Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis

Yuan Zhou, Gu Zhu, Jac C. Charlesworth, Steve Simpson, Rohina Rubicz, Harald H.H. Göring, Nikolaos A. Patsopoulos, Caroline Laverty, Feitong Wu, Anjali Henders, Jonathan J. Ellis, Ingrid Van Der Mei, Grant W. Montgomery, John Blangero, Joanne E. Curran, Matthew P. Johnson, Nicholas G. Martin, Dale R. Nyholt, Bruce V. Taylor

    Research output: Contribution to journalArticlepeer-review

    23 Scopus citations

    Abstract

    Background: Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS). Objective: We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk. Methods: We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size (Neff) = 5555) and a large MS GWAS (Neff = 15,231). Results: We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 (p = 4.11 × 10-9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP (p = 3.32 × 10-20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance (p < 5 × 10-8). Conclusions: Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.

    Original languageEnglish (US)
    Pages (from-to)1655-1664
    Number of pages10
    JournalMultiple Sclerosis
    Volume22
    Issue number13
    DOIs
    StatePublished - Nov 1 2016

    Keywords

    • EBNA-1
    • Epstein-Barr virus
    • GWAS
    • multiple sclerosis
    • non-HLA
    • polygenic risk

    ASJC Scopus subject areas

    • Neurology
    • Clinical Neurology

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