Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study
Authors: Hayes Bryony , Robinson Tim , Kar Siddhartha , Ruth Katherine S , Tsilidis Konstantinos K , Frayling Tim , Murray Anna , Martin Richard M , Lawlor Deborah A , Richmond Rebecca C 
Published: April 2021

ABSTRACTBackgroundPrevious research has demonstrated that a morning-preference chronotype is protective against both breast and prostate cancer. Sex hormones have been implicated in relation to both chronotype and the development of both cancers. This study aims to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer risk using a Mendelian Randomization (MR) framework.MethodsWe obtained genetic variants strongly (p<5×10−8) associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin (SHBG), and oestradiol from previously published genome-wide association studies (GWAS) that had been undertaken in UK Biobank and 23andMe (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with risk of breast and prostate cancer using summary data from the largest available consortia in breast (nCases/nControls=133,384/ 113,789) and prostate cancer (nCases/nControls=79,148/61,106). This was achieved using a series of MR approaches: univariable, bidirectional and multivariable.ResultsOverall, we found evidence for a protective effect of genetically predicted tendency towards morning preference on both breast (OR=0.93, 95% CI:0.88, 1.00) and prostate (OR=0.90, 95% CI:0.83, 0.97) cancer risk. There was evidence that an increased tendency to morning preference reduces bioavailable testosterone levels in both females (mean SD difference=-0.08, 95% CI:-0.12, - 0.05) and males (mean SD difference=-0.06, 95% CI:-0.09, -0.03), and reduces total testosterone levels in females (mean SD difference=-0.07, 95% CI:-0.10, -0.03). We also found evidence to support higher total and bioavailable testosterone increasing the risk of breast cancer (OR=1.15, 95% CI:1.07, 1.23, OR=1.10, 95% CI:1.01, 1.19 respectively) and higher bioavailable testosterone increasing prostate cancer risk (OR=1.22, 95% CI:1.08, 1.37). While findings from univariable and bidirectional MR analyses indicated that testosterone may lie on the causal pathway between chronotype and cancer risk, there was evidence for a bidirectional association between chronotype and testosterone in females, implicating testosterone as both a confounder and mediator of the chronotype effect on breast cancer risk. However, the effects of chronotype remained largely unchanged when accounting for testosterone in multivariable MR, suggesting that any confounding or mediating effect is likely to be minimal.ConclusionsThis study has extended previous findings regarding the protective effect of chronotype on breast cancer and found evidence to suggest that morning preference also reduces prostate cancer risk in men. While testosterone levels were found to be closely linked with both chronotype and cancer risk, there was inconsistent evidence for the role of testosterone in mediating the effect of morning preference chronotype on both breast and prostate cancer. Findings regarding the potential protective effect of chronotype on both breast and prostate cancer risk are clinically interesting. However, this may not serve as a direct target for intervention, since it is difficult to modify someone’s morning/evening preference. Given this, further studies are needed to investigate the mechanisms underlying this effect and to identify other potential modifiable intermediates.