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Psychosocial moderators of polygenic risk for suicidal ideation: Results from a 7-year population-based, prospective cohort study of U.S. veterans

Molecular Psychiatry volume 27, pages 1068–1074 (2022)Cite this article

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Abstract

Polygenic risk scores (PRS) may help inform the etiology of suicidal thoughts and behaviors. In this study, we evaluated whether a suicidality PRS derived from a large genome-wide association study (GWAS) of suicidality from the UK Biobank (N = 122,935) predicted suicidal ideation (SI) in a 7-year population-based, prospective cohort of European-American US veterans (N = 1326). Results revealed that 8.8% (n = 115) of veterans developed new-onset SI, 4.0% (n = 52) had chronic SI, 3.4% (n = 31) had remitted SI, and 83.8% (n = 1128) denied SI over the study period. Suicidality PRSstandardized was positively associated with chronic SI (relative risk ratio [RRR] = 4.54, 95% confidence interval [CI] = 1.01–20.48) and new-onset SI (RRR = 2.97, 95%CI = 1.22–7.23), and negatively associated with remitted SI (RRR = 0.12, 95% CI = 0.02–0.60). Among veterans with higher suicidality PRS, those with higher baseline dispositional optimism had a lower likelihood of chronic SI (RRR = 0.67, 95% CI = 0.49–0.91) and higher likelihood of remitted SI (RRR = 1.98, 95% CI = 1.18–3.31). Among veterans with higher suicidality PRS, those with higher baseline levels of social support were less likely to develop new-onset SI (RRR = 0.95, 95% CI = 0.92–0.99). These interaction effects were enriched for genes implicated in neuron recognition and development, while the PRS main effect was enriched for genes involved in mannosylation. Collectively, results of this study suggest that suicidality PRS is linked prospectively to symptomatic courses of SI, and that dispositional optimism and social support moderate these associations. Interventions targeting these modifiable psychosocial factors may help mitigate risk of SI in veterans with high polygenic risk for suicidality.

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Acknowledgements

The authors thank the veterans who participated in this study.

Disclaimer

The funding agency had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.

Funding

The National Health and Resilience in Veterans Study is supported by the US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder.

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Authors and Affiliations

  1. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Peter J. Na, Flavio De Angelis, Frank R. Wendt, John H. Krystal, Steven M. Southwick, Daniel F. Levey, Joel Gelernter, Renato Polimanti & Robert H. Pietrzak

  2. VA Connecticut Healthcare System, West Haven, CT, USA

    Peter J. Na, Flavio De Angelis, Frank R. Wendt, Daniel F. Levey, Joel Gelernter & Renato Polimanti

  3. Department of Psychiatry, University of California, San Diego, CA, USA

    Brandon Nichter

  4. National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA

    John H. Krystal & Robert H. Pietrzak

  5. Department of Social and Behavioral Sciences, Yale School of Public Health, New Haven, CT, USA

    Robert H. Pietrzak

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Contributions

P.J.N. assisted with the conceptualization, study design, and writing of the paper. F.D.A. and R.P. analyzed the data and collaborated in the writing and editing of the manuscript. B.N., F.R.W., J.H.K., D.F.L., S.M.S., and J.G. collaborated in the interpretation of the data, and writing and editing of the manuscript. RHP designed the study, analyzed the data, and collaborated in the writing and editing of the manuscript.

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Correspondence to Peter J. Na.

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Competing interests

Drs. Gelernter and Polimanti are paid for their editorial work on the journal Complex Psychiatry. Dr. Krystal is a scientific advisor to Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc., Cadent Therapeutics (Clinical Advisory Board), PsychoGenics, Inc., Stanley Center for Psychiatric research at the Broad Institute of MIT and Harvard, Lohocla Research Corporation. J.H.K. owns stock and/or stock options in Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Inc., BlackThorn Therapeutics, Inc., Terran Biosciences, Inc. J.H.K. reports income <$10,000 per year from: AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, Concert Pharmaceuticals, Inc., Epiodyne, Inc., Heptares Therapeutics, Limited (UK), Janssen Research & Development, L.E.K. Consulting, Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc. Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, Taisho Pharmaceutical Co., Ltd. J.H.K. reports income >$10,000 per year from Biological Psychiatry (Editor). J.H.K. received the drug, Saracatinib from AstraZeneca and Mavoglurant from Novartis for research related to NIAAA grant “Center for Translational Neuroscience of Alcoholism [CTNA-4] from AstraZeneca Pharmaceuticals. J.H.K. holds the following patents: (1) Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US Patent #:5447948.September 5, 1995; (2) Vladimir, Coric, Krystal, John H, Sanacora, Gerard—Glutamate Modulating Agents in the Treatment of Mental Disorders US Patent No. 8778979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15/695164: Filing Date: 09/05/2017; (3) Charney D, Krystal JH, Manji H, Matthew S, Zarate C—Intranasal Administration of Ketamine to Treat Depression United States Application No. 14/197767 filed on March 5, 2014; United States application or Patent Cooperation Treaty (PCT) International application No. 14/306382 filed on June 17, 2014; (4): Zarate, C, Charney, DS, Manji, HK, Mathew, Sanjay J, Krystal, JH, Department of Veterans Affairs “Methods for Treating Suicidal Ideation”, Patent Application No. 14/197.767 filed on March 5, 2014 by Yale University Office of Cooperative Research; (5) Arias A, Petrakis I, Krystal JH.— Composition and methods to treat addiction. Provisional Use Patent Application no. 61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research.; (6) Chekroud A, Gueorguieva R, Krystal JH. “Treatment Selection for Major Depressive Disorder” [filing date June 3, 2016, USPTO docket number Y0087.70116US00]. Provisional patent submission by Yale University; (7) Gihyun, Yoon, Petrakis I, Krystal JH—Compounds, compositions and methods for treating or preventing depression and other diseases. US Provisional Patent Application No. 62/444552, filed on January 10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01; and (8) Abdallah C, Krystal JH, Duman R, Sanacora G. Combination therapy for treating or preventing depression or other mood diseases. US Provisional Patent Application No. 62/719935 filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. The remaining authors declare no competing interests.

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Na, P.J., De Angelis, F., Nichter, B. et al. Psychosocial moderators of polygenic risk for suicidal ideation: Results from a 7-year population-based, prospective cohort study of U.S. veterans. Mol Psychiatry 27, 1068–1074 (2022). https://doi.org/10.1038/s41380-021-01352-2

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