Using human genetics to understand the phenotypic association between chronotype and breast cancer

Little is known regarding the shared genetic influences underlying the observed phenotypic association between chronotype and breast cancer in women. Leveraging summary statistics from the hitherto largest genome-wide association study conducted in each trait, we investigated the genetic correlation, pleiotropic loci, and causal relationship of chronotype with overall breast cancer, and with its subtypes defined by the status of oestrogen receptor. We identified a negative genomic correlation between chronotype and overall breast cancer ( $r_g$  = -0.06, p = 3.00 × 10^-4), consistent across oestrogen receptor-positive ( $r_g$  = -0.05, p = 3.30 × 10^-3) and oestrogen receptor-negative subtypes ( $r_g$  = -0.05, p = 1.11 × 10^-2). Five specific genomic regions were further identified as contributing a significant local genetic correlation. Cross-trait meta-analysis identified 78 loci shared between chronotype and breast cancer, of which 23 were novel. Transcriptome-wide association study revealed 13 shared genes, targeting tissues of the nervous, cardiovascular, digestive, and exocrine/endocrine systems. Mendelian randomisation demonstrated a significantly reduced risk of overall breast cancer (odds ratio 0.89, 95% confidence interval 0.83-0.94; p = 1.30 × 10^-4) for genetically predicted morning chronotype. No reverse causality was found. Our work demonstrates an intrinsic link underlying chronotype and breast cancer, which may provide clues to inform management of sleep habits to improve female health.