Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis

Abstract

Introduction: Permanent disability in multiple sclerosis (MS) is primarily driven by neuronal and axonal loss. While genome-wide association (GWAS) studies have begun identifying genetic variants associated with the clinical course of MS, the variants underpinning pathological severity have not been described. Understanding these novel variants and their influence on the clinical course of MS can be used to further develop our knowledge of this heterogenous disease.Aims: To uncover genetic variants and describe the expression of mapped genes that associate with the pathological severity of MS.Methods: Using data from an integrated GWAS expression quantitative trait loci COLOCation (eQTL COLOC) analysis of progressive MS (n = 310), we investigated the association between gene variant status and neuron density, extent of demyelination and retrospectively determined clinical milestones. In situ hybridisation (ISH) revealed gene expression and localisation in a subset of MS and controls (n = 20).Results: Previously described variant rs7289446 (SEZ6L) was not associated with quantitative measures of neuron density, demyelination or clinical outcomes. A 2nd variant mapping to DYSF:CYP26B1 (rs7564433), which represents the first GWAS validated mapped gene (rs10191329), was associated with higher neuron density, lower demyelination, slower disease progression and an older age at death in heterozygote allele carriers (p < 0.05). Independent single nucleotide polymorphisms (SNPs), mapping to PCSK5 and COMMD10, genes not previously linked to MS, were associated with increased neuron density in the thalamus, pons (p < 0.05; PCSK5) and frontal cortex (p <0.05; COMMD10), specifically among heterozygous carriers. The average age of onset was 4.6 yrs lower in COMMD10 major allele carriers compared to heterozygotes.COMMD10 and PCSK5 neuronal and glial expression was elevated in normal MS grey matter (GM) compared to control and lesion GM.Summary: We describe gene variants that associate with neuron density and show the altered expression of mapped genes in MS. Our findings provide insights into biological mechanisms underlying MS severity, offering potential opportunities for targeted therapies and personalised MS care