Similarities and dissimilarities between psychiatric cluster disorders.
Similarities and dissimilarities between psychiatric cluster disorders.
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DOI：
10.1038/s41380-021-01030-3
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发表时间：
2021-09
影响因子：
11
通讯作者：
Shukla R
中科院分区：
文献类型：
--
作者：
Smail MA;Wu X;Henkel ND;Eby HM;Herman JP;McCullumsmith RE;Shukla R
精神疾病的常见分子机制还不清楚。先前评估精神疾病病理机制的尝试受到可比疾病的偏倚选择、数据集/队列可用性以及数据标准化挑战的限制。在这里，使用DisGeNET，一个基因-疾病关联数据库，我们试图在疾病的数量和类型方面扩大此类调查。以自上而下的方式，我们分析了36种精神疾病和共病状况在生物途径，细胞类型，药物靶点和染色体水平上的无偏聚类，并部署了密度指数，这是一种新的度量标准，用于量化这些疾病在每个水平上的相似性（接近1）和差异性（接近0）。在通路水平上，我们发现认知和神经传递驱动相似性并涉及所有疾病，而免疫系统和信号反应耦合（细胞表面受体，信号转导，基因表达和代谢过程）驱动相异性并涉及特定疾病。药物靶点水平的分析支持这些疾病中神经传递相关变化的参与。在细胞类型水平，树突靶向的中间神经元，在所有层，是最参与。最后，通过在每个分析水平上匹配聚类模式，我们发现疾病之间的相似性在染色体水平上受到最大影响，在一定程度上在细胞水平上受到影响。总之，这些发现提供了对不同细胞和分子病理学的第一次洞察，与几种精神疾病和共病状况相关的药物机制，并证明这些疾病之间的相似性起源于染色体水平，并以自下而上的方式分散在细胞和途径水平。
The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets/cohort availability, and challenges with data normalization. Here, using DisGeNET, a gene-disease associations database, we sought to expand such investigations in terms of number and types of diseases. In a top-down manner, we analyzed an unbiased cluster of 36 psychiatric disorders and comorbid conditions at biological pathway, cell-type, drug-target, and chromosome levels and deployed density index, a novel metric to quantify similarities (close to 1) and dissimilarities (close to 0) between these disorders at each level. At pathway level, we show that cognition and neurotransmission drive the similarity and are involved across all disorders, whereas immune-system and signal-response coupling (cell surface receptors, signal transduction, gene expression, and metabolic process) drives the dissimilarity and are involved with specific disorders. The analysis at the drug-target level supports the involvement of neurotransmission-related changes across these disorders. At cell-type level, dendrite-targeting interneurons, across all layers, are most involved. Finally, by matching the clustering pattern at each level of analysis, we showed that the similarity between the disorders is influenced most at the chromosomal level and to some extent at the cellular level. Together, these findings provide first insights into distinct cellular and molecular pathologies, druggable mechanisms associated with several psychiatric disorders and comorbid conditions and demonstrate that similarities between these disorders originate at the chromosome level and disperse in a bottom-up manner at cellular and pathway levels.
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