Brain Gene Expression Profiling of Individuals With Dual Diagnosis Who Died by Suicide

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.

KEYWORDS:

• Transcriptome
• dual diagnosis
• substance use disorder
• comorbidity
• co-occurring disorders

Acknowledgments

We thank Professor Robert Simpson for his appreciable help in the language editing and proofreading of this manuscript. This project was awarded with the best oral presentation prize at the International Congress of Dual Diagnosis 2019.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability

The data that support the findings of this study are openly available in the Gene Expression Omnibus repository with access number GSE125681.

Additional information

Funding

This work was supported by the National Council for Science and Technology (CONACyT) under Grant number #233695. Brenda Cabrera-Mendoza is a doctoral student from the Plan of Combined Studies in Medicine at National Autonomous University of Mexico and was supported by CONACyT [#622945].