Shared Genetic Factors Between Stress-related Disorders and Cardiovascular Disease

Understanding whether and how shared genetic factors contribute to the comorbidity between stress-related disorders (SRDs) and cardiovascular disease (CVD) is important for integrated prevention and treatment, but current evidence remains limited. To address this gap, we integrated Swedish national registers (n = 4,123,631), UK Biobank (n = 502,291), and genome-wide association study summary statistics to explore shared genetic liability between SRDs and six CVD subtypes and to nominate pleiotropic loci, genes, and enriched pathways. Familial coaggregation analyses showed that the SRDs-CVD association attenuated with decreasing genetic relatedness among relatives, supporting the existence of shared genetic influences. Polygenic risk scores for SRDs significantly predicted a higher risk of any CVD and all subtypes (odds ratios = 1.05-1.09), and all SRDs-CVD pairs showed positive genetic correlations (rg = 0.09-0.35), whereas Mendelian randomization (MR) analyses did not support strong causal effects in either direction. Genome-wide cross-trait analyses identified 17 putative pleiotropic loci, and consensus-based gene mapping prioritized 16 putative pleiotropic genes. Enrichment analyses indicated that pleiotropic signals were enriched in processes related to hemostasis and coagulation, circulatory system development, and telomere maintenance. In validation analyses focusing on post-traumatic stress disorder (PTSD), we observed a similar pattern of genetic overlap with CVD and replicated a subset of loci, genes, and pathways. These findings support a genetic comorbidity framework in which shared genetic liability, largely driven by pleiotropic loci, contributes to the co-occurrence of SRDs and CVD and highlight candidate genes and biological processes for future experimental studies.