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. 2024 Jul:337:115950.
doi: 10.1016/j.psychres.2024.115950. Epub 2024 May 8.

Distinguishing vulnerability and resilience to posttraumatic stress disorder evaluating traumatic experiences, genetic risk and electronic health records

Solveig Løkhammer  1 , Dora Koller  2 , Frank R Wendt  3 , Karmel W Choi  4 , Jun He  5 , Eleni Friligkou  5 , Cassie Overstreet  5 , Joel Gelernter  6 , Stéphanie Le Hellard  7 , Renato Polimanti  8
Affiliations

Distinguishing vulnerability and resilience to posttraumatic stress disorder evaluating traumatic experiences, genetic risk and electronic health records

Solveig Løkhammer et al. Psychiatry Res. 2024 Jul.

Abstract

What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and electronic health records (EHR), we investigated and predicted the clinical comorbidities (co-phenome) of PTSD vulnerability and resilience in the UK Biobank (UKB) and All of Us Research Program (AoU), respectively. In 60,354 trauma-exposed UKB participants, we defined PTSD vulnerability and resilience considering PTSD symptoms, trauma burden, and polygenic risk scores. EHR-based phenome-wide association studies (PheWAS) were conducted to dissect the co-phenomes of PTSD vulnerability and resilience. Significant diagnostic endpoints were applied as weights, yielding a phenotypic risk score (PheRS) to conduct PheWAS of PTSD vulnerability and resilience PheRS in up to 95,761 AoU participants. EHR-based PheWAS revealed three significant phenotypes positively associated with PTSD vulnerability (top association "Sleep disorders") and five outcomes inversely associated with PTSD resilience (top association "Irritable Bowel Syndrome"). In the AoU cohort, PheRS analysis showed a partial inverse relationship between vulnerability and resilience with distinct comorbid associations. While PheRSvulnerability associations were linked to multiple phenotypes, PheRSresilience showed inverse relationships with eye conditions. Our study unveils phenotypic differences in PTSD vulnerability and resilience, highlighting that these concepts are not simply the absence and presence of PTSD.

Keywords: All of Us Research Program; Phenome; Polygenic risk score; Posttraumatic stress disorder; Resilience; UK Biobank; Vulnerability.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Polimanti received a research grant from Alkermes for the present study. Drs. Polimanti and Gelernter received honorariums for editorial work in the journal Complex Psychiatry. The other authors have no conflicts of interest to declare.

Figures

Figure 1.
Figure 1.. Study design overview.
First, only trauma-exposed individuals were investigated to define PTSD+ cases and PTSD- controls based on PTSD symptom burden. Contrasting these groups, weighted by GWAS summary statistics of PTSD, we calculated a polygenic risk score for each study participant. Assessing three criteria – trauma burden, PTSD symptom levels and polygenic risk score – we defined PTSD vulnerability and resilience. An electronic health record-based phenome-wide association study (PheWAS) was applied to each group, characterizing their medical co-phenome. Further, elastic net regression models were performed to generate phenotype weights to derive a phenotypic risk score (PheRS) applied in an independent EHR source to perform PheWAS of PTSD vulnerability and resilience PheRS. Created with BioRender.
Figure 2.
Figure 2.. Electronic Health Record (EHR)-based phenome-wide association studies of PTSD vulnerability (panel A) and resilience (panel B) in trauma-exposed UK Biobank participants.
Arrows pointing upwards represent positive associations, while arrows pointing downwards represent negative associations. Each logistic regression model included vulnerability or resilience status as the dependent variable, phecodes as the independent variable, and included sex, age, Townsend deprivation index, birth year, recruitment centre and genetically derived principal components 1–10 as covariates. Phecodes are displayed by their estimate on a negative logarithmic scale of p-value on the y-axis, and phecode categories are represented on the x-axis. The red horizontal line indicates a significant threshold at FDR q<0.05. Significant associations are annotated only.
Figure 3.
Figure 3.. Phenome-wide association studies of PTSD vulnerability and resilience phenotypic risk scores (PheRS; Panels A and B, respectively) in the All of Us Research Program cohort.
Arrows pointing upwards represent positive associations, while arrows pointing downwards represent negative associations. Each logistic regression model included phecode as the dependent variable, PheRSvulnerability (A) or PheRSresilience (B) as the independent variable and sex, age, income, and within-ancestry genetically derived principal components 1–10 as covariates. Phecodes are displayed by their estimate on a negative logarithmic scale of p-value on the y-axis, and phecode categories are represented on the x-axis. The red horizontal line indicates a significant threshold at FDR q<0.05. Labels are reported only for FDR-significant associations.
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