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

Yuan Zhou; Gu Zhu; Jac C. Charlesworth; Steve Simpson; Rohina Rubicz; Harald H.H. Göring; Nikolaos A. Patsopoulos; Caroline Laverty; Feitong Wu; Anjali Henders; Jonathan J. Ellis; Ingrid Van Der Mei; Grant W. Montgomery; John Blangero; Joanne E. Curran; Matthew P. Johnson; Nicholas G. Martin; Dale R. Nyholt; Bruce V. Taylor

doi:10.1177/1352458515626598

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

Yuan Zhou, Gu Zhu, Jac C. Charlesworth, Steve Simpson, Rohina Rubicz, Harald H.H. Göring, Nikolaos A. Patsopoulos, Caroline Laverty, Feitong Wu, Anjali Henders, Jonathan J. Ellis, Ingrid Van Der Mei, Grant W. Montgomery, John Blangero, Joanne E. Curran, Matthew P. Johnson, Nicholas G. Martin, Dale R. Nyholt, Bruce V. Taylor

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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 (N_eff) = 5555) and a large MS GWAS (N_eff = 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 language	English (US)
Pages (from-to)	1655-1664
Number of pages	10
Journal	Multiple Sclerosis
Volume	22
Issue number	13
DOIs	https://doi.org/10.1177/1352458515626598
State	Published - Nov 1 2016

Keywords

EBNA-1
Epstein-Barr virus
GWAS
multiple sclerosis
non-HLA
polygenic risk

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1177/1352458515626598

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Zhou, Y., Zhu, G., Charlesworth, J. C., Simpson, S., Rubicz, R., Göring, H. 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. (2016). Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis. Multiple Sclerosis, 22(13), 1655-1664. https://doi.org/10.1177/1352458515626598

Zhou, Y, Zhu, G, Charlesworth, JC, Simpson, S, Rubicz, R, Göring, HHH, Patsopoulos, NA, Laverty, C, Wu, F, Henders, A, Ellis, JJ, Van Der Mei, I, Montgomery, GW, Blangero, J, Curran, JE, Johnson, MP, Martin, NG, Nyholt, DR & Taylor, BV 2016, 'Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis', Multiple Sclerosis, vol. 22, no. 13, pp. 1655-1664. https://doi.org/10.1177/1352458515626598

@article{5d7df227980a49759ee76456815851d0,

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.",

keywords = "EBNA-1, Epstein-Barr virus, GWAS, multiple sclerosis, non-HLA, polygenic risk",

author = "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.}",

note = "Funding Information: QIMR Twin Family Cohort Study: We thank the Brisbane twins and their families for their participation. Funding: Australia National Health and Medical Research Council (NHMRC; grants 486682, 1009064, 389875). Mexican-American families EBNA-1 GWAS: We thank the participants of the San Antonio Family Heart Study and San Antonio Family Diabetes/Gallbladder Study. Funding: NIH R01 grant HL080149, HL045522, HL080149, DK053889, and DK047482. MS GWAS Meta-Analysis: We thank all the participants involved in the MS study and thank those who have contributed datasets to dbGaP and the ANZgene consortium for providing access to genotyped data. SSJ was supported by the MS Research Australia Postdoctoral Research Fellowship. DRN was supported by the Australian Research Council (FT0991022) and National Health and Medical Research Council (APP0613674). IvdM is supported by an Australian Research Council Future Fellowship. NAP is supported by a Career Independence Award from the National Multiple Sclerosis Society. Publisher Copyright: {\textcopyright} The Author(s), 2016.",

year = "2016",

month = nov,

day = "1",

doi = "10.1177/1352458515626598",

language = "English (US)",

volume = "22",

pages = "1655--1664",

journal = "Multiple Sclerosis Journal",

issn = "1352-4585",

publisher = "SAGE Publications Ltd",

number = "13",

}

TY - JOUR

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

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.

N1 - Funding Information: QIMR Twin Family Cohort Study: We thank the Brisbane twins and their families for their participation. Funding: Australia National Health and Medical Research Council (NHMRC; grants 486682, 1009064, 389875). Mexican-American families EBNA-1 GWAS: We thank the participants of the San Antonio Family Heart Study and San Antonio Family Diabetes/Gallbladder Study. Funding: NIH R01 grant HL080149, HL045522, HL080149, DK053889, and DK047482. MS GWAS Meta-Analysis: We thank all the participants involved in the MS study and thank those who have contributed datasets to dbGaP and the ANZgene consortium for providing access to genotyped data. SSJ was supported by the MS Research Australia Postdoctoral Research Fellowship. DRN was supported by the Australian Research Council (FT0991022) and National Health and Medical Research Council (APP0613674). IvdM is supported by an Australian Research Council Future Fellowship. NAP is supported by a Career Independence Award from the National Multiple Sclerosis Society. Publisher Copyright: © The Author(s), 2016.

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.

KW - EBNA-1

KW - Epstein-Barr virus

KW - GWAS

KW - multiple sclerosis

KW - non-HLA

KW - polygenic risk

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JO - Multiple Sclerosis Journal

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

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