Investigating the relationship between depression and breast cancer: observational and genetic analyses

Abstract

Abstract Background Both depression and breast cancer (BC) contribute to a substantial global burden of morbidity and mortality among women, and previous studies have observed a potential depression-BC link. We aimed to comprehensively characterize the phenotypic and genetic relationships between depression and BC. Methods We first evaluated phenotypic association using longitudinal follow-up data from the UK Biobank (N = 250,294). We then investigated genetic relationships leveraging summary statistics from the hitherto largest genome-wide association study of European individuals conducted for depression (N = 500,199), BC (N = 247,173), and its subtypes based on the status of estrogen receptor (ER + : N = 175,475; ER − : N = 127,442). Results Observational analysis suggested an increased hazard of BC in depression patients (HR = 1.10, 95%CIs = 0.95–1.26). A positive genetic correlation between depression and overall BC was observed ($${r}_{g}$$ r g = 0.08, P = 3.00 × 10–4), consistent across ER + ($${r}_{g}$$ r g = 0.06, P = 6.30 × 10–3) and ER − subtypes ($${r}_{g}$$ r g = 0.08, P = 7.20 × 10–3). Several specific genomic regions showed evidence of local genetic correlation, including one locus at 9q31.2, and four loci at, or close, to 6p22.1. Cross-trait meta-analysis identified 17 pleiotropic loci shared between depression and BC. TWAS analysis revealed five shared genes. Bi-directional Mendelian randomization suggested risk of depression was causally associated with risk of overall BC (OR = 1.12, 95%Cis = 1.04–1.19), but risk of BC was not causally associated with risk of depression. Conclusions Our work demonstrates a shared genetic basis, pleiotropic loci, and a putative causal relationship between depression and BC, highlighting a biological link underlying the observed phenotypic relationship; these findings may provide important implications for future studies aimed reducing BC risk.