Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records

ABSTRACT Background The association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed among affected individuals. To understand the dynamics underlying PTSD-CAD comorbidity, we conducted a genetically-informed causal inference analysis using large-scale genome-wide association (GWA) statistics and follow-up analysis using electronic health records (EHR) and PTSD Checklist (PCL-17 or PCL-6) assessments available from the Million Veteran Program (MVP) and the UK Biobank (UKB), respectively. Methods We used GWA statistics from MVP, UKB, the Psychiatric Genomics Consortium, and the CARDIoGRAMplusC4D Consortium to perform a bidirectional, two-sample Mendelian randomization (MR) analysis to assess cause-effect relationships between CAD and PTSD. We also conducted a pleiotropic meta-analysis to investigate loci with concordant vs. discordant effects between the traits investigated. Leveraging individual-level information derived from MVP and UKB EHRs, we assessed longitudinal changes in the association between CAD and posttraumatic stress severity. Findings We observed a genetic correlation of CAD with PTSD case-control and quantitative outcomes, ranging from 0.18 to 0.32. Our two-sample MR showed a significant bidirectional relationship between CAD and PTSD symptom severity. Genetically-determined PCL-17 total score was associated with increased CAD risk (odds ratio=1.04; 95% confidence interval, 95%CI=1.01-1.06). Conversely, CAD genetic liability was associated with reduced PCL-17 total score (beta=-0.42; 95%CI=-0.04 – -0.81). These estimates were consistent across datasets and were not affected by heterogeneity or horizontal pleiotropy. The pleiotropic meta-analysis between PCL-17 and CAD identified loci with concordant effect enriched for platelet amyloid precursor protein pathway (p=2.97×10 −7 ) and negative regulation of astrocyte activation (p=2.48×10 −6 ) while discordant-effect loci were enriched for biological processed related lipid metabolism (e.g., triglyceride-rich lipoprotein particle clearance, p=1.61×10 −10 ). The EHR-based follow-up analysis highlighted that earlier CAD diagnosis is associated with increased PCL-total score later in life, while lower PCL total score was associated with increased risk of a later CAD diagnosis (Mann-Kendall trend test: MVP tau=0.932, p<2×10 −16 ; UKB tau=0.376, p=0.005) Interpretation Our results highlight a complicated relationship between PTSD and CAD that may be affected by the long-term consequences of CAD on the mental health of the individuals affected. Funding This research was supported by funding from the VA Cooperative Studies Program (CSP, no. CSP575B) and the Veterans Affairs Office of Research and Development MVP (grant nos. MVP000 and VA Merit MVP025).