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bioRxiv · 10.1101/2020.07.11.198721

Impact of genetic susceptibility to multiple sclerosis on the T cell epigenome: proximal and distal effects

Tina Roostaei·Hans-Ulrich Klein·Daniel Felsky·Pia Kivisakk·Sarah M. Connor·Alexandra Kroshilina·Christina Yung·Yiyi Ma·Belinda J. Kaskow·Xiaorong Shao·Brooke Rhead·Jia Liu·Nikolaos Patsopoulos·Lisa F. Barcellos·Howard L. Weiner·Philip L. De Jager
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Abstract

We establish a genome-wide map of DNA methylation quantitative trait locus (mQTL) effects in CD4+ T cells isolated from multiple sclerosis (MS) patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both MS susceptibility and local (cis-) DNA methylation. We also identify two distant (trans-) mQTL effects of MS susceptibility loci: (1) a chromosome 16 MS locus affects PRDM8 methylation (a chromosome 4 region not previously associated with MS susceptibility), and (2) the aggregate effect of MS variants in the major histocompatibility complex (MHC, chromosome 6) influences DNA methylation near PRKCA on chromosome 17. Both effects are replicated in independent samples. Overall, we present a new methylome-wide mQTL resource for a key cell type in inflammatory disease research, uncover functional consequences of MS susceptibility variants, including the convergence of MHC risk alleles onto a new gene target involved in predisposition to MS.

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Tina Roostaei, Hans-Ulrich Klein, Daniel Felsky, Pia Kivisakk, Sarah M. Connor, Alexandra Kroshilina, Christina Yung, Yiyi Ma, Belinda J. Kaskow, Xiaorong Shao, Brooke Rhead, Jia Liu, Nikolaos Patsopoulos, Lisa F. Barcellos, Howard L. Weiner, Philip L. De Jager. 2020-07-12. Impact of genetic susceptibility to multiple sclerosis on the T cell epigenome: proximal and distal effects. https://doi.org/10.1101/2020.07.11.198721

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