Sex-Specific Association Between Genetic Risk of Psychiatric Disorders and Cardiovascular Diseases

Abstract

BackgroundThe lack of research on female-specific risk factors for cardiovascular diseases (CVD) has led to sex-based disparities in cardiovascular health. Though epidemiological studies show increased CVD risks amongst individuals with psychiatric disorders, findings on sex differences in comorbidity have been inconsistent. MethodsThis genetic epidemiology study examined the sex-specific association between the genetic risk of three psychiatric disorders [major depression (MD), schizophrenia and bipolar disorder], estimated using polygenic scores (PGS), and risks of three CVDs [atrial fibrillation (AF), coronary artery disease (CAD) and heart failure (HF)] in 345,169 European-ancestry individuals (UK Biobank), with analyses replicated in an independent BioVU cohort (N=49,057). Mediation analysis was conducted to determine whether traditional CVD risk factors could explain any observed sex difference. ResultsIn UK Biobank, PGSMD was significantly associated with the incident risks of all three CVDs in females after multiple testing correction [hazard ratio (HR)AF-female=1.04 (95% CI: 1.02-1.06; p=0.00015); HRCAD-female=1.07 (1.04-1.11; p=2.6E-06); HRHF-female=1.09 (1.06-1.13; p=9.7E-10)], but not in males. These female-specific associations remained even in the absence of any psychiatric disorder diagnosis or psychiatric medication use. Although mediation analysis demonstrated that the association between PGSMD and CVDs in females was partly mediated by baseline BMI, hypercholesterolemia, hypertension and smoking, these risk factors did not explain the higher risk compared to males. The association between PGSMD and CAD was consistent between females who were pre-menopausal and post-menopausal at baseline (mean baseline age of 44.9 and 60.8 years, respectively), while the association with AF and HF was only observed in the baseline post-menopausal cohort. No significant association with CVD risks was observed for the PGS of schizophrenia or bipolar disorder. The positive association of PGSMD with CAD and HF risk in females was replicated in BioVU, where the corresponding associations in males also reached nominal significance. ConclusionsGenetic predisposition to MD confers a greater risk of CVDs in females versus males, even in the absence of any depression diagnosis. This study warrants further investigation into whether genetic predisposition to depression could be useful for improving cardiovascular risk prediction even in the absence of a depression diagnosis, especially in women.