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Abstract

Background: The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established.

Objective: We aimed to identify genetic variants associated with progressive MS (PrMS).

Methods: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value<10⁻⁴) in two independent sets of primary progressive MS cases and controls.

Results: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934^T, p _combined=6.7×10^-16, OR=2.34, 95% CI=1.90–2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343^G, p _combined=2.4×10^-5, OR=0.70, 95% CI=0.59–0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a ‘cis’ effect on RNA expression in lymphoblastic cell lines, but pathway analyses of ‘trans’ effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p<0.01) and axonal guidance signalling (p<0.02).

Conclusions: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role.

Keywords

multiple sclerosis association studies in genetics single nucleotide polymorphism genome-wide association study primary progressive

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A genome-wide association study in progressive multiple sclerosis

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