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

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=2.97x10-7) and negative regulation of astrocyte activation (p=2.48x10-6) while discordant-effect loci were enriched for biological processed related lipid metabolism (e.g., triglyceride-rich lipoprotein particle clearance, p=1.61x10-10). 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<2x10-16; 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.