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A Multivariate Genomic Investigation of the Externalizing Spectrum and Suicide Risk.

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Externalizing disorders, characterized by behavioral disinhibition, are significantly linked to suicidal behaviors. This study highlights the genetic and phenotypic connections between externalizing traits and suicide risk, emphasizing the need for greater clinical attention.

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Area of Science:

  • Psychiatry
  • Genetics
  • Neuroscience

Background:

  • Suicidal thoughts and behaviors arise from complex mechanisms, including behavioral disinhibition seen in externalizing disorders.
  • Previous research indicates a substantial genetic overlap between externalizing disorders and suicide attempts.
  • The relationship between suicide and internalizing disorders has received more attention than externalizing factors.

Purpose of the Study:

  • To investigate the co-occurrence between a broad spectrum of suicide phenotypes and externalizing disorders.
  • To estimate a latent genomic factor for externalizing (MVP-EXT) using Million Veteran Program (MVP) data.
  • To examine the genetic overlap and prospective phenotypic associations between externalizing traits and suicide outcomes.

Main Methods:

  • Utilized genomic structural equation modeling (GenomicSEM) on MVP data to derive a genomic factor for externalizing (MVP-EXT).
  • Assessed genetic correlations, polygenic scores, and gene enrichment in post-mortem brain tissue.
  • Examined prospective associations between phenotypic externalizing scores and death by suicide in the MVP cohort.

Main Results:

  • Identified 155 loci associated with externalizing traits in European-like and African-like MVP participants.
  • MVP-EXT demonstrated strong genetic correlations with prior externalizing factors and suicide attempts across ancestries.
  • Externalizing polygenic scores predicted suicidal ideation and attempts in independent cohorts; phenotypic externalizing predicted death by suicide.

Conclusions:

  • Externalizing disorders represent a significant, yet often under-recognized, risk factor for suicide-related behaviors.
  • Genetic and phenotypic links between externalizing traits and suicide are robust, warranting further investigation.
  • Increased clinical focus on externalizing behaviors as potential antecedents of suicide is crucial for prevention efforts.