Abstract Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent and associated with adverse clinical outcomes, its neurobiology remains unclear. Furthermore, patients with DD are at higher risk for suicidal behavior in comparison with single disorder patients. Our objective was to evaluate brain gene expression patterns in individuals with DD who died by suicide. Methods: We compared the gene expression profile in the dorsolateral prefrontal cortex of suicides with DD (n = 10) to the transcriptome of suicides with substance use disorder alone (n = 10), suicides with mood disorders (MD) alone (n = 13), and suicides without mental comorbidities (n = 5). Gene expression profiles were assessed by microarrays. In addition, we performed a brain cell type enrichment to evaluate whether the gene expression profiles could reflect differences in cell type compositions among the groups. Results: When comparing the transcriptome of suicides with DD to suicides with substance use disorder alone and suicides with MD alone, we identified 255 and 172 differentially expressed genes (DEG), respectively. The overlap of DEG between both comparisons (112 genes) highlighted the presence of common disrupted pathways in substance use disorder and MD. When comparing suicides with DD to suicides without mental comorbidities, we identified 330 DEG, mainly enriched in neurogenesis. Cell type enrichment indicated higher levels of glial markers in suicides with DD compared to the other groups. Conclusions: Suicides with DD exhibited a gene expression profile distinct from that of suicides with a single disorder, being substance use disorder or MD, and suicides without mental disorders. Our results suggest alteration in the expression of genes involved in glial specific markers, glutamatergic and GABAergic neurotransmission in suicides with DD compared to suicides with a single disorder and suicides without mental comorbidities. Alterations in the expression of synaptic genes at different levels were found in substance use disorder and MD.

中文翻译：

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双重诊断死于自杀的个体的脑基因表达谱

摘要 目的：双重诊断 (DD) 是指在特定个体中同时发生至少一种物质使用障碍和一种或多种精神障碍。尽管这种合并症非常普遍并与不良临床结果相关，但其神经生物学仍不清楚。此外，与单一障碍患者相比，DD 患者有更高的自杀行为风险。我们的目标是评估死于自杀的 DD 个体的大脑基因表达模式。方法：我们将患有 DD 的自杀（n = 10）的背外侧前额叶皮层中的基因表达谱与单独患有物质使用障碍的自杀（n = 10）、单独患有情绪障碍（MD）的自杀（n = 13）的转录组进行了比较。 )，以及没有精神合并症的自杀 (n = 5)。通过微阵列评估基因表达谱。此外，我们进行了脑细胞类型富集，以评估基因表达谱是否能反映各组细胞类型组成的差异。结果：当比较 DD 自杀与单独物质使用障碍自杀和单独 MD 自杀的转录组时，我们分别确定了 255 和 172 个差异表达基因（DEG）。两种比较（112 个基因）之间 DEG 的重叠突出了物质使用障碍和 MD 中常见的破坏途径的存在。在比较有 DD 的自杀与没有精神共病的自杀时，我们确定了 330 DEG，主要富含神经发生。细胞类型富集表明与其他组相比，DD 自杀者的神经胶质标志物水平更高。结论：患有 DD 的自杀者表现出的基因表达谱不同于患有单一障碍的自杀，即物质使用障碍或 MD，以及没有精神障碍的自杀。我们的结果表明，与患有单一疾病的自杀和没有精神合并症的自杀相比，患有 DD 的自杀中涉及神经胶质特异性标志物、谷氨酸能和 GABA 能神经传递的基因表达发生了改变。在物质使用障碍和 MD 中发现了不同水平的突触基因表达的改变。与患有单一疾病的自杀和没有精神合并症的自杀相比，DD 自杀中的谷氨酸能和 GABA 能神经传递。在物质使用障碍和 MD 中发现了不同水平的突触基因表达的改变。与患有单一疾病的自杀和没有精神共病的自杀相比，DD 自杀中的谷氨酸能和 GABA 能神经传递。在物质使用障碍和 MD 中发现了不同水平的突触基因表达的改变。