Genetics

As 2026 begins, multiple sclerosis genetics is increasingly readable in mechanistic terms rather than purely statistical associations. This post synthesizes several landmark 2024–2025 studies that collectively connect individual variants to specific immune cell programs, evolutionary history, and family-based rare-variant architectures. It highlights MPRA-based functional validation of thousands of MS-associated regulatory alleles in B cells, ancient-genome analyses showing how aggregated MS risk rose with steppe pastoralist ancestry and signals of positive selection at HLA-linked variants, and rare-variant burden studies indicating that predicted pathogenic coding variants in GWAS-implicated genes preferentially contribute to familial clustering. The post also summarizes our exome sequencing of 59 Turkish multiplex MS families, which implicates extracellular matrix and blood–brain barrier pathways—alongside incomplete HLA-DRB1*15:01 segregation—as population-specific contributors to susceptibility. Together, these results illustrate a shift toward clinically meaningful subgroups and actionable pathways defined by functional regulation, ancestry, and family-specific coding variation.