Genetics of multiple sclerosis (MS) are highly polygenic with few insights into mechanistic associations with pathology. In this study, we assessed MS genetics through linkage disequilibrium and missense variant interpretation to yield a MS gene network. This network of 96 genes was taken through pathway analysis, tissue expression profiles, single cell expression segregation, expression quantitative trait loci (eQTLs), genome annotations, transcription factor (TF) binding profiles, structural genome looping, and overlap with additional associated genetic traits. This work revealed immune system dysfunction, nerve cell myelination, energetic control, transcriptional regulation, and variants that overlap multiple autoimmune disorders. Tissue-specific expression and eQTLs of MS genes implicate multiple immune cell types including macrophages, neutrophils, and T cells, while the genes in neural cell types enrich for oligodendrocyte and myelin sheath biology. There are eQTLs in linkage with lead MS variants in 25 genes including the multitissue eQTL, rs9271640, for HLA-DRB1/DRB5. Using multiple functional genomic databases, we identified noncoding variants that disrupt TF binding for GABPA, CTCF, EGR1, YY1, SPI1, CLOCK, ARNTL, BACH1, and GFI1. Overall, this paper suggests multiple genetic mechanisms for MS associated variants while highlighting the importance of a systems biology and network approach when elucidating intersections of the immune and nervous system.

中文翻译：

---

分解多发性硬化症遗传学，以鉴定整合的疾病网络和潜在的变异机制。

多发性硬化症（MS）的遗传学是高度多基因的，很少了解与病理的机械关联。在这项研究中，我们通过连锁不平衡和错义变体解释产生了MS基因网络，从而评估了MS遗传学。这个96个基因的网络是通过途径分析，组织表达谱，单细胞表达分离，表达定量性状基因座（eQTL），基因组注释，转录因子（TF）结合谱，结构基因组环化以及与其他相关的遗传性状重叠而获得的。这项工作揭示了免疫系统功能障碍，神经细胞髓鞘形成，能量控制，转录调控以及与多种自身免疫性疾病重叠的变异。MS基因的组织特异性表达和eQTL涉及多种免疫细胞类型，包括巨噬细胞，中性粒细胞和T细胞，而神经细胞类型中的基因丰富了少突胶质细胞和髓鞘的生物学。在25个基因中有与主要MS变异体相关的eQTL，包括针对HLA-DRB1 / DRB5的多组织eQTL rs9271640。使用多个功能基因组数据库，我们确定了非编码变体，这些变体破坏了GABPA，CTCF，EGR1，YY1，SPI1，CLOCK，ARNTL，BACH1和GFI1的TF结合。总体而言，本文提出了MS相关变体的多种遗传机制，同时强调了阐明免疫系统和神经系统交叉点时系统生物学和网络方法的重要性。适用于HLA-DRB1 / DRB5。使用多个功能基因组数据库，我们确定了非编码变体，这些变体破坏了GABPA，CTCF，EGR1，YY1，SPI1，CLOCK，ARNTL，BACH1和GFI1的TF结合。总体而言，本文提出了MS相关变体的多种遗传机制，同时强调了阐明免疫系统和神经系统交叉点时系统生物学和网络方法的重要性。适用于HLA-DRB1 / DRB5。使用多个功能基因组数据库，我们确定了非编码变体，这些变体破坏了GABPA，CTCF，EGR1，YY1，SPI1，CLOCK，ARNTL，BACH1和GFI1的TF结合。总体而言，本文提出了MS相关变体的多种遗传机制，同时强调了阐明免疫系统和神经系统交叉点时系统生物学和网络方法的重要性。