Leveraging Large-Scale Genetics of PTSD and Cardiovascular Disease to Demonstrate Robust Shared Risk and Improve Risk Prediction Accuracy

Abstract

Objective: Individuals with posttraumatic stress disorder (PTSD) are significantly more likely to be diagnosed with cardiovascular disease (CVD) (e.g., myocardial infarction, stroke). The evidence for this link is so compelling that the National Institutes of Health convened a working group to determine gaps in the literature, including the need for large-scale genomic studies to identify shared genetic risk. The aim of the present study was to address some of these gaps by utilizing PTSD and CVD genome-wide association study (GWAS) summary statistics in a large biobank sample to determine the shared genetic risk of PTSD and CVD.

Methods: A large health care biobank data set was used (N=36,412), combined with GWAS summary statistics from publicly available large-scale PTSD and CVD studies. Disease phenotypes (e.g., PTSD) were collected from electronic health records. De-identified genetic data from the biobank were genotyped using Illumina SNP array. Summary statistics data sets were processed with the following quality-control criteria: 1) SNP heritability h² >0.05, 2) compute z-statistics (z=beta/SE or z=log(OR)/SE), 3) filter nonvariable SNPs (0<freq<1), and 4) filter SNPs with low number of samples. The multitrait analysis of GWAS (MTAG) approach was used to combine GWAS summary statistics.

Results: Significant genetic correlations were found between PTSD and CVD (r_G=0.24, SE=0.06), and Mendelian randomization analyses indicated a potential causal link from PTSD to hypertension (β=0.20, SE=0.04), but not the reverse. PTSD summary statistics significantly predicted PTSD diagnostic status (R²=0.27), and this was significantly improved by incorporating summary statistics from CVD and major depressive disorder (R²=1.30). Further, pathway enrichment analyses indicated that genetic variants involved in shared PTSD-CVD risk included those involved in postsynaptic structure, synapse organization, and interleukin-7-mediated signaling pathways.

Conclusions: The results from this study suggest that PTSD and CVD may share genetic risk. Further, these results implicate PTSD as a risk factor leading to the development of hypertension and coronary artery disease. Additional research is needed to determine the clinical utility of these findings.

Keywords: Cardiovascular Disease; Depressive Disorders; Genetics/Genomics; Major Depressive Disorder; Posttraumatic Stress Disorder (PTSD).

Figure 1:

Workflow of data acquisition, processing, and analysis.

Figure 2:. Stratification and discrimination ability of the polygenic risk score (PRS) constructed with various summary statistics.

Figure 2a: Odds-ratio of PTSD diagnosis in PRS stratified risk groups. The first risk group is used as reference. Figure 2b: Fraction of participants diagnosed with PTSD in risk groups stratified into deciles (using PTSD, MDD, and CVD summary statistics). Figure 2c: Fraction of participants diagnosed with PTSD in risk groups stratified into quintiles (using PTSD, MDD, and CVD summary statistics). Figure 2d: Discrimination ability of the various PRS as measured by area under the curve (AUC), with greatest AUC for PTSD+MDD+CVD summary statistics.

Figure 2:. Stratification and discrimination ability of the polygenic risk score (PRS) constructed with various summary statistics.

Figure 2a: Odds-ratio of PTSD diagnosis in PRS stratified risk groups. The first risk group is used as reference. Figure 2b: Fraction of participants diagnosed with PTSD in risk groups stratified into deciles (using PTSD, MDD, and CVD summary statistics). Figure 2c: Fraction of participants diagnosed with PTSD in risk groups stratified into quintiles (using PTSD, MDD, and CVD summary statistics). Figure 2d: Discrimination ability of the various PRS as measured by area under the curve (AUC), with greatest AUC for PTSD+MDD+CVD summary statistics.

Figure 2:. Stratification and discrimination ability of the polygenic risk score (PRS) constructed with various summary statistics.

Figure 2a: Odds-ratio of PTSD diagnosis in PRS stratified risk groups. The first risk group is used as reference. Figure 2b: Fraction of participants diagnosed with PTSD in risk groups stratified into deciles (using PTSD, MDD, and CVD summary statistics). Figure 2c: Fraction of participants diagnosed with PTSD in risk groups stratified into quintiles (using PTSD, MDD, and CVD summary statistics). Figure 2d: Discrimination ability of the various PRS as measured by area under the curve (AUC), with greatest AUC for PTSD+MDD+CVD summary statistics.

Figure 2:. Stratification and discrimination ability of the polygenic risk score (PRS) constructed with various summary statistics.

Figure 2a: Odds-ratio of PTSD diagnosis in PRS stratified risk groups. The first risk group is used as reference. Figure 2b: Fraction of participants diagnosed with PTSD in risk groups stratified into deciles (using PTSD, MDD, and CVD summary statistics). Figure 2c: Fraction of participants diagnosed with PTSD in risk groups stratified into quintiles (using PTSD, MDD, and CVD summary statistics). Figure 2d: Discrimination ability of the various PRS as measured by area under the curve (AUC), with greatest AUC for PTSD+MDD+CVD summary statistics.