The structure of psychopathology can be organized hierarchically into a set of transdiagnostic dimensional phenotypes. No studies have examined whether these phenotypes are associated with brain structure or dementia in older adults.

Data were drawn from a longitudinal study of older adults aged 70–90 years at baseline (N = 1072; 44.8% male). Confirmatory factor models were fit to baseline psychiatric symptoms, with model fit assessed via traditional fit indices, model-based reliability estimates, and evaluation of model parameters. Bayesian plausible values were generated from the best-fitting model for use in subsequent analyses. Linear mixed models examined intraindividual change in global and regional gray matter volume (GMV) and cortical thickness over 6 years. Logistic regression examined whether symptom dimensions predicted incident dementia over 12 years.

A higher-order model showed a good fit to the data (BIC = 28,691.85; ssaBIC = 28,396.47; CFI = 0.926; TLI = 0.92; RMSEA = 0.047), including a general factor and lower-order dimensions of internalizing, disinhibited externalizing, and substance use. Baseline symptom dimensions did not predict change over time in total cortical and subcortical GMV or average cortical thickness; regional GMV or cortical thickness in the frontal, parietal, temporal, or occipital lobes; or regional GMV in the hippocampus and cerebellum (all p-values >0.5). Finally, baseline symptom dimensions did not predict incident dementia across follow-ups (all p-values >0.5).

We found no evidence that transdiagnostic dimensions are associated with gray matter structure or dementia in older adults. Future research should examine these relationships using psychiatric indicators capturing past history of chronic mental illness rather than current symptoms.

Polygenic risk scores (PRSs) capture genetic vulnerability to psychiatric conditions. However, PRSs are often associated with multiple mental health problems in children, complicating their use in research and clinical practice. The current study is the first to systematically test which PRSs associate broadly with all forms of childhood psychopathology, and which PRSs are more specific to one or a handful of forms of psychopathology.

The sample consisted of 4717 unrelated children (mean age = 9.92, s.d. = 0.62; 47.1% female; all European ancestry). Psychopathology was conceptualized hierarchically as empirically derived general factor (p-factor) and five specific factors: externalizing, internalizing, neurodevelopmental, somatoform, and detachment. Partial correlations explored associations between psychopathology factors and 22 psychopathology-related PRSs. Regressions tested which level of the psychopathology hierarchy was most strongly associated with each PRS.

Thirteen PRSs were significantly associated with the general factor, most prominently Chronic Multisite Pain-PRS (r = 0.098), ADHD-PRS (r = 0.079), and Depression-PRS (r = 0.078). After adjusting for the general factor, Depression-PRS, Neuroticism-PRS, PTSD-PRS, Insomnia-PRS, Chronic Back Pain-PRS, and Autism-PRS were not associated with lower order factors. Conversely, several externalizing PRSs, including Adventurousness-PRS and Disinhibition-PRS, remained associated with the externalizing factor (|r| = 0.040–0.058). The ADHD-PRS remained uniquely associated with the neurodevelopmental factor (r = 062).

PRSs developed to predict vulnerability to emotional difficulties and chronic pain generally captured genetic risk for all forms of childhood psychopathology. PRSs developed to predict vulnerability to externalizing difficulties, e.g. disinhibition, tended to be more specific in predicting behavioral problems. The results may inform translation of existing PRSs to pediatric research and future clinical practice.

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.