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

Background: Though epidemiological studies show increased cardiovascular disease (CVD) risks among individuals with psychiatric disorders, findings on sex differences in comorbidity have been inconsistent.

Methods: This genetic epidemiology study examined the sex-specific association between the genetic risk of 3 psychiatric disorders (major depression [MD], schizophrenia, and bipolar disorder), estimated using polygenic scores (PGSs), and risks of 3 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.

Results: In the UK Biobank, a 1-SD increase in PGS was significantly associated with the incident risks of all 3 CVDs in females after multiple testing corrections (hazard ratio [HR]=1.04 [95% CI, 1.02-1.06]; =1.5×10; HR=1.07 [95% CI, 1.04-1.11]; =2.6×10; and HR=1.09 [95% CI, 1.06-1.13]; =9.7×10), 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 PGS and CVDs in females was partly mediated by baseline body mass index, hypercholesterolemia, hypertension, and smoking, these risk factors did not explain the higher risk compared with males. The association between PGS and CAD was consistent between females who were premenopausal and postmenopausal at baseline, while the association with AF and HF was only observed in the baseline postmenopausal cohort. No significant association with CVD risks was observed for the PGS of schizophrenia or bipolar disorder. The female-specific positive association of PGS with CAD risk was replicated in BioVU.

Conclusions: Genetic 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, especially in women.