Abstract
Patients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208–795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20–22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.
Highlights
People with bipolar disorder (BIP) have on average twice as high risk of cardiovascular disease (CVD) compared to the general population, contributing to a reduction in life expectancy [1,2,3]
We investigated the polygenic overlap between BIP, CVD risk factors, and coronary artery disease (CAD) beyond genetic correlations with the MiXeR method [27], and applied the cond/ conjFDR approach to identify specific shared loci [28]
We discovered the same effect direction of 52.2% of SNPs shared with body mass index (BMI), 49.1% SNPs shared with systolic blood pressure (SBP), 47.2% SNPs shared with diastolic blood pressure (DBP), 26.7% SNPs shared with total cholesterol (TC), 46.2% SNPs shared with low-density lipoprotein (LDL), 40% SNPs shared with high-density lipoprotein (HDL), 25% SNPs shared with type 2 diabetes (T2D), and 70% SNPs shared with CAD (Table 2; Supplementary Tables 17–24)
Summary
People with bipolar disorder (BIP) have on average twice as high risk of cardiovascular disease (CVD) compared to the general population, contributing to a reduction in life expectancy [1,2,3]. CVD comorbidity and mortality have remained high during the past decades, indicating that most patients with BIP have not benefited from recent advances in medicine [4,5,6,7]. A genetic susceptibility to CVD may play a role, similar to what has been indicated in schizophrenia [9, 10], including overlapping genetic loci [11, 12]. This is supported by the considerable genetic overlap between schizophrenia and BIP [13]. There is a large individual variation in CVD comorbidity [2,3,4], which suggests increased genetic risk for CVD in subgroups of BIP
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