A genome-wide association study in progressive multiple sclerosis

Filippo Martinelli-Boneschi, Federica Esposito, Paola Brambilla, Eva Lindström, Giovanni Lavorgna, Jim Stankovich, Mariaemma Rodegher, Ruggero Capra, Angelo Ghezzi, Gabriella Coniglio, Bruno Colombo, Melissa Sorosina, Vittorio Martinelli, David Booth, Annette Bang Oturai, Graeme Stewart, Hanne F. Harbo, Trevor John Kilpatrick, Jan Hillert, Justin P. RubioHadi Abderrahim, Jerome Wojcik, Giancarlo Comi

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    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 (rs3129934T, pcombined=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 (rs996343G, pcombined=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.

    Original languageEnglish
    Pages (from-to)1384-1394
    Number of pages11
    JournalMultiple Sclerosis Journal
    Issue number10
    Publication statusPublished - Oct 2012



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

    ASJC Scopus subject areas

    • Neurology
    • Clinical Neurology

    Cite this

    Martinelli-Boneschi, F., Esposito, F., Brambilla, P., Lindström, E., Lavorgna, G., Stankovich, J., Rodegher, M., Capra, R., Ghezzi, A., Coniglio, G., Colombo, B., Sorosina, M., Martinelli, V., Booth, D., Oturai, A. B., Stewart, G., Harbo, H. F., Kilpatrick, T. J., Hillert, J., ... Comi, G. (2012). A genome-wide association study in progressive multiple sclerosis. Multiple Sclerosis Journal, 18(10), 1384-1394. https://doi.org/10.1177/1352458512439118