Genetics and brain transcriptomics of completed suicide

OBJECTIVE: The authors sought to study the transcriptomic and genomic features of completed suicide by parsing the method chosen, to capture molecular correlates of the distinctive frame of mind of individuals who die by suicide while reducing heterogeneity. METHOD: The authors analyzed gene expression (RNA sequencing) from postmortem dorsolateral prefrontal cortex of patients who died by suicide with violent versus non-violent means and other non-suicide patients with the same psychiatric disorders, and also of neurotypicals (total n=329). They then examined genomic risk-scores (GRS) for each psychiatric disorder included, and GRS for cognition (IQ) and for suicide attempt, testing how they predict diagnosis or traits (total n=888). RESULTS: Patients who died by suicide by violent means (vS-pt) showed a transcriptomic pattern remarkably divergent from each of the other patient groups but less from neurotypicals; consistently, their genomic profile of risk was relatively low for their diagnosed illness as well as for suicide attempt and relatively high for IQ, i.e., more similar to neurotypicals than other patients. Differentially expressed genes (DEGs) associated with vS-pt pointed to purinergic signaling in microglia, showing similarities to GWAS of Drosophila aggression. WGCNA revealed that these DEGs were co-expressed in a context of mitochondrial metabolic activation unique to vS-pt. CONCLUSIONS: These findings suggest that vS-pt are in part biologically separable from other patients with the same diagnoses, and their behavioral outcome may be less dependent on genetic risk for conventional psychiatric disorders while associated with an alteration of purinergic signaling and mitochondrial metabolism.