27. SHARED GENETIC FACTORS BETWEEN STRESS-RELATED DISORDERS AND CARDIOVASCULAR DISEASES

Epidemiological studies have consistently demonstrated bidirectional associations between stress-related disorders and cardiovascular diseases (CVDs). However, the potentially pleiotropic genes and genetic pathways underlying such associations remain to be identified. Based on phenotype data from the Swedish national registers (∼4 million), we first conducted familial coaggregation analyses to explore the common genetic liability between stress-related disorders and CVD (including any CVD and six CVD subtypes). Using publicly available genome-wide association study (GWAS) summary statistics, along with individual-level genotype data from the UK Biobank (∼0.4 million), we then performed polygenic risk score (PRS) analyses, genetic correlation estimation, and mendelian randomization (MR) analyses to demonstrate the existence of genetic overlaps between stress-related disorders and CVD. Finally, we applied genome-wide cross-trait analyses, consensus-based gene mapping, and enrichment analyses, to identify shared pleiotropic variants, genes, and biological pathways underlying the comorbidity of these two diseases. The familial coaggregation analyses demonstrated decreasing odds of CVD by stress-related disorders in relatives with descending genetic relatedness (p-value for trend=0.002). The odds ratios of CVD ranged from 1.91 (95% confidence interval [CI]=1.33-2.73) if one's monozygotic co-twin had stress-related disorders while 1.06 (95% CI=1.02-1.10) if one's half cousin had stress-related disorders. PRS for stress-related disorders was associated with the risk of any CVD (OR=1.09, 95% CI=1.08-1.10) as well as six CVD subtypes (ORs=1.06-1.10). Statistically significant associations were also observed for the PRS of 5 out of 6 CVD subtypes and the risk of stress-related disorders (ORs=1.00-1.05). Moreover, positive genetic correlations were found between stress-related disorders and all subtypes of CVD at the Bonferroni-corrected significance level, ranging from 0.09 for arrhythmia/conduction disorder to 0.35 for heart failure and cardiomyopathy. MR analyses indicated no significant causal associations between stress-related disorders and CVD in neither direction after controlling for genetic pleiotropy. Using cross-trait analyses, we identified 17 putative pleiotropic loci, including 13 novel for stress-related disorders. These loci were further mapped to 16 putative pleiotropic genes, which were all supported by evidence from at least two different sources in the consensus-based gene mapping. Finally, enrichment analyses highlighted several shared pathways between stress-related disorders and CVD, such as pathways related to hemostasis and coagulation, development of circulatory systems, and telomere maintenance. This study provides evidence for genetic overlaps between stress-related disorders and CVD and highlights several shared putative pleiotropic genes and pathways potentially underlying the comorbidity between these two conditions. Further experimental investigations are needed to validate these findings.