Genetic subtypes of multiple sclerosis severity are uncoupled from inflammatory lesion burden.

Determinants of long-term disability in multiple sclerosis (MS) remain incompletely understood, with clinical course varying greatly among individuals. Recent integrative genetic models have identified genomic clusters associated with divergent disability trajectories. Here, we integrated clinical, genetic, and postmortem neuropathological data from 291 MS brain donors from the UK MS Society Tissue Bank to test whether genomic severity clusters converge on distinct tissue phenotypes. Consistent with prior stratification, donors in genomic cluster 2 had lower age-adjusted disease duration score (ADDS) than cluster 3 (β = - 0.195, P = 0.023) and a shorter interval from progression to death than cluster 1 (β = - 0.225, P = 0.049). However, this adverse clinical profile did not reflect greater active or chronic active lesion burden. Instead, chronic active broad-rim lesions were more frequent in cluster 1 than clusters 2 and 3 (37.3% vs 24.0% and 27.2%; both FDR = 0.043), whereas chronic inactive lesions were enriched in clusters 2 and 3 relative to cluster 1 (58.2% vs 70.0% and 73.8%; FDR = 0.154 and 0.030, respectively). This dissociation was strongly influenced by HLA genetic background: cluster 1 carried the highest HLA genetic burden, which was associated with greater non-lesional HLA-D immunoreactivity (rho = 0.48, FDR < 0.001), higher HLA-DRB1 (rho = 0.514, FDR < 0.001) and HLA-DRB5 (rho = 0.740, FDR < 0.001) mRNA expression, more active lesions (rho = 0.21, FDR = 0.007) and chronic active broad-rim lesions (rho = 0.19, FDR = 0.017), and fewer chronic inactive lesions (rho = - 0.26, FDR < 0.001), but not with clinical severity. Although chronic active lesion burden remained a strong tissue correlate of severity, adjustment for it strengthened the association between cluster 2 and worse outcome (ADDS: cluster 2 vs 1: β = - 0.216, Holm-adjusted P = 0.038; cluster 2 vs 3: β = - 0.246, Holm-adjusted P = 0.012; time from progression to death: cluster 2 vs 1: β = - 0.288, Holm-adjusted P = 0.049). Overall, these findings indicate that (i) HLA genetic background shapes the neuropathological representation of inflammatory lesions, and (ii) the adverse clinical profile of cluster 2 is not fully explained by HLA-D-defined chronic active lesion burden in the sampled postmortem tissue, suggesting that genomic severity clusters and chronic active lesion burden capture complementary aspects of MS progression.