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Genetics of posttraumatic stress disorder and cardiovascular conditions using Life's Essential 8, Electronic Health
Jie Shen1,2, Wander Valentim2,3, Eleni Friligkou2,4
1Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China.
Insights
Post-traumatic stress disorder (PTSD) shares genetic risk loci and genes with cardiovascular diseases. These findings highlight tissue-specific mechanisms and potential drug targets for treating these common comorbidities.
Area of Science:
- Genetics and Genomics
- Cardiovascular Medicine
- Psychiatry
Background:
- Patients with post-traumatic stress disorder (PTSD) have an elevated risk of adverse cardiovascular (CV) outcomes.
- This study investigates shared genetic factors between PTSD and various cardiovascular conditions.
- Cardiovascular conditions were assessed through electronic health records (CV-EHR), cardiac and aortic imaging, and Life's Essential 8 (LE8) health behaviors.
Purpose of the Study:
- To identify shared genetic loci and genes between PTSD and cardiovascular diseases.
- To explore the tissue-specific regulatory mechanisms underlying PTSD-CV comorbidities.
- To identify potential common drug targets for psychiatric and cardiovascular conditions.
Main Methods:
- Utilized genome-wide association studies (GWAS) for PTSD, CV diagnoses (from Million Veteran Program and UK Biobank), cardiac/aortic imaging traits, and LE8 factors.
- Identified shared loci using local genetic correlations (rg) and colocalization analysis for shared causal variants.
- Investigated overlapping genes through proteome expression in brain and blood, followed by pathway and drug-target analysis, with epidemiological replication in the AllofUS cohort.
Main Results:
- Significant genetic correlations and shared causal variants were found between PTSD and numerous CV-EHR traits, heart imaging traits, and LE8 factors.
- Observational analysis confirmed associations between PTSD and several CV-EHR traits.
- Identified shared genes in blood and brain proteomes, implicating neuronal, immune, metabolic, and calcium-modulating pathways; highlighted DRD2, NOS1, GFAP, and POR as potential drug targets.
Conclusions:
- Post-traumatic stress disorder and cardiovascular comorbidities share common genetic risk loci.
- These shared genetic factors involve tissue-specific regulatory mechanisms.
- The identified genes and pathways offer insights into the biological underpinnings of PTSD-CV comorbidity and suggest potential therapeutic targets.
Background:
Patients with post-traumatic stress disorder (PTSD) experience higher risk of adverse cardiovascular (CV) outcomes. This study explores shared loci, and genes between PTSD and CV conditions from three major domains: CV diagnoses from electronic health records (CV-EHR), cardiac and aortic imaging, and CV health behaviors defined in Life's Essential 8 (LE8).
Methods:
We used genome-wide association study (GWAS) of PTSD (N=1,222,882), 246 CV diagnoses based on EHR data from Million Veteran Program (MVP; N=458,061), UK Biobank (UKBB; N=420,531), 82 cardiac and aortic imaging traits (N=26,893), and GWAS of traits defined in the LE8 (N = 282,271 ~ 1,320,016). Shared loci between PTSD and CV conditions were identified using local genetic correlations (rg), and colocalization (shared causal variants). Overlapping genes between PTSD and CV conditions were identified from genetically regulated proteome expression in brain and blood tissues, and subsequently tested to identify functional pathways and gene-drug targets. Epidemiological replication of EHR-CV diagnoses was performed in AllofUS cohort (AoU; N=249,906).
Results:
Among the 76 PTSD-susceptibility risk loci, 33 loci exhibited local rg with 45 CV-EHR traits (|rg|≥0.4), four loci with eight heart imaging traits(|rg|≥0.5), and 44 loci with LE8 factors (|rg|≥0.36) in MVP. Among significantly correlated loci, we found shared causal variants (colocalization probability > 80%) between PTSD and 17 CV-EHR (in MVP) at 11 loci in MVP, that also replicated in UKBB and/or other cohorts. Of the 17 traits, the observational analysis in the AoU showed PTSD was associated with 13 CV-EHR traits after accounting for socioeconomic factors and depression diagnosis. PTSD colocalized with eight heart imaging traits on 2 loci and with LE8 factors on 31 loci. Leveraging blood and brain proteome expression, we found 33 and 122 genes, respectively, shared between PTSD and CVD. Blood proteome genes were related to neuronal and immune processes, while the brain proteome genes converged on metabolic and calcium-modulating pathways (FDR p <0.05). Drug repurposing analysis highlighted DRD2, NOS1, GFAP, and POR as common targets of psychiatric and CV drugs.
Conclusion:
PTSD-CV comorbidities exhibit shared risk loci, and genes involved in tissue-specific regulatory mechanisms.
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