Genetics and Brain Transcriptomics of Completed Suicide

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.

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.

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.