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

Mult Scler. 2016 Nov;22(13):1655-1664. doi: 10.1177/1352458515626598. Epub 2016 Jan 27.

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.

Keywords: EBNA-1; Epstein-Barr virus; GWAS; multiple sclerosis; non-HLA; polygenic risk.

Publication types

  • Meta-Analysis
  • Twin Study

MeSH terms

  • Epstein-Barr Virus Nuclear Antigens*
  • Genetic Loci
  • Genome-Wide Association Study*
  • Humans
  • Multiple Sclerosis / etiology*
  • Risk

Substances

  • Epstein-Barr Virus Nuclear Antigens
  • EBV-encoded nuclear antigen 1