Center for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's disease and the Aging brain, Columbia University Irving Medical Center, New York, NY, USA.
Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
Nat Commun. 2021 Dec 6;12(1):7078. doi: 10.1038/s41467-021-27427-w.
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.
确定遗传变异对疾病相关细胞类型中表观基因组的影响有助于深入了解遗传易感性对疾病发病的最初分子贡献。在这里，我们建立了一个从多发性硬化症患者中分离出的 CD4 T 细胞中 DNA 甲基化数量性状基因座的全基因组图谱。利用该图谱进行共定位分析，我们鉴定出 19 个单倍型既驱动多发性硬化症易感性又驱动局部 DNA 甲基化的位点。我们还鉴定出多发性硬化症易感性位点的两个远距离甲基化效应：一个位于 16 号染色体的位点影响 PRDM8 甲基化（一个以前与多发性硬化症无关的 4 号染色体区域），主要组织相容性复合体中与多发性硬化症相关的变异的总体效应影响 PRKCA 附近的 DNA 甲基化（17 号染色体）。总体而言，我们为炎症性疾病研究中的关键细胞类型提供了一个新的资源，并揭示了多发性硬化症易感性研究的新基因靶点。
