Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study

Bryony Hayes*, Tim Robinson, Siddhartha Kar, Katherine S Ruth, Konstantinos K Tsilidis, Tim Frayling, Anna Murray, Richard M Martin, Deborah A Lawlor, Rebecca C Richmond

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on
breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p<5×10−8) were obtained from published genome-wide
association studies (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with breast (nCases/nControls=133,384/113,789) and prostate (nCases/nControls=79,148/61,106) cancer using univariable, bidirectional and multivariable MR. In females, we found evidence for: I) Reduced risk of breast cancer per category increase in morning preference (OR=0.93, 95% CI:0. 88, 1.00); II) Increased risk of breast cancer per SD increase in bioavailable testosterone (OR=1.10, 95% CI: 1.01, 1.19) and total testosterone (OR=1.15, 95%
CI:1.07, 1.23); III) Bidirectional effects between morning-preference and both bioavailable and total testosterone (e.g. mean SD difference in bioavailable testosterone =-0.08, 95% CI:-0.12, -0.05 per category increase in morning-preference vs difference in morning-preference category=-0.04, 95%
CI: -0.08, 0.00 per SD increase in bioavailable testosterone). In males, we found evidence for: I) Reduced risk of prostate cancer per category increase in morning-preference (OR=0.90, 95% CI: 0.83, 0.97) and II) Increased risk of prostate cancer per SD increase in bioavailable testosterone (OR=1.22,
95% CI: 1.08, 1.37). No bidirectional effects were found between morning-preference and testosterone in males. While testosterone levels were causally implicated with both chronotype and cancer, there was inconsistent evidence for testosterone as a mediator of the relationship. The protective effect of morning-preference on both breast and prostate cancer is clinically interesting, although it may be difficult to effectively modify chronotype. Further studies are needed to
investigate other potentially modifiable intermediates.
Original languageEnglish
Article numbere1009887
Number of pages34
JournalPLoS Genetics
Volume18
Issue number1
Early online date21 Jan 2022
DOIs
Publication statusPublished - 21 Jan 2022

Bibliographical note

Publisher Copyright:
© 2022 Hayes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Structured keywords

  • ICEP

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