Illuminating the Role of Rare Genetic Variants in Multiple Sclerosis Susceptibility
Multiple sclerosis (MS) is a complex neurological disease whose genetic architecture has been extensively explored through genome-wide association studies. While these efforts have successfully identified more than 200 common susceptibility loci, a substantial proportion of MS heritability remains unexplained. This gap has increasingly directed attention toward rare and low-frequency genetic variants, which are poorly captured by conventional genotyping arrays but may exert meaningful biological effects. The study discussed here addresses this challenge by systematically investigating the contribution of such variants to MS susceptibility in a relatively homogeneous Italian continental population.
Beyond Common Variants: A Targeted Sequencing Strategy
To explore the role of rare genetic variation, the researchers adopted a targeted next-generation sequencing approach focused on 98 genes located within established MS risk loci. Rather than performing a genome-wide scan, they leveraged prior knowledge from large international studies to maximize statistical power. By sequencing pooled DNA samples from MS patients and matched healthy controls, the study achieved a cost-effective yet robust interrogation of low-frequency and rare variants that are often overlooked in large-scale association studies.
Gene-Based Burden Testing as an Analytical Framework
Recognizing that rare variants individually lack statistical power, the investigators employed gene-based burden and variance-component tests to assess the cumulative effect of multiple variants within the same gene. Several filtering strategies were applied, distinguishing disruptive, damaging, missense, synonymous, and regulatory variants. This flexible analytical framework allowed the authors to model different genetic architectures and identify genes in which rare variants collectively influence disease risk.
EFCAB13 Emerges as a Novel Susceptibility Gene
Across discovery and replication cohorts, one gene—EFCAB13—consistently showed the strongest association with MS. In particular, disruptive variants within this gene, including stop-gain and splice-site mutations, were significantly enriched in patients compared with controls. Among these, a specific stop-gain variant demonstrated a reproducible association across three independent cohorts, including an array-based dataset, underscoring the robustness of the signal.
Functional Evidence Supports a Biological Role
To move beyond statistical association, the authors conducted transcriptional analyses to explore the functional consequences of the identified stop-gain variant. Their experiments revealed that transcripts carrying this variant were absent at the RNA level, consistent with degradation via nonsense-mediated decay. Importantly, carriers of the variant exhibited reduced expression of EFCAB13, providing mechanistic support for the hypothesis that altered gene expression contributes to MS susceptibility.
Integrating Genetics with Immunological Context
Although EFCAB13 is a poorly characterized gene, in silico analyses offered intriguing clues about its potential role. Co-expression data linked EFCAB13 to genes involved in immune-related pathways, including those associated with Th1 and Th17 cells—key players in MS pathogenesis. These findings suggest that reduced expression of EFCAB13, driven in part by rare disruptive variants, may influence immune regulation in a manner relevant to disease development.
Implications for the Study of Complex Diseases
This study illustrates both the promise and the limitations of rare-variant analyses in complex diseases. While rare and low-frequency variants appear to explain only a modest fraction of MS heritability overall, the identification of EFCAB13 highlights how such variants can reveal novel biological insights that complement findings from common-variant studies. As sequencing technologies and reference panels continue to improve, integrating rare-variant discovery with functional validation will be essential for deepening our understanding of MS and other multifactorial disorders.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
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.
