Severe mental illness and the risk of breast cancer: A two-sample, two-step multivariable Mendelian randomization study

BACKGROUND: Based on epidemiological reports, severe mental illness (SMI) and breast cancer (BC) risk are linked positively. However, it is susceptible to clinical confounding factors, such as smoking, alcohol consumption, etc. Here, we performed a two-sample, two-step multivariable Mendelian randomization (MR) research to explore how the SMI etiologically influences BC risk and to quantify mediating effects of known modifiable risk factors. METHODS: Data concerning the single nucleotide polymorphism (SNP)-associated with schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), and BC were obtained from two large consortia: the Breast Cancer Association Consortium (BCAC) and the Psychiatric Genomics Consortium (PGC). Then, the correlations of the previous SMI with the BC prevalence and the potential impact of mediators were explored through the two-sample and two-step MR analyses. RESULTS: In two-sample MR, schizophrenia increased BC incidence (odds ratio (OR) 1.06, 95% confidence interval (CI) 1.02–1.10, P = 0.001). In subgroup analysis, schizophrenia increased ER+ BC (OR 1.06, 95% CI 1.03–1.10, P = 0.0009) and ER-BC (OR 1.06, 95% CI 1.01–1.11, P = 0.0123) incidences. Neither MDD nor BD elevated the BC risk. In two-step MR, smoking explained 11.29% of the schizophrenia-all BC risk association. CONCLUSIONS: Our study indicates that schizophrenia increases susceptibility to breast cancer, with smoking playing a certain mediating role. Therefore, BC screening and smoking should be incorporated into the health management of individuals with schizophrenia.