): HDAC7 is involved in the regulation of T cell development and function. The identified variant, p.R166H, may influence T cell survival and the regulation of immune responses, further implicating immune dysregulation in MS pathogenesis.

TYK2 (Tyrosine Kinase 2): TYK2 is a kinase involved in signaling pathways critical for immune cell function. The p.P1104A variant in TYK2 has been associated with both protective and risk effects in different immune-related conditions, highlighting its complex role in MS.

PRKRA (Protein Kinase RNA-Activated): PRKRA is involved in the cellular response to viral infections and regulation of NF-κB signaling, a pathway known to be altered in MS. Variants in PRKRA may influence the inflammatory response in MS.

NLRP8 (NLR Family Pyrin Domain Containing 8): NLRP8 is part of the innate immune system, and the p.I942M variant identified in this study is specific to individuals of European ancestry, consistent with the higher prevalence of MS in these populations.

GALC (Galactocerebrosidase): GALC is involved in lipid metabolism, and the synonymous variant p.D84D, though not affecting protein structure, may have regulatory effects that contribute to MS risk.

Implications for MS Research and Treatment
The IMSGC’s findings provide a rich resource for further research into the genetic basis of MS. Future studies will need to explore the specific mechanisms by which these low-frequency variants influence disease risk and how they interact with other genetic and environmental factors. Moreover, the identification of these variants offers potential targets for therapeutic intervention, particularly in modulating immune responses in MS patients.

As genetic research continues to advance, studies like this one bring us closer to unraveling the complex genetic landscape of MS, offering hope for better diagnosis, treatment, and ultimately, prevention of this debilitating disease.

Reference:
Mitrovič, M., Patsopoulos, N. A., Beecham, A. H., Dankowski, T., Goris, A., Dubois, B., ... & Cotsapas, C. (2018). Low-frequency and rare-coding variation contributes to multiple sclerosis risk. Cell, 175(6), 1679-1687.