Genetically predicted bipolar disorder is causally associated with an increased risk of breast cancer: a two-sample Mendelian randomization analysis

BACKGROUND: Epidemiologic findings suggested that bipolar disorder (BD) may be associated with an increased risk of breast cancer. However, there are few studies that comprehensively evaluating their correlation and the causal effect remains unknown. With a two-sample Mendelian randomization (MR) approach, we were able to investigate the causal relationship between genetically predicted BD and breast cancer risk. METHODS: Utilizing 14 BD-related single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) identified by the latest genome-wide association studies (GWASs), we investigated the correlation between genetically predicted BD and breast cancer risk using summary statistics from the Breast Cancer Association Consortium, with a total of 122,977 cases and 105,974 controls. Study-specific estimates were summarized using inverse variance weighted (IVW) method. To further evaluate the pleiotropy, the weighted median and the MR-Egger regression method were implemented. Subgroup analyses according to different immunohistochemical types of breast cancer were also conducted. RESULTS: MR analyses demonstrated that genetically predicted BD was causally associated with an increased risk of breast cancer (OR =1.059; 95% CI: 1.008–1.112, P=0.0229). When results were examined by immunohistochemical type, no causal effects between genetically predicted BD and estrogen receptor (ER)-positive breast cancer (OR =1.049, 95% CI: 0.999–1.102 P=0.0556) and ER-negative breast cancer (OR =1.032, 95% CI: 0.953–1.116 P=0.4407) were observed. Additionally, the results demonstrated the absence of the horizontal pleiotropy. CONCLUSIONS: Our findings provided evidence for a causal relationship between genetically predicted BD and an increased risk of breast cancer overall. Further studies are warranted to investigate the underlying mechanism.