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Genetics and Brain Transcriptomics of Completed Suicide.

Giovanna Punzi1, Gianluca Ursini1, Qiang Chen1

  • 1Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore (Punzi, Ursini, Chen, Radulescu, Tao, Huuki, Di Carlo, Collado-Torres, Shin, Jaffe, Hyde, Kleinman, Weinberger); Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore (Ursini, Hyde, Kleinman, Weinberger); Section of Forensic Psychiatry and Criminology, Institute of Legal Medicine, D.I.M., University of Bari "Aldo Moro," Bari, Italy (Catanesi); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Jaffe); Department of Neurology, Johns Hopkins School of Medicine, Baltimore (Hyde, Weinberger); Department of Genetics and Biochemistry and Center for Human Genetics, Clemson University, Greenwood, S.C. (Mackay); Departments of Neuroscience and Genetic Medicine, Johns Hopkins School of Medicine, Baltimore (Weinberger).

The American Journal of Psychiatry
|March 3, 2022
PubMed
Summary

Completed suicide by violent means may involve distinct biological pathways, including altered purinergic signaling and mitochondrial metabolism, separating these individuals from others with similar psychiatric diagnoses. This research offers new insights into the molecular underpinnings of suicide.

Keywords:
Genomic RiskMitochondriaPostmortem BrainPurinergic SignalingRNA SequencingSuicide Method

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Completed suicide is a complex phenomenon with significant heterogeneity.
  • Understanding the molecular correlates of distinct suicide methods is crucial for identifying unique biological profiles.

Purpose of the Study:

  • To investigate transcriptomic and genomic differences in completed suicide based on the method used.
  • To identify molecular signatures associated with the specific mindset of individuals who die by suicide, reducing study heterogeneity.

Main Methods:

  • Gene expression (RNA sequencing) was analyzed from postmortem brain tissue (dorsolateral prefrontal cortex) of individuals who died by suicide (violent vs. nonviolent means), non-suicide psychiatric patients, and neurotypical controls (N=329).
  • Genomic risk scores (GRSs) for psychiatric disorders, cognition (IQ), and suicide attempt were examined in a separate cohort (N=888) to assess predictive value for diagnosis or traits.

Main Results:

  • Individuals who died by suicide using violent means exhibited a transcriptomic profile distinct from other patient groups but similar to neurotypical controls.
  • These individuals also showed lower genomic risk for their diagnosed illness and suicide attempt, but higher genomic risk for IQ, indicating a unique biological profile.
  • Differentially expressed genes (DEGs) were linked to purinergic signaling in microglia and mitochondrial metabolic activation, a pattern specific to suicide by violent means.

Conclusions:

  • Patients who die by suicide by violent means represent a biologically distinct subgroup within psychiatric diagnoses.
  • Their behavioral outcome may be less influenced by genetic risk for conventional psychiatric disorders.
  • Alterations in purinergic signaling and mitochondrial metabolism are potentially associated with suicide by violent means.