Sex-Specific Association Between Genetic Risk of Psychiatric Disorders and Cardiovascular Diseases
Jiayue-Clara Jiang1, Kritika Singh2,3, Rachana Nitin2,3
1Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia (J.-C.J., N.R.W., S.S.).
Insights
Genetic predisposition to major depression (MD) increases cardiovascular disease (CVD) risk in women more than men. This genetic link to CVD in females, even without diagnosed depression, warrants further study for improved risk prediction.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Psychiatry
Background:
- Epidemiological studies indicate a link between psychiatric disorders and increased cardiovascular disease (CVD) risk.
- However, findings regarding sex differences in this comorbidity remain inconsistent.
Purpose of the Study:
- To investigate the sex-specific association between genetic risk for major depression (MD), schizophrenia, and bipolar disorder.
- To examine the relationship between genetic risk scores (PGSs) for these disorders and the risks of atrial fibrillation (AF), coronary artery disease (CAD), and heart failure (HF).
Main Methods:
- A large-scale genetic epidemiology study using European-ancestry individuals from the UK Biobank (n=345,169) and BioVU (n=49,057).
- Polygenic scores (PGSs) were calculated for MD, schizophrenia, and bipolar disorder.
- Mediation analysis was employed to assess the role of traditional CVD risk factors in observed sex differences.
Main Results:
- A 1-SD increase in PGS for MD was significantly associated with increased risks of AF, CAD, and HF in females, but not in males.
- These female-specific associations persisted even without a diagnosis of psychiatric disorder or use of related medication.
- While traditional risk factors partially mediated the PGS-MD to CVD link in females, they did not account for the sex disparity. The association of PGS-MD with CAD was consistent across menopausal status, while AF and HF associations were specific to postmenopausal females. No significant associations were found for schizophrenia or bipolar disorder PGS with CVD risks. The female-specific association between PGS-MD and CAD risk was replicated in the BioVU cohort.
Conclusions:
- Genetic predisposition to MD confers a greater risk of CVDs in females compared to males, irrespective of a depression diagnosis.
- Further research is recommended to explore the utility of genetic predisposition to depression in enhancing cardiovascular risk prediction, particularly for women.
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 PGSMD was significantly associated with the incident risks of all 3 CVDs in females after multiple testing corrections (hazard ratio [HR]AF-female=1.04 [95% CI, 1.02-1.06]; P=1.5×10-4; HRCAD-female=1.07 [95% CI, 1.04-1.11]; P=2.6×10-6; and HRHF-female=1.09 [95% CI, 1.06-1.13]; P=9.7×10-10), 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 body mass index, hypercholesterolemia, hypertension, and smoking, these risk factors did not explain the higher risk compared with males. The association between PGSMD 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 PGSMD 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.
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