Investigating the relationship between depression and breast cancer: observational and genetic analyses
Xueyao Wu, Wenqiang Zhang, Xunying Zhao, Li Zhang, Minghan Xu, Yu Hao, Jinyu Xiao, Ben Zhang, Jiayuan Li, Peter Kraft, Jordan W. Smoller, Xia Jiang
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 ( $${r}_{g}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>r</mml:mi> <mml:mi>g</mml:mi> </mml:msub> </mml:math> = 0.08, P = 3.00 × 10 –4 ), consistent across ER + ( $${r}_{g}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>r</mml:mi> <mml:mi>g</mml:mi> </mml:msub> </mml:math> = 0.06, P = 6.30 × 10 –3 ) and ER − subtypes ( $${r}_{g}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>r</mml:mi> <mml:mi>g</mml:mi> </mml:msub> </mml:math> = 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.