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Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study

BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l2327 (Published 26 June 2019) Cite this as: BMJ 2019;365:l2327

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Larks, owls, and breast cancer

  1. Rebecca C Richmond, research fellow12,
  2. Emma L Anderson, research fellow12,
  3. Hassan S Dashti, postdoctoral researcher34,
  4. Samuel E Jones, research fellow5,
  5. Jacqueline M Lane, postdoctoral researcher34,
  6. Linn Beate Strand, associate professor6,
  7. Ben Brumpton, research fellow67,
  8. Martin K Rutter, senior lecturer89,
  9. Andrew R Wood, lecturer5,
  10. Kurt Straif, scientist10,
  11. Caroline L Relton, professor12,
  12. Marcus Munafò, professor111,
  13. Timothy M Frayling, professor5,
  14. Richard M Martin, professor1212,
  15. Richa Saxena, professor341314,
  16. Michael N Weedon, associate professor5,
  17. Debbie A Lawlor, professor1212,
  18. George Davey Smith, professor1212
  1. 1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
  2. 2Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
  3. 3Centre for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  4. 4Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
  5. 5Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK
  6. 6K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health sciences, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
  7. 7Clinic of Thoracic and Occupational Medicine, St Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway
  8. 8Division of Endocrinology, Diabetes and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
  9. 9Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, Manchester, UK
  10. 10International Agency for Research on Cancer, Lyon, France
  11. 11School of Experimental Psychology, University of Bristol, Bristol, UK
  12. 12National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK
  13. 13Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
  14. 14Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
  1. Correspondence to: R C Richmond, Office BS4, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK Rebecca.richmond{at}bristol.ac.uk (or @beckyrichmond90 on Twitter)
  • Accepted 26 April 2019

Abstract

Objective To examine whether sleep traits have a causal effect on risk of breast cancer.

Design Mendelian randomisation study.

Setting UK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study.

Participants 156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis.

Exposures Self reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits.

Main outcome measure Breast cancer diagnosis.

Results In multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy.

Conclusions Findings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.

Footnotes

  • Contributors: RCR conceived the study and conducted the main analysis. HSD, SEJ, and JML conducted the female specific genome-wide association studies and assisted with sensitivity analyses. RCR, ELA, and GDS drafted the initial manuscript. All authors assisted with interpretation, commended on drafts of the manuscript, and approved the final version. RCR is the guarantor and attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec and grant PSR-SIIRI-701, the National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710), and the European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al.25 RCR, ELA, BMB, CLR, RMM, MM, DAL, and GDS are members of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the Medical Research Council (grant Nos MM_UU_00011/1, MC_UU_00011/2, MC_UU_00011/5, MC_UU_00011/6, and MC_UU_00011/7). RCR is a de Pass VC research fellow at the University of Bristol. This study was supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, National Institute for Health Research, or Department of Health and Social Care. This work was also supported by Cancer Research UK (grant No C18281/A19169) and the Economic and Social Research Council (grant No ES/N000498/1). SEJ is funded by the Medical Research Council (grant No MR/M005070/1). TMF is supported by the European Research Council (grant No 323195:GLUCOSEGENES-FP7-IDEAS-ERC). MNW is supported by the Wellcome Trust Institutional Strategic Support Award (grant No WT097835MF).

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf. MKR reports receiving research funding from Novo Nordisk, consultancy fees from Novo Nordisk and Roche Diabetes Care, and modest owning of shares in GlaxoSmithKline, outside the submitted work. DAL reports receiving research support from Medtronic and Roche Diagnostics for research outside the submitted work. All other authors declare no support from any organisation for the submitted work, no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: UK Biobank has received ethical approval from the UK National Health Service’s National Research Ethics Service (ref 11/ NW/0382).

  • Data sharing: Scripts for the two sample mendelian randomisation analysis are available on GitHub at: https://github.com/rcrichmond/sleep_breastcancer_mr/. For statistical code relating to the individual level data analysis in UK Biobank, please contact the corresponding author at rebecca.richmond@bristol.ac.uk.

  • Transparency: The lead author (RCR) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

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