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

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

Author information

¹Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Clinical Science, University of Bergen, Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. Electronic address: solveig.lokhammer@uib.no.

²Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Genetics, Microbiology, and Statistics, Faculty of Biology, University of Barcelona, Catalonia, Spain.

³Department of Anthropology, University of Toronto, Mississauga, Canada; Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.

⁴Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

⁵Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.

⁶Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA; Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA; Wu Tsai Institute, Yale University, New Haven, CT, USA.

⁷Department of Clinical Science, University of Bergen, Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; Bergen Center of Brain Plasticity, Haukeland University Hospital, Bergen, Norway.

⁸Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA; Wu Tsai Institute, Yale University, New Haven, CT, USA; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.

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 PheRS_{vulnerability} associations were linked to multiple phenotypes, PheRS_resilience 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.