Table_3_Exploring the Impact of Cerebrovascular Disease and Major Depression on Non-diseased Human Tissue Transcriptomes.XLSX

BackgroundThe development of complex diseases is contributed by the combination of multiple factors and complicated interactions between them. Inflammation has recently been associated with many complex diseases and may cause long-term damage to the human body. In this study, we examined whether two types of complex disease, cerebrovascular disease (CVD) or major depression (MD), systematically altered the transcriptomes of non-diseased human tissues and whether inflammation is linked to identifiable molecular signatures, using post-mortem samples from the Genotype-Tissue Expression (GTEx) project.
ResultsFollowing a series of differential expression analyses, dozens to hundreds of differentially expressed genes (DEGs) were identified in multiple tissues between subjects with and without a history of CVD or MD. DEGs from these disease-associated tissues—the visceral adipose, tibial artery, caudate, and spinal cord for CVD; and the hypothalamus, putamen, and spinal cord for MD—were further analyzed for functional enrichment. Many pathways associated with immunological events were enriched in the upregulated DEGs of the CVD-associated tissues, as were the neurological and metabolic pathways in DEGs of the MD-associated tissues. Eight gene-tissue pairs were found to overlap with those prioritized by our transcriptome-wide association studies, indicating a potential genetic effect on gene expression for circulating cytokine phenotypes.
ConclusionCerebrovascular disease and major depression cause detectable changes in the gene expression of non-diseased tissues, suggesting that a possible long-term impact of diseases, lifestyles and environmental factors may together contribute to the appearance of “transcriptomic scars” on the human body. Furthermore, inflammation is probably one of the systemic and long-lasting effects of cerebrovascular events.

**背景** 复杂疾病的发生由多种因素及其间复杂的相互作用共同促成。炎症（inflammation）近年来被发现与诸多复杂疾病相关，并可能对人体造成长期损伤。本研究借助基因型组织表达（Genotype-Tissue Expression, GTEx）项目的死后组织样本，探究两种复杂疾病——脑血管疾病（cerebrovascular disease, CVD）与重度抑郁症（major depression, MD）是否会系统性改变非病变人体组织的转录组（transcriptome），以及炎症是否与可识别的分子特征存在关联。

**结果** 经一系列差异表达分析（differential expression analyses）后，在有与无CVD、MD病史的受试者的多种组织中，分别鉴定出数十至数百个差异表达基因（differentially expressed genes, DEGs）。针对与疾病相关的组织（CVD相关组织为内脏脂肪、胫骨动脉、尾状核与脊髓；MD相关组织为下丘脑、壳核与脊髓）中的DEGs，进一步开展功能富集分析。结果显示，CVD相关组织的上调DEGs显著富集于免疫相关事件通路；而MD相关组织的DEGs则富集于神经与代谢通路。另有8个基因-组织对与本研究全转录组关联研究（transcriptome-wide association studies）所优先筛选的结果存在重叠，提示循环细胞因子表型（circulating cytokine phenotypes）可能存在对基因表达的遗传调控效应。

**结论** 脑血管疾病与重度抑郁症可引起非病变组织的基因表达发生可检测到的变化，提示疾病、生活方式与环境因素的潜在长期影响共同促成了人体“转录组瘢痕”的形成。此外，炎症可能是脑血管事件带来的系统性、长期性效应之一。