Whole exome sequencing analysis of suicidal thoughts and behaviors in a veteran cohort implicates inflammatory pathways and genes previously associated with psychiatric and neurodegenerative diseases.

BACKGROUND: Suicide is a leading cause of death among younger veterans; however, the genetic basis of suicide remains largely unknown. While prior genome-wide association studies (GWAS) have identified common variants associated with suicidal ideation and attempts, a pressing need remains for unbiased assessment of rare and coding genetic variation with respect to suicide phenotypes. METHODS: Here, we conducted an exome-wide association study (ExWAS), examining both single variant and gene-based tests in relation to suicidal ideation and attempts in a cohort of post-9/11 era veterans (N = 139) and ancestry-matched controls (N = 329). RESULTS: ExWAS for ideation identified 19 significant variants, 12 of which were also associated with attempts. The most significant variant for ideation was in the 3' untranslated region of KRTAP9-4; the top variant associated with attempts was an intergenic variant on chromosome 14. Several coding variants were identified, including nonsynonymous variants in GBGT1, NCF1, OR4A16, and CYP2B6. Gene-based analysis identified 46 genes associated with ideation, 31 of which were also associated with attempts. The gene most strongly associated with both ideation and attempts was HLA-DRB1, followed by GXYLT1 for ideation and ANKRD30B for attempts. CONCLUSIONS: Our results confirm the importance of genes and pathways identified by prior GWAS of suicidal thoughts and behaviors and propose novel loci in biologically relevant pathways. Associated genes implicate inflammation and immune dysfunction, as well as shared genetic signals with psychiatric disorders and neurodegenerative diseases frequently co-occurring with suicidal thoughts and behaviors. These findings, if replicated in larger cohorts, suggest targets for future treatments and interventions.

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