Objective: To examine whether sleep traits have a causal effect on risk of breast cancer. Design: Multivariable regression, one- and two-sample Mendelian randomization. Setting: The UK Biobank prospective cohort study and the Breast Cancer Association Consortium (BCAC) case-control genome-wide association study. Participants: 156,848 women in the multivariable regression and one-sample Mendelian randomization analysis in UK Biobank (7,784 with a breast cancer diagnosis) and 122,977 breast cancer cases and 105,974 controls from BCAC in the two-sample Mendelian randomization analysis. Exposures: Self-reported chronotype (morning/evening preference), insomnia and sleep duration in multivariable regression, and genetic variants that were robustly associated with these exposures in UK Biobank. Main outcome measures: Breast cancer (prevalent and incident cases in UK Biobank, prevalent cases only in BCAC). Results: In multivariable regression analysis using data on breast cancer incidence in the UK Biobank study, morning preference was inversely associated with breast cancer (HR 0.95, 95% CI 0.93, 0.98 per category increase) while there was little evidence for an association with sleep duration and insomnia risk. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated sleep duration and 57 SNPs associated with insomnia, one-sample MR analysis in UK Biobank provided some evidence for a protective effect of morning preference on breast cancer risk (HR 0.85, 95% 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia. Findings for a protective effect of morning preference (OR 0.88, 95% CI 0.82, 0.93 per category increase) and adverse effect of increased sleep duration (OR 1.19, 95% CI 1.02, 1.39 per hour increase) on breast cancer (both estrogen receptor positive and negative) were supported by two-sample MR using data from BCAC, while there was inconsistent evidence for insomnia. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy. Conclusions: We found consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of sleep duration on breast cancer risk.

Investigating causal relationships between sleep traits and risk of breast cancer: a Mendelian randomization study