Uncovering the Role of Rare Genetic Variants in Multiple Sclerosis: Insights from the Italian Population
The study titled "Contribution of Rare and Low-Frequency Variants to Multiple Sclerosis Susceptibility in the Italian Continental Population" by Ferdinando Clarelli et al. aims to explore how rare and low-frequency genetic variants contribute to the risk of developing multiple sclerosis (MS). This research is a continuation of previous genome-wide association studies (GWAS), which identified over 200 common risk loci associated with MS but left a significant portion of the disease's heritability unexplained.
Overview of the Study
MS is a multifactorial disease characterized by chronic inflammation, demyelination, and axonal loss in the central nervous system. Both genetic and environmental factors play a role in the disease's onset. The genetic architecture of MS, as highlighted by previous GWAS, largely focuses on common variants, such as single nucleotide polymorphisms (SNPs), which explain around 50% of the heritability of MS. However, other factors such as rare variants, gene-gene interactions, and structural variations may also contribute to MS susceptibility, raising the issue of "missing heritability."
This study focuses on identifying rare and low-frequency functional variants that may explain additional heritability in MS. The authors sequenced 98 genes across two cohorts: 588 Italian MS patients and 408 matched healthy controls. They aimed to investigate the cumulative effect (burden) of rare variants in MS-associated regions.
Key Findings
Identification of Disruptive Variants in EFCAB13: The researchers found significant evidence of rare disruptive variants (such as stop-gain, stop-loss, and splice-site variants) in the EFCAB13 gene, which encodes for a protein with an unknown function. The stop-gain variant in EFCAB13 showed a significantly higher frequency in MS patients compared to healthy controls. Real-time PCR analysis further suggested that this stop-gain variant undergoes nonsense-mediated decay, leading to lower gene expression levels in carriers. This finding suggests that EFCAB13 could play a role in MS susceptibility.
Replication and Meta-Analysis: The disruptive variants in EFCAB13 were tested and confirmed in independent replication cohorts. A meta-analysis combining data from three cohorts strengthened the association of these variants with MS susceptibility. In particular, the stop-gain variant rs118004742 showed consistent association with MS across multiple cohorts, with a higher frequency observed in MS patients.
Contribution of Other Genes: The study also identified other candidate genes, such as MYC, which showed significant associations with MS in different variant categories, although the effect size was smaller than that of EFCAB13. Overall, the analysis suggests that rare variants in several genes may contribute to MS risk.
Gene-Based Testing Approach: To evaluate the contribution of rare variants, the researchers employed gene-wise tests, such as the weighted sum statistics (WSS) burden test and the variance component C-alpha test. This gene-based approach is advantageous in assessing the cumulative impact of multiple variants within a gene, improving the detection of genetic risk signals in complex diseases like MS.
Implications for MS Pathogenesis: The association of EFCAB13 with MS is a novel finding, and its role in immune regulation and calcium signaling (suggested by its EF-hand calcium-binding domain) could provide insights into the pathogenesis of MS. Although the exact function of EFCAB13 remains unclear, its involvement in immune-related pathways, such as Th1 and Th17 cell function, highlights its potential relevance in MS.
Conclusion
This study provides evidence that rare and low-frequency variants, particularly those in the EFCAB13 gene, contribute to MS susceptibility. While common variants identified through GWAS explain a substantial portion of MS heritability, rare variants in genes like EFCAB13 may account for additional risk, offering new insights into the genetic underpinnings of MS. The study underscores the importance of sequencing rare variants in known susceptibility loci and calls for further functional studies to elucidate the biological mechanisms by which these variants influence MS development.
The research emphasizes that rare variants may have an isoform-specific effect on gene expression, as observed in the case of EFCAB13. The down-regulation of this gene in MS patients may be a key factor in disease susceptibility, warranting further investigation into its role in immune function and MS pathogenesis.
References:
Clarelli, F., Barizzone, N., Mangano, E., Zuccalà, M., Basagni, C., Anand, S., ... & D'Alfonso, S. (2022). Contribution of rare and low-frequency variants to multiple sclerosis susceptibility in the Italian continental population. Frontiers in genetics, 12, 800262.
