Abstract
Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and crossvalidated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS metaanalysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: 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. Results: 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. Conclusions: 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.
| Original language | English |
|---|---|
| Pages (from-to) | 723-738 |
| Number of pages | 16 |
| Journal | American Journal of Psychiatry |
| Volume | 180 |
| Issue number | 10 |
| DOIs | |
| State | Published - 2023 |
| Externally published | Yes |
Funding
This work was supported by NIMH (grants R01MH123619, R01MH123489, R01MH099134, K01MH109765, R01MH116269, and R01MH121455). This research is also based on data from the U.S. Department of Veterans Affairs Million Veteran Program (MVP) and was supported by award I01CX001729 from the Clinical Science Research and Development Service of the Veterans Health Administration Office of Research and Development. Dr. Beckham was also supported by a Senior Research Career Scientist Award (lK6BX003777) from Clinical Science Research and Development. Research reported here was supported bythe National Institute of General Medical Sciences under award T32GM007347 (Dr. Kang). This work was also supported by Brain and Behavior Research Foundation/NARSAD Young Investigator Awards to Dr. Mullins (29551), to Dr. Shabalin (28686), and to Dr. DiBlasi (28132). Work was supported by the Huntsman Mental Health Institute, the American Foundation for Suicide Prevention (Drs. Docherty, Shabalin, DiBlasi, Bakian, and Coon), and the Clark Tanner Research Foundation. This work was also supported by research funding from Janssen Research and Development to University of Utah. Data from the Utah cohort are available through the Utah Population Database, which is partially supported by the Huntsman Cancer Institute and award P30CA42014 from the National Cancer Institute. Several statistical analyses were carried out on the Mount Sinai high-performance computing cluster (http://hpc.mssm.edu), which is supported by the NIH Office of Research Infrastructure (grants S10OD018522 and S10OD026880). This work was also conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University and the Huntsman Mental Health Institute at the University of Utah School of Medicine.
