title: Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis.
abstract: 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.
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Gu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
authors.forename: Jac C
authors.initials: JC
authors.lastname: Charlesworth
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Simpson
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Rohina
authors.initials: R
authors.lastname: Rubicz
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
authors.forename: Harald Hh
authors.initials: HH
authors.lastname: Göring
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA/Harvard Medical School, Boston, MA, USA/Broad Institute, Cambridge, MA, USA.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.affiliation: Monash Antibody Technologies Facility, Monash University, Melbourne, VIC, Australia.
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverty
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
authors.forename: Feitong
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Anjali
authors.initials: A
authors.lastname: Henders
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Ellis
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Mei
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Johnson
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia/Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia Bruce.Taylor@utas.edu.au.
authors.forename: Bruce V
authors.initials: BV
authors.lastname: Taylor
mesh_terms: D019309:Epstein-Barr Virus Nuclear Antigens; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D009103:Multiple Sclerosis / Q000209:etiology*; D012306:Risk
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; C417029:EBV-encoded nuclear antigen 1
keywords: EBNA-1; Epstein-Barr virus; GWAS; multiple sclerosis; non-HLA; polygenic risk