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

ANZgene Consortium, Lotti Tajouri

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

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
Pages (from-to)1655-1664
Number of pages10
JournalMultiple Sclerosis
Volume22
Issue number13
DOIs
Publication statusPublished - 1 Nov 2016

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Epstein-Barr Virus Nuclear Antigens
Genetic Loci
Multiple Sclerosis
Genome-Wide Association Study
HLA Antigens
Meta-Analysis
Immunoglobulin G
Single Nucleotide Polymorphism
Epstein-Barr Virus Infections
Sample Size
Joints
Genome

Cite this

@article{fc3f4ca254744c9b84a1a323803efdd6,
title = "Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis",
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.",
author = "{ANZgene Consortium} and Yuan Zhou and Gu Zhu and Charlesworth, {Jac C.} and Steve Simpson and Rohina Rubicz and G{\"o}ring, {Harald H.H.} and Patsopoulos, {Nikolaos A.} and Caroline Laverty and Feitong Wu and Anjali Henders and Ellis, {Jonathan J.} and {Van Der Mei}, Ingrid and Montgomery, {Grant W.} and John Blangero and Curran, {Joanne E.} and Johnson, {Matthew P.} and Martin, {Nicholas G.} and Nyholt, {Dale R.} and Taylor, {Bruce V.} and Lotti Tajouri",
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language = "English",
volume = "22",
pages = "1655--1664",
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}

Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis. / ANZgene Consortium ; Tajouri, Lotti.

In: Multiple Sclerosis, Vol. 22, No. 13, 01.11.2016, p. 1655-1664.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis

AU - ANZgene Consortium

AU - Zhou, Yuan

AU - Zhu, Gu

AU - Charlesworth, Jac C.

AU - Simpson, Steve

AU - Rubicz, Rohina

AU - Göring, Harald H.H.

AU - Patsopoulos, Nikolaos A.

AU - Laverty, Caroline

AU - Wu, Feitong

AU - Henders, Anjali

AU - Ellis, Jonathan J.

AU - Van Der Mei, Ingrid

AU - Montgomery, Grant W.

AU - Blangero, John

AU - Curran, Joanne E.

AU - Johnson, Matthew P.

AU - Martin, Nicholas G.

AU - Nyholt, Dale R.

AU - Taylor, Bruce V.

AU - Tajouri, Lotti

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

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U2 - 10.1177/1352458515626598

DO - 10.1177/1352458515626598

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JO - Multiple Sclerosis

JF - Multiple Sclerosis

SN - 1352-4585

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