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000265360 0247_ $$2doi$$a10.1176/appi.ajp.21121266
000265360 0247_ $$2ISSN$$a0002-953X
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000265360 1001_ $$aDocherty, Anna R.$$b0
000265360 245__ $$aGWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors
000265360 260__ $$aStanford, Calif.$$bHighWire Press$$c2023
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000265360 520__ $$aSuicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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000265360 650_7 $$2Other$$aBiological Markers
000265360 650_7 $$2Other$$aDepressive Disorders
000265360 650_7 $$2Other$$aGenetics
000265360 650_7 $$2Other$$aSchizophrenia Spectrum and Other Psychotic Disorders
000265360 650_7 $$2Other$$aSelf-Harm
000265360 650_7 $$2Other$$aSuicide
000265360 650_2 $$2MeSH$$aHumans
000265360 650_2 $$2MeSH$$aGenome-Wide Association Study
000265360 650_2 $$2MeSH$$aSuicide, Attempted
000265360 650_2 $$2MeSH$$aDepressive Disorder, Major: genetics
000265360 650_2 $$2MeSH$$aRisk Factors
000265360 650_2 $$2MeSH$$aSuicidal Ideation
000265360 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide: genetics
000265360 650_2 $$2MeSH$$aGenetic Predisposition to Disease: genetics
000265360 650_2 $$2MeSH$$aGenetic Loci: genetics
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