Genome-wide association study meta-analysis of suicide attempt identifies twelve genome-wide significant loci and implicates genetic risks for specific health factors

Objective Suicidal behavior is heritable and a major cause of death worldwide. Two large-scale genome-wide association studies (GWAS) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The current 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. Methods This study was comprised of 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 eQTL 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<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 was observed. There was shared genetic variation of SA with ADHD, smoking, and risk tolerance after conditioning SA on both major depressive disorder and post-traumatic 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 major ancestry admixtures, in veteran and civilian populations, and in attempt versus death. ### Competing Interest Statement Disclosures: Dr. Qingqin Li, a co-author, is employed by Janssen Pharmaceuticals. All other authors have no financial relationships with commercial interests. ### Funding Statement Acknowledgements: This work was supported by the National Institute of Mental Health (R01MH123619, R01MH123489, R01MH099134, K01MH109765, R01MH116269, R01MH121455). This research is also based on data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP) program and was supported by Award #I01CX001729 from the Clinical Science Research and Development Service of the Veterans Health Administration Office of Research and Development. J.C. Beckham was also supported by a Senior Research Career Scientist Award (#lK6BX003777) from CSR&D. Research reported in this publication was supported by NIGMS of the National Institutes of Health under award number T32GM007347 (J.K.). This work was also supported by the Brain & Behavior Research Foundation/NARSAD Young Investigator Awards No. 29551 to N. Mullins, No. 28686 to A. Shabalin, and No. 28132 to E. DiBlasi. Work was supported by the Huntsman Mental Health Institute, the American Foundation for Suicide Prevention (A. Docherty, A. Shabalin, E. DiBlasi, A. Bakian, H. Coon), and the Clark Tanner Research Foundation. This work was also supported by research funding from Janssen Research & Development, LLC to University of Utah. Data from the Utah cohort is available through the Utah Population Database, which is partially supported by the Huntsman Cancer Institute and award number P30CA42014 from the National Cancer Institute. Several statistical analyses were carried out on the Mount Sinai high performance computing cluster (), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. 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, Nashville, TN and the Huntsman Mental Health Institute at the University of Utah School of Medicine, Salt Lake City, UT. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We also thank and acknowledge MVP, the MVP Suicide Exemplar Workgroup, and the ISGC for their contributions to this manuscript. A complete listing of contributors from the MVP, MVP Suicide Exemplar Workgroup, and the ISGC is provided in the Supplementary Materials. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Full details of the ethical and institutional review boards that gave ethical approval for each of the cohorts examined in this study are presented in the attached Supplementary Table 1. All study cohorts were approved by corresponding site IRBs, as named in the table. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.