Polygenic prediction of PTSD trajectories in 9/11 responders

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

From genetics to systems biology of stress-related mental disorders

“…For example, PRS for depression predicted approximately 2.1% of the variance for anxiety in an elderly population group ( Demirkan et al, 2011 ). PRS derived from a GWAS for depression significantly predicted the variance in depression and PTSD in a target dataset ( Shen et al, 2020 ; Waszczuk et al, 2020 ). Additionally, PRS for anxiety predicted PTSD with a high severity trajectory class, estimated from growth mixture model analysis ( Waszczuk et al, 2020 ).…”

“…PRS derived from a GWAS for depression significantly predicted the variance in depression and PTSD in a target dataset ( Shen et al, 2020 ; Waszczuk et al, 2020 ). Additionally, PRS for anxiety predicted PTSD with a high severity trajectory class, estimated from growth mixture model analysis ( Waszczuk et al, 2020 ). These PRS findings provided further support of shared genetic contributions across stress-related disorders.…”

A Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population

“…In other words, PRS represent the additive effect of thousands to hundreds of thousands of genetic variants as a single measure of genetic risk, on an individual level, toward developing a particular trait. Therefore, PRS has the potential to identify individuals at risk for developing PTSD following trauma exposure and in fact, the genetic risk for PTSD (PTSD-PRS) has been shown to be more predictive of PTSD diagnosis than trauma exposure severity ( Waszczuk et al, 2020 ). The predictive utility of PRS can also explain some of the phenotypic variance in response to trauma exposure, for example, PTSD-PRS explained 4.68% of the variation observed in PTSD onset and 4.35% of PTSD symptom severity in a cohort of war veterans ( Misganaw et al, 2019 ).…”

“…Polygenic risk scores can also be used to examine shared genetic risk between traits of interest such as associated co-morbidities (e.g., MetS) and other psychiatric disorders. For example, a modest genetic risk overlap was observed between PTSD and MDD ( Duncan et al, 2018b ) and MDD-PRS significantly predicted PTSD diagnoses in a cohort of 9/11 responders ( Waszczuk et al, 2020 ) as well as in a civilian Peruvian cohort ( Shen et al, 2020 ). Shared genetic risk strongly suggests joint underlying genetic and physiological mechanisms exist between traits and PRS can therefore also be used to identify shared molecular pathways to provide insight into mechanisms underlying co-morbid disorders.…”

Neurobiological mechanisms underlying delayed expression of posttraumatic stress disorder: A scoping review

“…Other behavioral and polygenic risk factors: Polygenic risk scores based on multiple genetic variants known to contribute to psychopathology were calculated for individuals with European ancestry in a large, long-term prospective follow-up study of first responders working at the World Trade Center site (New York) following the 9/11/2001 terrorist attacks[ 46 ]. Re-experiencing, generalized anxiety, and schizophrenia polygenic risk scores were predictive of a severe PTSD symptom trajectory characterized by increasing incidence of chronic symptoms over the course of 17 years, and a depression polygenic risk score predicted a diagnosis of PTSD[ 46 ]. In a very large sample of community-dwelling women participating in the Nurses’ Health Study[ 47 ], time spent viewing TV was analyzed in relation to the onset of PTSD symptoms following exposure to trauma.…”