Multiple sclerosis severity variant in the DYSF–ZNF638 locus associates with increased neuronal loss and inflammation

A recent genome-wide association study identified homozygous carriership of the A allele at variant rs10191329 to associate with faster disability accrual in multiple sclerosis (MS). We investigated the impact of rs10191329AA carriership on MS pathology in the Netherlands Brain Bank MS cohort (n=290) and explored its impact on neuro-axonal damage, lymphocyte accumulation, and protein expression of the flanking genes dysferlin (DYSF) and zinc finger protein 638 (ZNF638) by comparing homozygous carriers (n=6) to non-carriers (rs10191329CC; n=12). Homozygous carriership associated with more amyloid precursor protein (APP)+ bulbs/axons, reflecting increased acute axonal stress, in normal-appearing white matter (NAWM) and white matter lesions, as well as with reduced neuronal density in cortical normal-appearing grey matter (NAGM). Further, homozygous carriers showed a higher proportion of active and mixed active/inactive lesions with foamy microglia, which associate with higher cerebrospinal fluid neurofilament light chain levels. DYSF and ZNF638 were expressed by neurons and oligodendrocytes. In homozygous carriers, NAWM was characterized by a higher proportion of ZNF638+ oligodendrocytes, and NAGM showed more DYSF+ cells. Unexpectedly, nuclear RNA sequencing did not show changes in DYSF or ZNF638 expression in oligodendrocytes and neurons but rather an upregulation of mitochondrial genes in homozygous carriers, specifically those associated with Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease that can have a mechanistic interaction with MS. These data suggest that the association between MS severity and rs10191329 may be driven by increased susceptibility to neurodegeneration, demyelination, and chronic inflammatory lesions. Further understanding of the role of DYSF and ZNF638 as well as LHON-associated mitochondrial pathways in MS pathology may reveal new therapeutic targets to attenuate MS progression.