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Genetic liability to suicidal thoughts and behaviors and risk of suicide attempt in US military veterans: moderating effects of cumulative trauma burden

Published online by Cambridge University Press:  29 November 2022

Brandon Nichter*
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
Dora Koller
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA VA Connecticut Healthcare System, West Haven, CT, USA,
Flavio De Angelis
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
Jiawei Wang
Computational Biology & Bioinformatics, Yale University, New Haven, CT, USA
Matthew J. Girgenti
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA
Peter J. Na
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA
Melanie L. Hill
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA VA San Diego Healthcare System, San Diego, CA, USA
Sonya B. Norman
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA VA San Diego Healthcare System, San Diego, CA, USA National Center for PTSD, White River Junction, VT, USA
John H. Krystal
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA
Joel Gelernter
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA
Renato Polimanti
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA VA Connecticut Healthcare System, West Haven, CT, USA,
Robert H. Pietrzak
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA Department of Social and Behavioral Sciences, Yale School of Public Health, New Haven, CT, USA
Author for correspondence: Brandon Nichter, E-mail:



Little is known about environmental factors that may influence associations between genetic liability to suicidality and suicidal behavior.


This study examined whether a suicidality polygenic risk score (PRS) derived from a large genome-wide association study (N = 122,935) was associated with suicide attempts in a population-based sample of European-American US military veterans (N = 1664; 92.5% male), and whether cumulative lifetime trauma exposure moderated this association.


Eighty-five veterans (weighted 6.3%) reported a history of suicide attempt. After adjusting for sociodemographic and psychiatric characteristics, suicidality PRS was associated with lifetime suicide attempt (odds ratio 2.65; 95% CI 1.37–5.11). A significant suicidality PRS-by-trauma exposure interaction emerged, such that veterans with higher levels of suicidality PRS and greater trauma burden had the highest probability of lifetime suicide attempt (16.6%), whereas the probability of attempts was substantially lower among those with high suicidality PRS and low trauma exposure (1.4%). The PRS-by-trauma interaction effect was enriched for genes implicated in cellular and developmental processes, and nervous system development, with variants annotated to the DAB2 and SPNS2 genes, which are implicated in inflammatory processes. Drug repurposing analyses revealed upregulation of suicide gene-sets in the context of medrysone, a drug targeting chronic inflammation, and clofibrate, a triacylglyceride level lowering agent.


Results suggest that genetic liability to suicidality is associated with increased risk of suicide attempt among veterans, particularly in the presence of high levels of cumulative trauma exposure. Additional research is warranted to investigate whether incorporation of genomic information may improve suicide prediction models.

Original Article
Copyright © The Author(s), 2022. Published by Cambridge University Press

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Aas, M., Alameda, L., Di Forti, M., Quattrone, D., Dazzan, P., Trotta, A., … Morgan, C. (2021). Synergistic effects of childhood adversity and polygenic risk in first-episode psychosis: The EU-GEI study. Psychological Medicine, 19. doi:10.1017/S0033291721003664.CrossRefGoogle Scholar
Afifi, T. O., Taillieu, T., Zamorski, M. A., Turner, S., Cheung, K., & Sareen, J. (2016). Association of child abuse exposure with suicidal ideation, suicide plans, and suicide attempts in military personnel and the general population in Canada. JAMA Psychiatry, 73(3), 229238.CrossRefGoogle ScholarPubMed
Baeyens, A. A., & Schwab, S. R. (2020). Finding a way out: S1P signaling and immune cell migration. Annual Review of Immunology, 38, 759784.CrossRefGoogle ScholarPubMed
Brundin, L., Erhardt, S., Bryleva, E. Y., Achtyes, E. D., & Postolache, T. T. (2015). The role of inflammation in suicidal behaviour. Acta Psychiatrica Scandinavica, 132(3), 192203.CrossRefGoogle Scholar
Bryan, C. J., & Rozek, D. C. (2018). Suicide prevention in the military: A mechanistic perspective. Current Opinion in Psychology, 22, 2732.CrossRefGoogle ScholarPubMed
Carballo, J. J., Akamnonu, C. P., & Oquendo, M. A. (2008). Neurobiology of suicidal behavior. An integration of biological and clinical findings. Archives of suicide research, 12(2), 93110.CrossRefGoogle ScholarPubMed
Carlson, E. B., Smith, S. R., Palmieri, P. A., Dalenberg, C., Ruzek, J. I., Kimerling, R., … Spain, D. A. (2011). Development and validation of a brief self-report measure of trauma exposure: The Trauma History Screen. Psychological Assessment, 23(2), 463.CrossRefGoogle ScholarPubMed
Centers for Disease Control and Prevention (2021). Suicide mortality in the United States, 1999–2019. Accessed February 6, 2022. Scholar
Chelala, C., Khan, A., & Lemoine, N. R. (2009). SNPnexus: A web database for functional annotation of newly discovered and public domain single nucleotide polymorphisms. Bioinformatics, 25(5), 655661.CrossRefGoogle ScholarPubMed
Chen, J., Ingham, N., Kelly, J., Jadeja, S., Goulding, D., Pass, J., … Steel, K. P. (2014). Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss. PLoS Genetics, 10(10), e1004688.CrossRefGoogle ScholarPubMed
Choi, S. W., & O'Reilly, P. F. (2019). PRSice-2: Polygenic risk score software for biobank-scale data. Gigascience, 8(7), giz082.CrossRefGoogle ScholarPubMed
DiBlasi, E., Kang, J., & Docherty, A. R. (2021). Genetic contributions to suicidal thoughts and behaviors. Psychological Medicine, 51(13), 21482155.CrossRefGoogle ScholarPubMed
Fu, Q., Heath, A. C., Bucholz, K. K., Nelson, E. C., Glowinski, A. L., Goldberg, J., … Eisen, S. A. (2002). A twin study of genetic and environmental influences on suicidality in men. Psychological Medicine, 32(1), 1124.CrossRefGoogle ScholarPubMed
Fuehrlein, B. S., Mota, N., Arias, A. J., Trevisan, L. A., Kachadourian, L. K., Krystal, J. H., … Pietrzak, R. H. (2016). The burden of alcohol use disorders in US military veterans: Results from the National Health and Resilience in Veterans Study. Addiction, 111(10), 17861794.CrossRefGoogle ScholarPubMed
Gibb, B. E., McGeary, J. E., Beevers, C. G., & Miller, I. W. (2006). Serotonin transporter (5-HTTLPR) genotype, childhood abuse, and suicide attempts in adult psychiatric inpatients. Suicide and Life-Threatening Behavior, 36(6), 687693.CrossRefGoogle ScholarPubMed
Gibbons, R., Kwan, H., Lavigne, J., Wang, J., & Mann, J. (2019). Medications and suicide: High Dimensional Empirical Bayes Screening (iDEAS). Harvard Data Science Review, 1(2), 160.Google Scholar
Howie, B. N., Donnelly, P., & Marchini, J. (2009). A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genetics, 5(6), e1000529.CrossRefGoogle ScholarPubMed
Hughes, K., Bellis, M. A., Hardcastle, K. A., Sethi, D., Butchart, A., Mikton, C., … Dunne, M. P. (2017). The effect of multiple adverse childhood experiences on health: A systematic review and meta-analysis. The Lancet Public Health, 2(8), e356e366.CrossRefGoogle Scholar
Kuballa, P., Nolte, W. M., Castoreno, A. B., & Xavier, R. J. (2012). Autophagy and the immune system. Annual Review of Immunology, 30, 611646.CrossRefGoogle ScholarPubMed
Lecrubier, Y., Sheehan, D. V., Weiller, E., Amorim, P., Bonora, I., Sheehan, K. H., … Dunbar, G. C. (1997). The Mini International Neuropsychiatric Interview (MINI). A short diagnostic structured interview: Reliability and validity according to the CIDI. European Psychiatry, 12(5), 224231.CrossRefGoogle Scholar
Levey, D. F., Gelernter, J., Polimanti, R., Zhou, H., Cheng, Z., Aslan, M., … Stein, M. B. (2020). Reproducible genetic risk loci for anxiety: Results from ~200 000 participants in the Million Veteran Program. American Journal of Psychiatry, 177(3), 223232.CrossRefGoogle ScholarPubMed
Levey, D. F., Stein, M. B., Wendt, F. R., Pathak, G. A., Zhou, H., Aslan, M., … Gelernter, J. (2021). Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nature Neuroscience, 24(7), 954963.CrossRefGoogle Scholar
McIntosh, I., & Story, G. W. (2021). Psychotic PTSD? Sudden traumatic loss precipitating very late onset schizophrenia. BMJ Case Reports CP, 14(1), e235384.CrossRefGoogle ScholarPubMed
Mok, S. C., Wong, K. K., Chan, R. K., Lau, C. C., Tsao, S. W., Knapp, R. C., & Berkowitz, R. S. (1994). Molecular cloning of differentially expressed genes in human epithelial ovarian cancer. Gynecologic Oncology, 52(2), 247252.CrossRefGoogle ScholarPubMed
Moore, R., Casale, F. P., Jan Bonder, M., Horta, D., Franke, L., Barroso, I., & Stegle, O. (2019). A linear mixed-model approach to study multivariate gene–environment interactions. Nature Genetics, 51(1), 180186.CrossRefGoogle ScholarPubMed
Mullins, N., Bigdeli, T. B., Børglum, A. D., Coleman, J. R., Demontis, D., Mehta, D., … Lewis, C. M. (2019). GWAS of suicide attempt in psychiatric disorders and association with major depression polygenic risk scores. American Journal of Psychiatry, 176(8), 651660.CrossRefGoogle ScholarPubMed
Mullins, N., Kang, J., Campos, A. I., Coleman, J. R., Edwards, A. C., Galfalvy, H., … Leboyer, M. (2022). Dissecting the shared genetic architecture of suicide attempt, psychiatric disorders, and known risk factors. Biological Psychiatry, 91(3), 313327.CrossRefGoogle ScholarPubMed
Murray, G. K., Lin, T., Austin, J., McGrath, J. J., Hickie, I. B., & Wray, N. R. (2021). Could polygenic risk scores be useful in psychiatry?: A review. JAMA Psychiatry, 78(2), 210219.CrossRefGoogle ScholarPubMed
Na, P. J., De Angelis, F., Nichter, B., Wendt, F. R., Krystal, J. H., Southwick, S. M., … Pietrzak, R. H. (2021). Psychosocial moderators of polygenic risk for suicidal ideation: Results from a 7-year population-based, prospective cohort study of US veterans. Molecular Psychiatry, 17.Google Scholar
Napolitano, F., Carrella, D., Mandriani, B., Pisonero-Vaquero, S., Sirci, F., Medina, D. L., … Di Bernardo, D. (2018). Gene2drug: A computational tool for pathway-based rational drug repositioning. Bioinformatics, 34(9), 14981505.CrossRefGoogle ScholarPubMed
Ni, G., Zeng, J., Revez, J. A., Wang, Y., Zheng, Z., Ge, T., … McDonald, C. (2021). A comparison of ten polygenic score methods for psychiatric disorders applied across multiple cohorts. Biological Psychiatry, 90(9), 611620.CrossRefGoogle ScholarPubMed
Nichter, B., Norman, S., Haller, M., & Pietrzak, R. H. (2019). Psychological burden of PTSD, depression, and their comorbidity in the US veteran population: Suicidality, functioning, and service utilization. Journal of Affective Disorders, 256, 633640.CrossRefGoogle ScholarPubMed
Nichter, B., Hill, M., Norman, S., Haller, M., & Pietrzak, R. H. (2020a). Associations of childhood abuse and combat exposure with suicidal ideation and suicide attempt in US military veterans: A nationally representative study. Journal of Affective Disorders, 276, 11021108.CrossRefGoogle ScholarPubMed
Nichter, B., Hill, M., Norman, S., Haller, M., & Pietrzak, R. H. (2020b). Impact of specific combat experiences on suicidal ideation and suicide attempt in US military veterans: Results from the National Health and Resilience in Veterans Study. Journal of Psychiatric Research, 130, 231239.CrossRefGoogle ScholarPubMed
Nichter, B., Stein, M. B., Norman, S. B., Hill, M. L., Straus, E., Haller, M., … Pietrzak, R. H. (2021a). Prevalence, correlates, and treatment of suicidal behavior in US Military veterans: Results from the 2019–2020 National Health and Resilience in Veterans Study. The Journal of Clinical Psychiatry, 82(5), 35870.CrossRefGoogle ScholarPubMed
Nichter, B., Hill, M. L., Na, P. J., Kline, A. C., Norman, S. B., Krystal, J. H., … Pietrzak, R. H. (2021b). Prevalence and trends in suicidal behavior among US military veterans during the COVID-19 pandemic. JAMA psychiatry, 78(11), 12181227.CrossRefGoogle ScholarPubMed
Nichter, B., Stein, M. B., Monteith, L. L., Herzog, S., Holliday, R., Hill, M. L., … Pietrzak, R. H. (2022). Risk factors for suicide attempts among US military veterans: A 7-year population-based, longitudinal cohort study. Suicide and Life-Threatening Behavior, 52(2), 303316.CrossRefGoogle ScholarPubMed
Nock, M. K., Deming, C. A., Fullerton, C. S., Gilman, S. E., Goldenberg, M., Kessler, R. C., … Ursano, R. J. (2013). Suicide among soldiers: A review of psychosocial risk and protective factors. Psychiatry: Interpersonal & Biological Processes, 76(2), 97125.CrossRefGoogle ScholarPubMed
Nock, M. K., Millner, A. J., Joiner, T. E., Gutierrez, P. M., Han, G., Hwang, I., … Kessler, R. C. (2018). Risk factors for the transition from suicide ideation to suicide attempt: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Journal of Abnormal Psychology, 127(2), 139.CrossRefGoogle ScholarPubMed
Osimo, E. F., Pillinger, T., Rodriguez, I. M., Khandaker, G. M., Pariante, C. M., & Howes, O. D. (2020). Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain, Behavior, and Immunity, 87, 901909.CrossRefGoogle ScholarPubMed
Pandey, G. N. (2013). Biological basis of suicide and suicidal behavior. Bipolar Disorders, 15(5), 524541.CrossRefGoogle ScholarPubMed
Pedersen, N. L., & Fiske, A. (2010). Genetic influences on suicide and nonfatal suicidal behavior: Twin study findings. European Psychiatry, 25(5), 264267.CrossRefGoogle ScholarPubMed
Popovic, D., Schmitt, A., Kaurani, L., Senner, F., Papiol, S., Malchow, B., … Falkai, P. (2019). Childhood trauma in schizophrenia: Current findings and research perspectives. Frontiers in Neuroscience, 13, 274.CrossRefGoogle ScholarPubMed
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics, 38(8), 904909.CrossRefGoogle ScholarPubMed
Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., Amorim, P., Janavs, J., Weiller, E., … Dunbar, G. C. (1998). The Mini-International Neuropsychiatric Interview (MINI): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry, 59(20), 2233.Google ScholarPubMed
Stein, M. B., Jain, S., Campbell-Sills, L., Ware, E. B., Choi, K. W., He, F., … Ursano, R. J. (2021a). Polygenic risk for major depression is associated with lifetime suicide attempt in US soldiers independent of personal and parental history of major depression. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 186(8), 469475.CrossRefGoogle ScholarPubMed
Stein, M. B., Levey, D. F., Cheng, Z., Wendt, F. R., Harrington, K., Pathak, G. A., … Gelernter, J. (2021b). Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program. Nature Genetics, 53(2), 174184.CrossRefGoogle ScholarPubMed
Strawbridge, R. J., Ward, J., Ferguson, A., Graham, N., Shaw, R. J., Cullen, B., … Smith, D. J. (2019). Identification of novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide. EBioMedicine, 41, 517525.CrossRefGoogle ScholarPubMed
Subramanian, A., Narayan, R., Corsello, S. M., Peck, D. D., Natoli, T. E., Lu, X., … Golub, T. R. (2017). A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell, 171(6), 14371452.CrossRefGoogle ScholarPubMed
Sun, J., Wan, C., Jia, P., Fanous, A. H., Kendler, K. S., Riley, B. P., & Zhao, Z. (2011). Application of systems biology approach identifies and validates GRB2 as a risk gene for schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample. Schizophrenia Research, 125(2–3), 201208.CrossRefGoogle ScholarPubMed
Supek, F., Bošnjak, M., Škunca, N., & Šmuc, T. (2011). REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS ONE, 6(7), e21800.CrossRefGoogle ScholarPubMed
Thomas, P. D., Campbell, M. J., Kejariwal, A., Mi, H., Karlak, B., Daverman, R., … Narechania, A. (2003). PANTHER: A library of protein families and subfamilies indexed by function. Genome Research, 13(9), 21292141.CrossRefGoogle ScholarPubMed
United States Department of Veterans Affairs (2020). 2019 National Veteran Suicide Prevention Annual Report. Washington, DC: US Dept of Health and Human Services.Google Scholar
Voracek, M., & Loibl, L. M. (2007). Genetics of suicide: A systematic review of twin studies. Wiener Klinische Wochenschrift, 119(15), 463475.CrossRefGoogle ScholarPubMed
Weathers, F., Litz, B., Huska, J., & Keane, T. (1994). PTSD checklist-specific version. Boston, MA: National Center for PTSD.Google Scholar
Wendt, F. R., Pathak, G. A., Levey, D. F., Nuñez, Y. Z., Overstreet, C., Tyrrell, C., … Polimanti, R. (2021). Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality. Neurobiology of Stress, 14, 100309.CrossRefGoogle ScholarPubMed
Wilcox, H. C., Fullerton, J. M., Glowinski, A. L., Benke, K., Kamali, M., Hulvershorn, L. A., … Nurnberger, J. I. Jr (2017). Traumatic stress interacts with bipolar disorder genetic risk to increase risk for suicide attempts. Journal of the American Academy of Child & Adolescent Psychiatry, 56(12), 10731080.CrossRefGoogle ScholarPubMed
World Health Organization (2014). Preventing suicide: A global imperative. Geneva, Switzerland: World Health Organization.Google Scholar
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