Shared genetic architecture of posttraumatic stress disorder with cardiovascular imaging, risk, and diagnoses

Abstract

Patients with post-traumatic stress disorder face increased cardiovascular risk. This study examines shared genetic regions between post-traumatic stress disorder and 246 cardiovascular conditions across electronic health records, 82 cardiac imaging, and health behaviors defined by Life's Essential 8. Post-traumatic stress disorder is genetically correlated with cardiovascular diagnoses in 33 regions, imaging traits in 4 regions, and health behaviors in 44 regions. Potentially shared causal variants between post-traumatic stress disorder and 17 cardiovascular conditions were observed in 11 regions. Subsequent observational analysis in AllofUS cohort showed post-traumatic stress disorder is associated with 13 diagnoses even after accounting for socioeconomic factors and depression. Genetically regulated proteome expression in brain and blood tissues identified 33 blood and 122 brain genes shared between the two conditions, revealing neuronal, immune, metabolic, and calcium-related mechanisms, with several genes as targets for existing drugs. These findings exhibit shared risk loci and genes are involved in tissue-specific mechanisms.

Fig. 1. Study design.

We investigated loci shared between posttraumatic stress disorder (PTSD) and cardiovascular (CV)-related traits, including the 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 the UK Biobank and a follow-up analysis in the 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.

Fig. 2. Local genetic correlation between PTSD and CV conditions.

Matrix plot of local genetic correlation between PTSD and conditions grouped by their CV category (a) Life’s Essential 8 from different sources (b) heart imaging from UKBB and c the EHR-based CV definitions (i.e., phecodes) are from Million Veteran Program. The x-axis shows loci as cytoband positions. 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.

Fig. 3. Shared causal variants between PTSD and CV conditions.

The x-axis shows on top shows H4 colocalization probability i.e., same causal variant between traits (gene closest to the variant), between PTSD and CV traits. The y-axis is CV conditions, grouped by EHR (green) and AHA’s Life’s essential 8 traits (purple).

Fig. 4. Shared genes 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 (two-sided), respectively.

Fig. 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 Data for more details).