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

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Zhou, Y., Zhu, G., Charlesworth, J. C., Simpson, Jr. S., Rubicz, R., Goring, H. H., Patsopoulos, N. A., Laverty, C., Wu, F., Henders, A., Ellis, J. J., van der Mei, I., Montgomery, G. W., Blangero, J., Curran, J. E., Johnson, M. P., Martin, N. G., Nyholt, D. R., Taylor, B. V., & ANZgene consortium. (2016). Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis. Multiple Sclerosis, 1-10.

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Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS).


We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk.


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).


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)).


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.



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