Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2023 Feb 1;80(2):135-145.
doi: 10.1001/jamapsychiatry.2022.3896.

Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans

Nathan A Kimbrel  1   2   3   4 , Allison E Ashley-Koch  5   6 , Xue J Qin  1   5 , Jennifer H Lindquist  3 , Melanie E Garrett  5 , Michelle F Dennis  1   4 , Lauren P Hair  1   4 , Jennifer E Huffman  7 , Daniel A Jacobson  8   9   10 , Ravi K Madduri  11   12 , Jodie A Trafton  13 , Hilary Coon  14   15 , Anna R Docherty  14   16 , Niamh Mullins  17   18 , Douglas M Ruderfer  19   20   21 , Philip D Harvey  22   23 , Benjamin H McMahon  24 , David W Oslin  25   26 , Jean C Beckham  1   2   4 , Elizabeth R Hauser  1   5   27 , Michael A Hauser  5   6 ; Million Veteran Program Suicide Exemplar Workgroup, the International Suicide Genetics Consortium, the Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup, and the Veterans Affairs Million Veteran Program
Collaborators, Affiliations
Meta-Analysis

Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans

Nathan A Kimbrel et al. JAMA Psychiatry. .

Abstract

Importance: Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.

Objective: To identify novel, replicable genomic risk loci for SITB.

Design, setting, and participants: This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.

Main outcome and measures: SITB.

Results: A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10-8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry-specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.

Conclusions and relevance: The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Dr Lindquist reported grants from the Department of Veterans Affairs during the conduct of the study. Dr Dennis reported grants from Durham VA Health Care System during the conduct of the study. Dr Jacobson reported grants from the DOE-VA MVP CHAMPION program during the conduct of the study. Dr Trafton reported being employed by and serving on the board of directors at the Institute for Brain Potential, a continuing medical education nonprofit organization that provides training in behavioral health, outside the submitted work. Dr Ruderfer reported grants from PTC Therapeutics and personal fees from Alkermes outside the submitted work. Dr Harvey reported grants from US Department of Veterans Affairs during the conduct of the study, which reviewed Dr Harvey’s outside activities and determined that they do not constitute a conflict of interest with the present work. Dr Oslin reported grants from the Office of Research and Development, Department of Veterans Affairs, during the conduct of the study. Dr M. A. Hauser reported grants from Million Veteran Project during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Manhattan Plots Summarizing Results From the Cross-Ancestry and Ancestry-Specific Genome-Wide Association Studies
Figure 2.
Figure 2.. Cross-Ancestry Locus Zoom Plots for Top Replicated Genome-Wide Significant Loci on Chromosomes 6, 11, 14, and 18
SNVs indicates single-nucleotide variants.
Figure 3.
Figure 3.. Functional Mapping and Annotation Results for Cross-Ancestry and European Subset Genome-Wide Association Study Results
See this image and copyright information in PMC

References

    1. World Health Organization . Suicide in the world: global estimates, 2019. Accessed July 1, 2022. https://www.who.int/publications/i/item/suicide-in-the-world
    1. Hedegaard H, Curtin S, Warner M. Suicide Mortality in the United States, 1999–2019. NCHS data brief no. 398, February 2021. Accessed July 1, 2022. https://www.cdc.gov/nchs/products/databriefs/db398.htm#:~:text=This%20re... - PubMed
    1. Department of Veterans Affairs Office of Mental Health and Suicide Prevention . 2020 National strategy for preventing veteran suicide. Accessed May 4, 2022. https://www.mentalhealth.va.gov/suicide_prevention/docs/Office-of-Mental...
    1. Franklin JC, Ribeiro JD, Fox KR, et al. . Risk factors for suicidal thoughts and behaviors: a meta-analysis of 50 years of research. Psychol Bull. 2017;143(2):187-232. doi:10.1037/bul0000084 - DOI - PubMed
    1. Substance Abuse and Mental Health Services Administration . Key Substance Use and Mental Health Indicators in the United States: Results from the 2019 National Survey on Drug Use and Health. HHS Publication No PEP20-07-01-001, NSDUH Series H-55. 2020. Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration; 2021.

Publication types