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.