Genetics of posttraumatic stress disorder and cardiovascular conditions using Life's Essential 8, Electronic Health Records, and Heart Imaging

Abstract

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.

Keywords: Brain; Cardiovascular Disease; GWAS; Heart; Life’s Essential 8; PTSD; electronic health records.

Figure 1:. Study Design:

We investigated loci shared between posttraumatic stress disorder (PTSD) and cardiovascular (CV)-related traits, including American Heart Association’s Life Essential 8 factors, CV diagnoses derived from electronic health records (EHR), and cardiac imaging phenotypes. After identifying genetically correlated loci between PTSD and CV conditions, we investigated shared causal variants. For the EHR-based CV diagnoses, we performed replication of shared causal variants in UK Biobank and a follow-up analysis in All of US Research Program. The traits with evidence of PTSD-CV shared causal variants were tested with respect to tissue-specific transcriptomic and proteomic profiles. The overlapping genes were investigated for overrepresented pathways and drug targets.

Figure 2:. Local Genetic Correlation between PTSD and CV conditions:

Matrix plot of local genetic correlation between PTSD and conditions grouped by their CV category (left y-axis); the EHR-based CV definitions (i.e., phecodes) are from Million Veteran Program. The x-axis shows loci as cytobands grouped by chromosomes. The positive correlation is denoted in orange, cyan indicates negative correlation, and the size of the squares corresponds to the magnitude of the genetic correlation.

Figure 3:. Shared causal variants between PTSD and CV conditions:

A) Top. The x-axis shows colocalization probability(different LD-linked causal variants-H3 hypothesis; same causal variant – H4 hypothesis), and y-axis is marked with CV conditions. between PTSD and CV conditions based on colocalization. A subset of 11 loci that replicated for EHR-derived diagnosis are indicated with a blue line. The shared causal variants based on H4 hypothesis are labelled and their nearest genes are in parenthesis. We highlight genes at each locus that had colocalization evidence with molecular profiles (gene/splicing/proteome expression) and CV conditions (Supplementary Table S7); B) Bottom. A stacked bar plot showing number of traits (y-axis) observed at each locus, marked as cytoband and position range in base pairs (x-axis). The traits are grouped into three CV categories.

Figure 3:. Shared causal variants between PTSD and CV conditions:

A) Top. The x-axis shows colocalization probability(different LD-linked causal variants-H3 hypothesis; same causal variant – H4 hypothesis), and y-axis is marked with CV conditions. between PTSD and CV conditions based on colocalization. A subset of 11 loci that replicated for EHR-derived diagnosis are indicated with a blue line. The shared causal variants based on H4 hypothesis are labelled and their nearest genes are in parenthesis. We highlight genes at each locus that had colocalization evidence with molecular profiles (gene/splicing/proteome expression) and CV conditions (Supplementary Table S7); B) Bottom. A stacked bar plot showing number of traits (y-axis) observed at each locus, marked as cytoband and position range in base pairs (x-axis). The traits are grouped into three CV categories.

Figure 4:. Shared genes and pathways between PTSD and CV conditions based on proteome-wide associations:

Distribution of z-scores across significant PWAS genes between PTSD and CV conditions using A) brain proteome in blue and B) blood proteome in red. Genes are grouped based on two blood-based proteome panels/brain-based panel (y-axis) and respective CV conditions (x-axis). Significant genes are shown as red (blood) or blue (brain) triangles, wherein triangles facing up and down represent positive and negative z-scores, respectively.

Figure 5:. Comparing common drugs and their gene-targets between PTSD and CV conditions:

This Sankey plot shows the psychiatric drugs and their classes (first & second panel) that target genes – DRD2, GFAP,POR and NOS1 (third panel), which are also targeted by CV drugs (third panel) and their corresponding CV categories (fourth & fifth panel) (see Supplementary Tables for more details).