Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome

Tina Roostaei; Hans Ulrich Klein; Yiyi Ma; Daniel Felsky; Pia Kivisäkk; Sarah M. Connor; Alexandra Kroshilina; Christina Yung; Belinda J. Kaskow; Xiaorong Shao; Brooke Rhead; José M. Ordovás; Devin M. Absher; Donna K. Arnett; Jia Liu; Nikolaos Patsopoulos; Lisa F. Barcellos; Howard L. Weiner; Philip L. De Jager

doi:10.1038/s41467-021-27427-w

Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome

Tina Roostaei, Hans Ulrich Klein, Yiyi Ma, Daniel Felsky, Pia Kivisäkk, Sarah M. Connor, Alexandra Kroshilina, Christina Yung, Belinda J. Kaskow, Xiaorong Shao, Brooke Rhead, José M. Ordovás, Devin M. Absher, Donna K. Arnett, Jia Liu, Nikolaos Patsopoulos, Lisa F. Barcellos, Howard L. Weiner, Philip L. De Jager

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Abstract

Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+ T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.

Original language	English
Article number	7078
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27427-w
Publication status	Published - Dec 2021
Externally published	Yes

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Roostaei, T., Klein, H. U., Ma, Y., Felsky, D., Kivisäkk, P., Connor, S. M., Kroshilina, A., Yung, C., Kaskow, B. J., Shao, X., Rhead, B., Ordovás, J. M., Absher, D. M., Arnett, D. K., Liu, J., Patsopoulos, N., Barcellos, L. F., Weiner, H. L., & De Jager, P. L. (2021). Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome. Nature Communications, 12(1), [7078]. https://doi.org/10.1038/s41467-021-27427-w

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title = "Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome",

abstract = "Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+ T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.",

author = "Tina Roostaei and Klein, {Hans Ulrich} and Yiyi Ma and Daniel Felsky and Pia Kivis{\"a}kk and Connor, {Sarah M.} and Alexandra Kroshilina and Christina Yung and Kaskow, {Belinda J.} and Xiaorong Shao and Brooke Rhead and Ordov{\'a}s, {Jos{\'e} M.} and Absher, {Devin M.} and Arnett, {Donna K.} and Jia Liu and Nikolaos Patsopoulos and Barcellos, {Lisa F.} and Weiner, {Howard L.} and {De Jager}, {Philip L.}",

note = "Funding Information: We are grateful to all the participants for their invaluable contribution to the study. We also thank Albert Boulanger for helping with data organization for the purpose of sharing the summary statistics. The study was funded by a grant to PLD from the Massachusetts Life Sciences Center. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-27427-w",

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Roostaei, T, Klein, HU, Ma, Y, Felsky, D, Kivisäkk, P, Connor, SM, Kroshilina, A, Yung, C, Kaskow, BJ, Shao, X, Rhead, B, Ordovás, JM, Absher, DM, Arnett, DK, Liu, J, Patsopoulos, N, Barcellos, LF, Weiner, HL & De Jager, PL 2021, 'Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome', Nature Communications, vol. 12, no. 1, 7078. https://doi.org/10.1038/s41467-021-27427-w

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AU - Roostaei, Tina

AU - Klein, Hans Ulrich

AU - Ma, Yiyi

AU - Felsky, Daniel

AU - Kivisäkk, Pia

AU - Connor, Sarah M.

AU - Kroshilina, Alexandra

AU - Yung, Christina

AU - Kaskow, Belinda J.

AU - Shao, Xiaorong

AU - Rhead, Brooke

AU - Ordovás, José M.

AU - Absher, Devin M.

AU - Arnett, Donna K.

AU - Liu, Jia

AU - Patsopoulos, Nikolaos

AU - Barcellos, Lisa F.

AU - Weiner, Howard L.

AU - De Jager, Philip L.

N1 - Funding Information: We are grateful to all the participants for their invaluable contribution to the study. We also thank Albert Boulanger for helping with data organization for the purpose of sharing the summary statistics. The study was funded by a grant to PLD from the Massachusetts Life Sciences Center. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+ T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.

AB - Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+ T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.

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JO - Nature Communications

JF - Nature Communications

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Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome

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