Epidemiological and Genetic Analyses of Schizophrenia and Breast Cancer

Abstract Background and Hypothesis While the phenotypic association between schizophrenia and breast cancer has been observed, the underlying intrinsic link is not adequately understood. We aim to conduct a comprehensive interrogation on both phenotypic and genetic relationships between schizophrenia and breast cancer. Study Design We first used data from UK Biobank to evaluate a phenotypic association and performed an updated meta-analysis incorporating existing cohort studies. We then leveraged genomic data to explore the shared genetic architecture through a genome-wide cross-trait design. Study Results Incorporating results of our observational analysis, meta-analysis of cohort studies suggested a significantly increased incidence of breast cancer among women with schizophrenia (RR = 1.30, 95% CIs = 1.14–1.48). A positive genomic correlation between schizophrenia and overall breast cancer was observed (rgrg = 0.12, P = 1.80 × 10−10), consistent across ER+ (rgrg = 0.10, P = 5.74 × 10−7) and ER– subtypes (rgrg = 0.09, P = .003). This was further corroborated by four local signals. Cross-trait meta-analysis identified 23 pleiotropic loci between schizophrenia and breast cancer, including five novel loci. Gene-based analysis revealed 27 shared genes. Mendelian randomization demonstrated a significantly increased risk of overall breast cancer (OR = 1.07, P = 4.81 × 10−10) for genetically predisposed schizophrenia, which remained robust in subgroup analysis (ER+: OR = 1.10, P = 7.26 × 10−12; ER–: OR = 1.08, P = 3.50 × 10−6). No mediation effect and reverse causality was found. Conclusions Our study demonstrates an intrinsic link underlying schizophrenia and breast cancer, which may inform tailored screening and management of breast cancer in schizophrenia.