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Polygenic prediction of PTSD trajectories in 9/11 responders

Published online by Cambridge University Press:  23 October 2020

Monika A. Waszczuk*
Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA
Anna R. Docherty
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
Andrey A. Shabalin
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA
Jiaju Miao
Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA
Xiaohua Yang
World Trade Center Health and Wellness Program, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
Pei-Fen Kuan
Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA
Evelyn Bromet
Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA
Roman Kotov
Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA
Benjamin J. Luft
World Trade Center Health and Wellness Program, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
Author for correspondence: Monika Waszczuk, E-mail:



Genetics hold promise of predicting long-term post-traumatic stress disorder (PTSD) outcomes following trauma. The aim of the current study was to test whether six hypothesized polygenic risk scores (PRSs) developed to capture genetic vulnerability to psychiatric conditions prospectively predict PTSD onset, severity, and 18-year course after trauma exposure.


Participants were 1490 responders to the World Trade Center (WTC) disaster (mean age at 9/11 = 38.81 years, s.d. = 8.20; 93.5% male; 23.8% lifetime WTC-related PTSD diagnosis). Prospective longitudinal data on WTC-related PTSD symptoms were obtained from electronic medical records and modelled as PTSD trajectories using growth mixture model analysis. Independent regression models tested whether six hypothesized psychiatric PRSs (PTSD-PRS, Re-experiencing-PRS, Generalized Anxiety-PRS, Schizophrenia-PRS, Depression-PRS, and Neuroticism-PRS) are predictive of WTC-PTSD outcomes: lifetime diagnoses, average symptom severity, and 18-year symptom trajectory. All analyses were adjusted for population stratification, 9/11 exposure severity, and multiple testing.


Depression-PRS predicted PTSD diagnostic status (OR 1.37, CI 1.17–1.61, adjusted p = 0.001). All PRSs, except PTSD-PRS, significantly predicted average PTSD symptoms (β = 0.06–0.10, adjusted p < 0.05). Re-experiencing-PRS, Generalized Anxiety-PRS and Schizophrenia-PRS predicted the high severity PTSD trajectory class (ORs 1.21–1.28, adjusted p < 0.05). Finally, PRSs prediction was independent of 9/11 exposure severity and jointly accounted for 3.7 times more variance in PTSD symptoms than the exposure severity.


Psychiatric PRSs prospectively predicted WTC-related PTSD lifetime diagnosis, average symptom severity, and 18-year trajectory in responders to 9/11 disaster. Jointly, PRSs were more predictive of subsequent PTSD than the exposure severity. In the future, PRSs may help identify at-risk responders who might benefit from targeted prevention approaches.

Original Article
Copyright © The Author(s), 2020. Published by Cambridge University Press

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Denotes joint Senior Authors.


Assary, E., Vincent, J. P., Keers, R., & Pluess, M. (2018). Gene-environment interaction and psychiatric disorders: Review and future directions. Seminars in cell & Developmental Biology, 77, 133143.CrossRefGoogle ScholarPubMed
Avinun, R. (2019). The E Is in the G: Gene–environment–trait correlations and findings from genome-wide association studies. Perspectives on Psychological Science, 15(1), 8189.CrossRefGoogle Scholar
Bigdeli, T. B., Genovese, G., Georgakopoulos, P., Meyers, J. L., Peterson, R. E., Iyegbe, C. O., … Pato, C. N. (2019). Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry. Molecular Psychiatry, 25(10), 24552467.CrossRefGoogle ScholarPubMed
Bogdan, R., Baranger, D. A., & Agrawal, A. (2018). Polygenic risk scores in clinical psychology: Bridging genomic risk to individual differences. Annual Review of Clinical Psychology, 14, 119157.CrossRefGoogle ScholarPubMed
Bromet, E., Hobbs, M., Clouston, S., Gonzalez, A., Kotov, R., & Luft, B. (2016). DSM-IV post-traumatic stress disorder among World Trade Center responders 11–13 years after the disaster of 11 September 2001 (9/11). Psychological Medicine, 46(04), 771783.CrossRefGoogle Scholar
Dasaro, C. R., Holden, W. L., Berman, K. D., Crane, M. A., Kaplan, J. R., Lucchini, R. G., … Todd, A. C. (2015). Cohort profile: World trade center health program general responder cohort. International Journal of Epidemiology, 46(2), e9e9. doi:10.1093/ije/dyv099.CrossRefGoogle Scholar
Docherty, A. R., Moscati, A., Dick, D., Savage, J. E., Salvatore, J. E., Cooke, M., … Riley, B. P. (2018). Polygenic prediction of the phenome, across ancestry, in emerging adulthood. Psychological Medicine, 48(11), 1814.CrossRefGoogle ScholarPubMed
Duncan, L., Cooper, B. N., & Shen, H. (2018). Robust findings from 25 years of PSTD genetics research. Current Psychiatry Reports, 20(12), 115.CrossRefGoogle Scholar
Duncan, L., Ratanatharathorn, A., Aiello, A. E., Almli, L. M., Amstadter, A. B., Ashley-Koch, A. E., … Koenen, K. C. (2017). Largest GWAS of PTSD (N = 20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Molecular Psychiatry, 23(3), 666673. doi:10.1038/mp.2017.77.CrossRefGoogle ScholarPubMed
Dunn, E. C., Wiste, A., Radmanesh, F., Almli, L. M., Gogarten, S. M., Sofer, T., … Weir, D. R. (2016). Genome-wide association study (GWAS) and genome-wide by environment interaction study (GWEIS) of depressive symptoms in African American and Hispanic/Latina women. Depression and Anxiety, 33(4), 265280.CrossRefGoogle ScholarPubMed
Euesden, J., Lewis, C. M., & O'Reilly, P. F. (2015). PRSice: Polygenic risk score software. Bioinformatics (Oxford, England), 31(9), 14661468.CrossRefGoogle ScholarPubMed
First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. (1998). Structured Clinical Interview for DSM-IV Axis I Disorders: Patient Edition (February 1996 Final), SCID-I/P: Biometrics Research Department, New York State Psychiatric Institute.CrossRefGoogle Scholar
Freedy, J. R., Steenkamp, M. M., Magruder, K. M., Yeager, D. E., Zoller, J. S., Hueston, W. J., & Carek, P. J. (2010). Post-traumatic stress disorder screening test performance in civilian primary care. Family Practice, 27(6), 615624.CrossRefGoogle ScholarPubMed
Gaziano, J. M., Concato, J., Brophy, M., Fiore, L., Pyarajan, S., Breeling, J., … Humphries, D. (2016). Million Veteran Program: A mega-biobank to study genetic influences on health and disease. Journal of Clinical Epidemiology, 70, 214223.CrossRefGoogle Scholar
Gelernter, J., Sun, N., Polimanti, R., Pietrzak, R., Levey, D. F., Bryois, J., … Radhakrishnan, K. (2019). Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in> 165 000 US veterans. Nature Neuroscience, 22(9), 13941401.CrossRefGoogle ScholarPubMed
Hettema, J. M., Neale, M. C., Myers, J. M., Prescott, C. A., & Kendler, K. S. (2006). A population-based twin study of the relationship between neuroticism and internalizing disorders. American Journal of Psychiatry, 163(5), 857864.CrossRefGoogle ScholarPubMed
Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., … Wigmore, E. M. (2019). Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nature Neuroscience, 22(3), 343.CrossRefGoogle ScholarPubMed
Jones, H. J., Heron, J., Hammerton, G., Stochl, J., Jones, P. B., Cannon, M., … Linden, D. E. (2018). Investigating the genetic architecture of general and specific psychopathology in adolescence. Translational Psychiatry, 8(1), 145.CrossRefGoogle ScholarPubMed
Kessler, R. C., Aguilar-Gaxiola, S., Alonso, J., Benjet, C., Bromet, E. J., Cardoso, G., … Ferry, F. (2017). Trauma and PTSD in the WHO world mental health surveys. European Journal of Psychotraumatology, 8(Suppl 5), 1353383.CrossRefGoogle ScholarPubMed
King, D. W., Leskin, G. A., King, L. A., & Weathers, F. W. (1998). Confirmatory factor analysis of the clinician-administered PTSD Scale: Evidence for the dimensionality of posttraumatic stress disorder. Psychological Assessment, 10(2), 90.CrossRefGoogle Scholar
Koenen, K., Ratanatharathorn, A., Ng, L., McLaughlin, K., Bromet, E., Stein, D., … Scott, K. (2017). Posttraumatic stress disorder in the world mental health surveys. Psychological Medicine, 47(13), 22602274.CrossRefGoogle ScholarPubMed
Lee, P. H., Anttila, V., Won, H., Feng, Y.-C. A., Rosenthal, J., Zhu, Z., … Posthuma, D. (2019). Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell, 179(7), 14691482, e1411.CrossRefGoogle Scholar
Lehto, K., Hägg, S., Lu, D., Karlsson, R., Pedersen, N. L., & Mosing, M. A. (2019). Childhood adoption and mental health in adulthood: The role of gene-environment correlations and interactions in the UK Biobank. Biological Psychiatry, 87(8), 708716.CrossRefGoogle ScholarPubMed
Levey, D. F., Gelernter, J., Polimanti, R., Zhou, H., Cheng, Z., Aslan, M., … Bryois, J. (2020). Reproducible genetic risk loci for anxiety: Results from~ 200000 participants in the million veteran program. American Journal of Psychiatry, 177(3), 223232.CrossRefGoogle ScholarPubMed
Lewis, C. M., & Vassos, E. (2017). Prospects for using risk scores in polygenic medicine. Genome Medicine, 9(1), 96.CrossRefGoogle ScholarPubMed
Lewis, C. M., & Vassos, E. (2020). Polygenic risk scores: From research tools to clinical instruments. Genome Medicine, 12, 111.CrossRefGoogle ScholarPubMed
Luft, B., Schechter, C., Kotov, R., Broihier, J., Reissman, D., Guerrera, K., … Friedman-Jimenez, G. (2012). Exposure, probable PTSD and lower respiratory illness among World Trade Center rescue, recovery and clean-up workers. Psychological Medicine, 42(05), 10691079.CrossRefGoogle ScholarPubMed
Martin, A. R., Kanai, M., Kamatani, Y., Okada, Y., Neale, B. M., & Daly, M. J. (2019). Clinical use of current polygenic risk scores may exacerbate health disparities. Nature Genetics, 51(4), 584.CrossRefGoogle ScholarPubMed
McCarthy, S., Das, S., Kretzschmar, W., Delaneau, O., Wood, A. R., Teumer, A., … Sharp, K. (2016). A reference panel of 64 976 haplotypes for genotype imputation. Nature Genetics, 48(10), 1279.Google ScholarPubMed
Muthén, L., & Muthén, B. (2007). Mplus. Statistical analysis with latent variables. Version, 3.Google Scholar
Nagel, M., Jansen, P. R., Stringer, S., Watanabe, K., de Leeuw, C. A., Bryois, J., … Muñoz-Manchado, A. B. (2018). Meta-analysis of genome-wide association studies for neuroticism in 449484 individuals identifies novel genetic loci and pathways. Nature Genetics, 50(7), 920.CrossRefGoogle ScholarPubMed
Nievergelt, C. M., Maihofer, A. X., Klengel, T., Atkinson, E. G., Chen, C.-Y., Choi, K. W., … Gelernter, J. (2019). International meta-analysis of PTSD genome-wide association studies identifies sex-and ancestry-specific genetic risk loci. Nature Communications, 10(1), 116.CrossRefGoogle ScholarPubMed
Perrin, M. A., DiGrande, L., Wheeler, K., Thorpe, L., Farfel, M., & Brackbill, R. (2007). Differences in PTSD prevalence and associated risk factors among World Trade Center disaster rescue and recovery workers. American Journal of Psychiatry, 164(9), 13851394.CrossRefGoogle ScholarPubMed
Peterson, R. E., Cai, N., Dahl, A. W., Bigdeli, T. B., Edwards, A. C., Webb, B. T., … Kendler, K. S. (2018). Molecular genetic analysis subdivided by adversity exposure suggests etiologic heterogeneity in major depression. American Journal of Psychiatry, 175(6), 545554.CrossRefGoogle ScholarPubMed
Peyrot, W. J., Van der Auwera, S., Milaneschi, Y., Dolan, C. V., Madden, P. A., Sullivan, P. F., … Nivard, M. G. (2018). Does childhood trauma moderate polygenic risk for depression? A meta-analysis of 5765 subjects from the psychiatric genomics consortium. Biological Psychiatry, 84(2), 138147.CrossRefGoogle ScholarPubMed
Pietrzak, R., Feder, A., Singh, R., Schechter, C., Bromet, E. J., Katz, C., … Crane, M. (2014). Trajectories of PTSD risk and resilience in World Trade Center responders: An 8-year prospective cohort study. Psychological Medicine, 44(1), 205219.CrossRefGoogle ScholarPubMed
Renck, B., Weisaeth, L., & Skarbö, S. (2002). Stress reactions in police officers after a disaster rescue operation. Nordic Journal of Psychiatry, 56(1), 714.CrossRefGoogle ScholarPubMed
Rice, F., Riglin, L., Thapar, A. K., Heron, J., Anney, R., O'donovan, M. C., … Thapar, A. (2018). Characterizing developmental trajectories and the role of neuropsychiatric genetic risk variants in early-onset depression. JAMA Psychiatry, 76(3), 306313.CrossRefGoogle Scholar
Ripke, S., Neale, B. M., Corvin, A., Walters, J. T., Farh, K.-H., Holmans, P. A., … Huang, H. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511(7510), 421.Google Scholar
Sartor, C. E., Grant, J. D., Lynskey, M. T., McCutcheon, V. V., Waldron, M., Statham, D. J., … Martin, N. G. (2012). Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression. Archives of General Psychiatry, 69(3), 293299.CrossRefGoogle ScholarPubMed
Sartor, C. E., McCutcheon, V., Pommer, N., Nelson, E., Grant, J., Duncan, A. E., … Heath, A. (2011). Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychological Medicine, 41(7), 14971505.CrossRefGoogle ScholarPubMed
Schultebraucks, K., Shalev, A. Y., Michopoulos, V., Grudzen, C. R., Shin, S.-M., Stevens, J. S., … Galatzer-Levy, I. R. (2020). A validated predictive algorithm of post-traumatic stress course following emergency department admission after a traumatic stressor. Nature Medicine, 26(7), 10841088. doi:10.1038/s41591-020-0951-z.CrossRefGoogle ScholarPubMed
Smoller, J. W., Andreassen, O. A., Edenberg, H. J., Faraone, S. V., Glatt, S. J., & Kendler, K. S. (2018). Psychiatric genetics and the structure of psychopathology. Molecular Psychiatry, 24(3), 409420.CrossRefGoogle ScholarPubMed
Stein, M. B., Jang, K. L., Taylor, S., Vernon, P. A., & Livesley, W. J. (2002). Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: A twin study. American Journal of Psychiatry, 159(10), 16751681.CrossRefGoogle ScholarPubMed
Sumner, J. A., Duncan, L., Ratanatharathorn, A., Roberts, A. L., & Koenen, K. C. (2016). PTSD has shared polygenic contributions with bipolar disorder and schizophrenia in women. Psychological Medicine, 46(3), 669671.CrossRefGoogle ScholarPubMed
Torkamani, A., Wineinger, N. E., & Topol, E. J. (2018). The personal and clinical utility of polygenic risk scores. Nature Reviews Genetics, 19(9), 581590.CrossRefGoogle ScholarPubMed
Waszczuk, M. A., Eaton, N. R., Krueger, R. F., Shackman, A. J., Waldman, I. D., Zald, D. H., … Kotov, R. (2020). Redefining phenotypes to advance psychiatric genetics: Implications from hierarchical taxonomy of psychopathology. Journal of Abnormal Psychology, 129(2), 143161. doi:10.31234/ ScholarPubMed
Waszczuk, M. A., Kotov, R., Ruggero, C. J., Gamez, W., & Watson, D. (2017). Hierarchical structure of internalizing psychopathology: From individual symptoms to the spectrum. Journal of Abnormal Psychology, 126(5), 613634.CrossRefGoogle Scholar
Weathers, F. W., Litz, B. T., Herman, D. S., Huska, J. A., & Keane, T. M. (1993). The PTSD Checklist (PCL): Reliability, validity, and diagnostic utility. Paper presented at the Annual Convention of the International Society for Traumatic Stress Studies.Google Scholar
Wilkins, K. C., Lang, A. J., & Norman, S. B. (2011). Synthesis of the psychometric properties of the PTSD checklist (PCL) military, civilian, and specific versions. Depression and Anxiety, 28(7), 596606.CrossRefGoogle ScholarPubMed
Wisnivesky, J. P., Teitelbaum, S. L., Todd, A. C., Boffetta, P., Crane, M., Crowley, L., … Herbert, R. (2011). Persistence of multiple illnesses in World Trade Center rescue and recovery workers: A cohort study. The Lancet, 378(9794), 888897.CrossRefGoogle ScholarPubMed
Wray, N. R., Lee, S. H., Mehta, D., Vinkhuyzen, A. A., Dudbridge, F., & Middeldorp, C. M. (2014). Research review: Polygenic methods and their application to psychiatric traits. Journal of Child Psychology and Psychiatry, 55(10), 10681087.CrossRefGoogle ScholarPubMed
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