A New Year, A Clearer Map of MS Risk: Functional Variants, Ancient DNA, and Familial Rare Variations
The recent genetic studies on multiple sclerosis (MS) provide concrete examples of how individual variants, cell types, evolutionary history, and rare mutations contribute to disease risk, allowing a more mechanistic reading of MS genetics as 2026 begins. Focusing on several landmark papers from 2024–2025 highlights how the field is moving from association toward functionally validated causal alleles and clinically relevant subgroups.[1][2][3][4]
Functional dissection of risk variants in B cells
Granitto and colleagues (2025) used a Massively Parallel Reporter Assay (MPRA) to test 14,275 variants located in or near known MS risk loci, systematically quantifying allele-specific regulatory activity at genome scale. By applying the MPRA library to Epstein–Barr virus–transformed B-cell lines from two MS patients and the GM12878 lymphoblastoid line, they could measure whether each allele increased (enhancer) or decreased (silencer) reporter expression in a disease-relevant immune cell context. This approach demonstrated that 150 variants acted as allelic enhancers and 286 as allelic silencers, together implicating genotype-dependent regulatory mechanisms at 83 of 217 independent MS risk loci.[2]
Allelic enhancers, silencers and immune pathways
The MPRA results refined the understanding that most MS risk variants reside in non-coding regions, acting as regulatory “switches” rather than altering protein sequences. Many functional variants overlapped chromatin marks of active enhancers and transcription factor binding sites in B cells, linking specific alleles to altered expression of immune genes involved in antigen presentation, cytokine signalling and B-cell activation. Pathway analyses from this work support a model in which subtle allelic perturbations in B-cell regulatory networks collectively skew immune responses, helping to explain why B-cell–depleting therapies can be so effective despite MS historically being framed as a T-cell–driven disease.[5][2]
Ancient DNA and the rise of MS risk in steppe pastoralists
The Nature study on elevated MS genetic risk in steppe pastoralist populations used thousands of ancient genomes, spanning Mesolithic hunter–gatherers to Bronze Age and Medieval individuals, to trace how MS-associated alleles entered and spread across Europe. By integrating fine-mapped MS GWAS loci with local ancestry inference from UK Biobank, the authors calculated a weighted average prevalence of risk alleles for each ancestral component and found that steppe ancestry carried the highest aggregated MS genetic risk, particularly at HLA-region SNPs.[4]
Positive selection on MS-associated alleles
Selection modelling revealed a significant polygenic selection gradient on MS risk between roughly 5,000 and 2,000 years ago, with especially strong signals along Western and Eastern hunter–gatherer–derived lineages that contributed to steppe pastoralists. One of the strongest drivers of changing genetic risk over time was rs3129934, a variant tagging the HLA-DRB1*15:01 haplotype, which is the major MS risk allele in modern European populations. The study proposes that infectious pressures, shifts in diet and population density, and new pathogen exposures may have favoured immune alleles that today increase MS susceptibility, illustrating how past adaptation can underlie present-day autoimmune risk.[4]
Rare variants in familial MS and GWAS genes
A 2025 Scientific Reports study focused on familial MS (FMS) to test whether rare, predicted pathogenic coding variants in genes highlighted by GWAS are enriched in multiplex families compared with sporadic MS (SMS) and controls. Using a panel of 111 GWAS-associated genes, the authors sequenced 87 FMS patients, 89 SMS patients, and 3,866 controls and quantified the burden of rare, predicted pathogenic variants (RPP) in each group. RPP variants were significantly overrepresented in the combined MS group and, more strikingly, in FMS relative to controls, while SMS did not show an increased burden, indicating that rare coding variants in GWAS genes preferentially contribute to familial clustering of MS.[3]
Specific rare-variant genes and biological implications
Gene-level burden analyses identified six genes—LAMA5, ALPK2, ANKRD55, INTS8, IQCB1, JADE2 and MALT1—as significantly enriched for rare, predicted pathogenic variants in familial MS. Several of these genes participate in immune regulation and signalling; for example, ANKRD55 has been implicated in T-cell function, and MALT1 encodes a paracaspase involved in NF-κB activation, consistent with an exaggerated or dysregulated immune response in carriers. Heritability modelling cited in the paper suggests that rare and low-frequency coding variants may account for up to about 5% of overall MS heritability, complementing the polygenic contribution of common non-coding variants and helping explain strong family histories in a subset of patients.[3]
Low-frequency and rare variants in Turkish multiplex MS families
Our study (2025) extended this rare-variant framework to one of the largest family-based MS cohorts from Türkiye, sequencing 215 individuals from 59 Turkish multiplex MS families to evaluate low-frequency and rare coding variants in an admixed population. Whole exome sequencing followed by segregation and gene-based burden analyses identified 38,851 filtered low-frequency and rare variants across 14,036 genes, with particular enrichment of variants in extracellular matrix (ECM)–related genes such as LAMA5 and LAMB1 and hemidesmosome-associated genes including DST and PLEC. Exome-wide segregation showed that HLA-DRB1*15:01 completely segregated with MS in only one family and incompletely in five, while ECM- and blood–brain barrier–related pathways (ECM–receptor interaction, focal adhesion, laminin interaction and collagen formation) emerged as key processes, indicating that population-specific structural and barrier genes can cooperate with classical immune risk alleles to shape familial MS susceptibility in Turkish families.[1]
Integrating functional, evolutionary, and familial insights
Taken together, these studies show how MS genetics is progressing from statistical associations toward mechanistic clarity by combining functional assays, population genomics and deep phenotyping in high-risk families. MPRA-defined regulatory alleles in B cells provide concrete molecular targets whose evolutionary trajectory can be reconstructed in ancient populations, while rare coding variants in GWAS genes and exome-defined ECM-related genes sharpen the picture of why some families and ancestries show heavy MS aggregation. As 2026 begins, such integrative work is expected to inform more nuanced risk stratification, from polygenic scores tuned by ancestry to family-specific counselling and, eventually, targeted interventions against pathways illuminated by both common regulatory variants and population-specific low-frequency coding variants.[1][2][4][3]
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:
1. Barton, A. R., et al. (2024). Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. *Nature, 625*(7994), 321–329.
2. Büyükgöl, F., Gürdamar, B., Bülbül, A. A., et al. (2025). Exome sequencing reveals low-frequency and rare variant contributions to multiple sclerosis susceptibility in Turkish families. *Scientific Reports, 15*, Article 94691.
3. Granitto, M., Lawson, L. P., & Kottyan, L. C. (2025). Genome-wide discovery of multiple sclerosis genetic risk variant allelic regulatory activity. *G3: Genes|Genomes|Genetics, 15*(11), jkaf192.
4. Žnidarič, T., et al. (2025). Increased burden of rare variants in GWAS associated genes in familial multiple sclerosis. *Scientific Reports, 15*, 12345.
