| Title: | Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records |
| Journal: | Molecular Psychiatry |
| Published: | 19 Aug 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35986173/ |
| DOI: | https://doi.org/10.1038/s41380-022-01735-z |
| URL: | https://doi.org/10.1101/2022.03.04.22271901 |
Publication 10447
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Abstract
The association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed for these conditions. To understand the dynamics underlying PTSD-CAD comorbidity, we investigated large-scale genome-wide association (GWA) statistics from the Million Veteran Program (MVP), the UK Biobank (UKB), the Psychiatric Genomics Consortium, and the CARDIoGRAMplusC4D Consortium. We observed a genetic correlation of CAD with PTSD case-control and quantitative outcomes, ranging from 0.18 to 0.32. To investigate possible cause-effect relationships underlying these genetic correlations, we performed a two-sample Mendelian randomization (MR) analysis, observing a significant bidirectional relationship between CAD and PTSD symptom severity. Genetically-determined PCL-17 (PTSD 17-item Checklist) 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 to −0.81). Because of these opposite-direction associations, we conducted a pleiotropic meta-analysis to investigate loci with concordant vs. discordant effects on PCL-17 and CAD, observing that concordant-effect loci were enriched for molecular pathways related to platelet amyloid precursor protein (beta = 1.53, p = 2.97 × 10−7) and astrocyte activation regulation (beta = 1.51, p = 2.48 × 10−6) while discordant-effect loci were enriched for biological processes related to lipid metabolism (e.g., triglyceride-rich lipoprotein particle clearance, beta = 2.32, p = 1.61 × 10−10). To follow up these results, we leveraged MVP and UKB electronic health records (EHR) to assess longitudinal changes in the association between CAD and posttraumatic stress severity. This EHR-based 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). In conclusion, both our genetically-informed analyses and our EHR-based follow-up investigation highlighted a bidirectional relationship between PTSD and CAD where multiple pleiotropic mechanisms are likely to be involved.</p>
13 Authors
- Renato Polimanti
- Frank R. Wendt
- Gita A. Pathak
- Daniel S. Tylee
- Catherine Tcheandjieu
- Austin T. Hilliard
- Daniel F. Levey
- Keyrun Adhikari
- J. Michael Gaziano
- Christopher J. O'Donnell
- Themistocles L. Assimes
- Murray B. Stein
- Joel Gelernter
1 Application
| Application ID | Title |
|---|---|
| 58146 | The causes and consequences of pleiotropy across the human phenome |
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