Genetics and Brain Transcriptomics of Completed Suicide

Punzi, Giovanna; Ursini, Gianluca; Chen, Qiang; Radulescu, Eugenia; Tao, Ran; Huuki, Louise A; Carlo, Pasquale Di; Collado‐Torres, Leonardo; Shin, Joo Heon; Catanesi, Roberto; Jaffe, Andrew E.; Hyde, Thomas M.; Kleinman, Joel E.; Mackay, Trudy F. C.; Weinberger, Daniel R.

doi:10.1176/appi.ajp.2021.21030299

Cited by 32 publications

(27 citation statements)

References 79 publications

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“…A rodent study showed that GRIK2-deficient mice were more impulsive and aggressive, suggesting that it has a unique role in controlling the behavioral symptoms of mania [99]. In particular, the outcome of completed suicide has been associated with increased expression of GRIK2 [73]. The present data further suggest that elevated kainate receptor signaling in the DMPFC can predispose the development of committing suicide, and hence can be a potential biomarker.…”

Section: Functional Implications Based On Pathway Analysessupporting

confidence: 58%

“…The role of immune dysfunction in suicide victims has been reported in the prefrontal cortex [51] and the insula [71]. It has also been proposed that neurodegeneration and impaired structural neuroplasticity [71,72], as well as mitochondrial dysfunction [53,73], are associated with suicide completion. The top 10 upregulated genes were involved in ATP signaling, protein and vesicle-mediated transport, and were components of membrane and cytoskeleton and regulating protein secretion.…”

Section: Conclusion Based On Individual Degsmentioning

confidence: 99%

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Transcriptome Profiling of the Dorsomedial Prefrontal Cortex in Suicide Victims

Dóra

Renner

Keller

et al. 2022

IJMS

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The default mode network (DMN) plays an outstanding role in psychiatric disorders. Still, gene expressional changes in its major component, the dorsomedial prefrontal cortex (DMPFC), have not been characterized. We used RNA sequencing in postmortem DMPFC samples to investigate suicide victims compared to control subjects. 1400 genes differed using log2FC > ±1 and adjusted p-value < 0.05 criteria between groups. Genes associated with depressive disorder, schizophrenia and impaired cognition were strongly overexpressed in top differentially expressed genes. Protein–protein interaction and co-expressional networks coupled with gene set enrichment analysis revealed that pathways related to cytokine receptor signaling were enriched in downregulated, while glutamatergic synaptic signaling upregulated genes in suicidal individuals. A validated differentially expressed gene, which is known to be associated with mGluR5, was the N-terminal EF-hand calcium-binding protein 2 (NECAB2). In situ hybridization histochemistry and immunohistochemistry proved that NECAB2 is expressed in two different types of inhibitory neurons located in layers II-IV and VI, respectively. Our results imply extensive gene expressional alterations in the DMPFC related to suicidal behavior. Some of these genes may contribute to the altered mental state and behavior of suicide victims.

show abstract

Section: Functional Implications Based On Pathway Analysessupporting

confidence: 58%

Section: Conclusion Based On Individual Degsmentioning

confidence: 99%

Transcriptome Profiling of the Dorsomedial Prefrontal Cortex in Suicide Victims

Dóra

Renner

Keller

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…The role of immune dysfunction in suicide victims has been reported in the prefrontal cortex (Pantazatos et al 2017) and insula (Jabbi et al 2020). It has also been proposed that neurodegeneration and impaired structural neuroplasticity (Jabbi et al 2020, Underwood and Arango 2011), as well as mitochondrial dysfunction (Punzi et al 2022, Cabrera et al 2019) are associated with suicide completion. The top 10 upregulated genes were involved in ATP signaling, protein and vesicle-mediated transport, component of membrane and cytoskeleton and regulating protein secretion.…”

Section: Discussionmentioning

confidence: 99%

“…A rodent study showed that GRIK2 deficient mice were more impulsive and aggressive, suggesting that it has a unique role in controlling the behavioral symptoms of mania (Shaltiel et al 2008). In particular, the outcome of completed suicide has been associated with increased expression of GRIK2 (Punzi et al 2022). The present data further suggest that elevated kainate signaling in the DMPFC can predispose the development of committing suicide and hence can be a potential biomarker.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling of the dorsomedial prefrontal cortex in suicide victims

Dóra

Renner

Keller

et al. 2022

Preprint

View full text Add to dashboard Cite

The default mode network (DMN) plays an outstanding role in psychiatric disorders. Still, gene expressional changes in its major component, the dorsomedial prefrontal cortex (DMPFC), have not been characterized. We used RNA-sequencing in postmortem DMPFC samples to investigate suicide victims compared to control subjects. Most of the data variance (79%) was associated with expression changes between suicide and control samples. 1400 genes differed using log2FC > ± 1 and adjusted p-value < 0.05 criteria between groups. Genes associated with depressive disorder, schizophrenia and impaired cognition were strongly overexpressed in top differentially expressed genes. Gene set enrichment and protein-protein interaction network analysis revealed that pathways related to cytokine receptor signaling were enriched in downregulated while glutamatergic synaptic signaling in upregulated genes in suicide individuals. A validated differentially expressed gene, which is known to be associated with mGluR5, was the N-terminal EF-hand calcium-binding proteins 2 (NECAB2). In situ hybridization histochemistry and immunohistochemistry proved that NECAB2 is expressed in 2 different types of inhibitory neurons located in layers II-IV and VI, respectively. Our results imply extensive gene expressional alterations in the DMPFC related to suicidal behavior. Some of these genes may contribute to the altered mental state and behavior of suicide victims.

show abstract

“…For instance, individuals who are at the highest levels of genetic risk for death by suicide may not be adequately represented in a longitudinal study such as COGA. Furthermore, the death by suicide GWAS included individuals who died by varied violent and nonviolent means [19], and as such may reflect a highly heterogeneous set of genetic liabilities [60].…”

Section: Discussionmentioning

confidence: 99%

Polygenic contributions to suicidal thoughts and behaviors in a sample ascertained for alcohol use disorders

Colbert

Mullins

Chan

et al. 2022

Preprint

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Suicidal thoughts and behaviors have partially distinct genetic etiologies. We used PRS-CS to create polygenic risk scores (PRS) from GWAS of non-suicidal self-injury, broad sense self-harm ideation, non-fatal suicide attempt, death by suicide, and depression. Using mixed-effect models, we estimated whether these PRS were associated with a range of suicidal thoughts and behaviors in the Collaborative Study on the Genetics of Alcoholism (N = 7,526). All PRS were significantly associated with suicidal ideation and suicide attempt (betas=0.08-0.44, FDR<0.023). All PRS except non-suicidal self-injury PRS were associated with active suicidal ideation and severity of suicidality (betas=0.04-0.22, FDR<0.034). Several associations remained significant in models where all significant PRS were included as simultaneous predictors, and when all PRS predicted suicide attempt, the PRS together explained 6.2% of the variance in suicide attempt. Significant associations were also observed between some PRS and persistent suicidal ideation, non-suicidal self-injury, attempt severity and desire to die. Our findings suggest that PRS for depression does not explain the entirety of the variance in suicidal thoughts and behaviors, with PRS specifically for suicidal thoughts and behaviors making additional and sometimes unique contributions.

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Genetics and Brain Transcriptomics of Completed Suicide

Cited by 32 publications

References 79 publications

Transcriptome Profiling of the Dorsomedial Prefrontal Cortex in Suicide Victims

Transcriptome Profiling of the Dorsomedial Prefrontal Cortex in Suicide Victims

Transcriptome profiling of the dorsomedial prefrontal cortex in suicide victims

Polygenic contributions to suicidal thoughts and behaviors in a sample ascertained for alcohol use disorders

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