Role of Rare Genetic Variants in Multiple Sclerosis Pathogenesis
Multiple sclerosis (MS) is a complex neuroinflammatory disorder with a substantial genetic component. While genome-wide association studies (GWAS) have successfully identified over 150 common variants associated with MS susceptibility, these variants collectively explain only a modest proportion of disease heritability. This discrepancy has driven renewed interest in the contribution of low-frequency and rare genetic variants, which may exert larger biological effects but are inherently more difficult to detect. The reviewed article synthesizes recent advances that leverage large international cohorts, family-based studies, and candidate gene approaches to address this gap in MS genetics.
Rare Coding Variants Identified Through Large-Scale Exome Analysis
One of the most significant studies discussed was conducted by the International Multiple Sclerosis Genetics Consortium using exome array data from more than 74,000 individuals across 12 countries. This large-scale approach enabled the identification of seven rare variants in six genes associated with MS risk. Notably, several of these genes—such as those involved in innate and adaptive immune responses—had not previously been implicated in MS. An unexpected finding was that most minor alleles conferred a protective effect, contrasting with the risk-increasing pattern typically observed for common variants. Despite its success, the study demonstrated that rare variants explain only an additional ~5% of MS heritability, underscoring the continued presence of unexplained genetic risk.
Targeting Phenotypic Overlap in Primary Progressive Disease
The article highlights a genome sequencing study focused specifically on primary progressive multiple sclerosis (PPMS), a less common and poorly understood disease subtype. By targeting genes known to cause hereditary spastic paraplegia—conditions with overlapping clinical features—the investigators identified pathogenic variants present exclusively in PPMS patients. Subsequent replication in larger cohorts strengthened the credibility of these findings. Importantly, the increased burden of such variants in PPMS relative to relapsing-onset MS suggests distinct pathogenic mechanisms and supports the stratification of MS phenotypes in genetic research.
Familial Studies and Shared Etiology with Monogenic Disorders
Another approach reviewed involved investigating families with multiple affected individuals to uncover rare variants segregating with disease. By focusing on genes responsible for MS-like monogenic disorders, researchers identified variants related to cholesterol metabolism and mitochondrial function. These findings expand the mechanistic framework of MS pathogenesis beyond immune dysregulation alone, implicating metabolic and bioenergetic pathways. The observation that multiple potentially relevant variants can coexist within a single family further reinforces the multigenic and heterogeneous nature of MS.
Linkage Analysis Reveals a Novel Candidate Gene
The review also discusses a linkage analysis conducted in a large Dutch family with a high prevalence of MS. This strategy led to the identification of a rare variant in an immunologically relevant gene that segregated with disease within the family. However, the absence of enrichment in sporadic MS cases highlights a recurring challenge in rare-variant research: variants may be highly penetrant in specific families yet contribute minimally to population-level risk. Such findings nevertheless provide valuable biological insight and may reveal pathways relevant to disease mechanisms.
Functional Validation of Purinergic Receptor Variants
A particularly notable strength of one of the reviewed studies was its inclusion of functional analyses. Rare variants affecting purinergic receptors—key mediators of inflammatory signaling—were shown to impair channel function and reduce phagocytic capacity. This direct link between genotype and cellular phenotype is essential for establishing biological plausibility and moves the field beyond purely statistical associations. The study also demonstrates the enduring value of well-phenotyped family cohorts in uncovering functionally relevant genetic variation.
Implications and Future Directions in MS Genetics
Collectively, the studies reviewed illustrate both the promise and the limitations of rare-variant discovery in multiple sclerosis. While rare variants contribute incrementally to heritability, their true value may lie in elucidating novel biological pathways and refining disease subtypes rather than in risk prediction alone. Future progress will likely depend on even larger datasets, integrative analytical methods, and systematic functional validation. As the genetic architecture of MS continues to unfold, these approaches will be critical for translating genetic insight into therapeutic innovation.
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:
Harding, K.E., Robertson, N.P. New rare genetic variants in multiple sclerosis. J Neurol 266, 278–280 (2019). https://doi.org/10.1007/s00415-018-9128-9
