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A major international collaboration has completed a meta-analysis that identifies 12 risk loci for suicide attempt using data from two pivotal large-scale genomic studies. These loci were mostly intergenic—along stretches of DNA located between genes, and implicated DRD2, SLCA9, FURIN, NLGN1, SOX5, PDE48, and CACNG2.   

Controlling for the well-known association of suicide attempt to PTSD and major depression disorder, the team also found shared genetic variations between this event with attention deficit hyperactivity disorder, smoking, and risk tolerance.

This was the largest genome wide association study (GWAS) meta-analysis of suicide attempt to date. It was published in The American Journal of Psychiatry on Oct. 1. The lead author is Anna R. Docherty of the Department of Psychiatry at Huntsman Mental Health Institute in Salt Lake City. Dozens of other researchers from multiple institutions were involved in the collaboration.

Suicidal behavior is heritable and is a major cause of death worldwide. Suicide accounted for more than 700,000 deaths globally in 2019 and was the fourth leading cause of death among 15- to 29-year-olds, according to WHO. Suicide attempt is even more common and is strongly associated with psychiatric conditions, poor quality of life, traumatic experiences, and social and economic burden. It is also the single strongest predictor of future suicide death.

The present study leveraged the genetic cohorts from both the International Suicide Genetics Consortium (ISGC) and the Million Veteran Program (MVP), which recently discovered and cross-validated genome-wide significant loci for suicide attempt. The meta-analysis comprised 22 cohorts, including 43,871 suicide attempt cases and 915,025 ancestry-matched controls. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.

Heritability estimates for suicidal thoughts and behaviors from twin and family studies range from 30% to 55%. Notably, the ISGC study (29,782 cases) identified two loci reaching genome-wide significance for suicide attempt in individuals of primarily European ancestry admixtures, on chromosomes 6 and 7. The MVP cohort GWAS of suicide attempt (14,089 cases) resulted in two genome-wide significant multi-ancestry loci, on chromosomes 20 and 1. A top signal identified at the dopamine receptor D2 locus also showed moderate association in the ISGC GWAS.

Docherty and colleagues write their work “… established the complexity of the common variant genetic architecture of suicide attempt and demonstrated the critical role of sample size for discovering novel, replicable risk loci for suicide phenotypes through GWASs. Together, these GWASs suggested that larger studies will identify additional genomic risk loci and refine genetic risk metrics.”

They say their results show, for the first time, that implicated genes are highly expressed in brain tissue, are enriched in pathways related to gene regulation and transcription, cellular response to stress, DNA repair, and immunologic signatures, and are shared with epidemiological risk factors

“Brain is the predominant tissue enriched for associated genes, and there is also significant enrichment in pituitary gland, consistent with previous association of SA [suicide attempt] with hypothalamic-pituitary-adrenal system dysregulation,” they write.

They add that, “The enrichment of pathways related to epigenetics and gene regulation and transcription suggest that epigenetic modifications, such as DNA methylation, may play a role in modulating the effect of SA [suicide attempt]-associated genetic variants.”

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