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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Published in Nature Communications, v. 12, article no. 7078.

© 2021 The Author(s)

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

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The study was funded by a grant to PLD from the Massachusetts Life Sciences Center.

Related Content

The genotyping and DNA methylation data from our MS CD4+ T cell dataset have been deposited in the Synapse database under accession codes syn26340457 [https://doi.org/10.7303/syn26340457] and syn26339303 [https://doi.org/10.7303/syn26339303], respectively. As sensitive human data, these data can be accessed upon request, following the establishment of a Data Use Agreement with the Brigham and Women’s Hospital. The initial request can be sent to the corresponding author, and the applicants will be contacted within a week. The complete set of summary statistics from the cis-mQTL analysis are available for download from the Synapse database under accession code syn26339302 [https://doi.org/10.7303/syn26339302]. The genome-wide significant cis-mQTL effects can be found in Supplementary Data 1. Data from the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN) study used for the cis-mQTL replication analyses can be obtained from dbGaP under accession code phs000741.v2.p1 [https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000741.v2.p1]. BLUEPRINT Epigenome Project’s9 publicly available cis-mQTL summary statistics were downloaded from ftp.ebi.ac.uk/pub/databases/blueprint/blueprint_Epivar/. BLUEPRINT genetic data were accessed from the European Genome-phenome Archive under accession code EGAD00001002663.

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Supplementary information

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Supplementary data 1

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