Zhou, Y and Zhu, G and Charlesworth, JC and Simpson Jr, S and Rubicz, R and Goring, HHH and Patsopoulos, NA and Laverty, C and Wu, F and Henders, A and Ellis, JJ and van der Mei, I and Montgomery, GW and Blangero, J and Curran, JE and Johnson, MP and Martin, NG and Nyholt, DR and Taylor, BV, ANZgene consortium, Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis, Multiple Sclerosis Journal, 22, (13) pp. 1655-1664. ISSN 1352-4585 (2016) [Refereed Article]
Copyright 2016 the authors
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.
|Item Type:||Refereed Article|
|Keywords:||Epstein-Barr virus, EBNA-1, multiple sclerosis, GWAS, polygenic risk, non-HLA|
|Research Division:||Biomedical and Clinical Sciences|
|Research Field:||Central nervous system|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Zhou, Y (Mr Yuan Zhou)|
|UTAS Author:||Charlesworth, JC (Dr Jac Charlesworth)|
|UTAS Author:||Simpson Jr, S (Dr Steve Simpson JR)|
|UTAS Author:||Wu, F (Dr Feitong Wu)|
|UTAS Author:||van der Mei, I (Professor Ingrid van der Mei)|
|UTAS Author:||Taylor, BV (Professor Bruce Taylor)|
|Web of Science® Times Cited:||24|
|Deposited By:||Menzies Institute for Medical Research|
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