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

View ORCID ProfileRebecca C. Richmond, Emma L. Anderson, View ORCID ProfileHassan S. Dashti, View ORCID ProfileSamuel E. Jones, Jacqueline M. Lane, Linn Beate Strand, View ORCID ProfileBen Brumpton, View ORCID ProfileMartin Rutter, Andrew R. Wood, View ORCID ProfileCaroline L. Relton, View ORCID ProfileMarcus Munafò, View ORCID ProfileTimothy M. Frayling, Richard M. Martin, View ORCID ProfileRicha Saxena, Michael N. Weedon, View ORCID ProfileDebbie A. Lawlor, View ORCID ProfileGeorge Davey Smith
doi: https://doi.org/10.1101/457572
Rebecca C. Richmond
1MRC Integrative Epidemiology Unit at the University of Bristol, UK
2Population Health Sciences, Bristol Medical School, University of Bristol, UK
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Emma L. Anderson
1MRC Integrative Epidemiology Unit at the University of Bristol, UK
2Population Health Sciences, Bristol Medical School, University of Bristol, UK
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Hassan S. Dashti
3Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA USA
4Program in Medical and Population Genetics, Broad Institute, Cambridge MA USA
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Samuel E. Jones
5Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK
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Jacqueline M. Lane
3Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA USA
4Program in Medical and Population Genetics, Broad Institute, Cambridge MA USA
12National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK
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Linn Beate Strand
6K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health sciences, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
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Ben Brumpton
6K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health sciences, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
7Department of Thoracic Medicine, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway
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Martin Rutter
8Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
9Division of Endocrinology, Diabetes & Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK
10Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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Andrew R. Wood
5Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK
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Caroline L. Relton
1MRC Integrative Epidemiology Unit at the University of Bristol, UK
2Population Health Sciences, Bristol Medical School, University of Bristol, UK
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Marcus Munafò
1MRC Integrative Epidemiology Unit at the University of Bristol, UK
11School of Experimental Psychology, University of Bristol, Bristol, UK
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Timothy M. Frayling
5Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK
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Richard M. Martin
1MRC Integrative Epidemiology Unit at the University of Bristol, UK
2Population Health Sciences, Bristol Medical School, University of Bristol, UK
12National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK
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Richa Saxena
3Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA USA
4Program in Medical and Population Genetics, Broad Institute, Cambridge MA USA
13Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA USA
14Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Michael N. Weedon
5Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK
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Debbie A. Lawlor
1MRC Integrative Epidemiology Unit at the University of Bristol, UK
2Population Health Sciences, Bristol Medical School, University of Bristol, UK
12National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK
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George Davey Smith
1MRC Integrative Epidemiology Unit at the University of Bristol, UK
2Population Health Sciences, Bristol Medical School, University of Bristol, UK
12National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK
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Abstract

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 symptoms and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits.

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 UK Biobank, 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 symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated 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 (HR 0.85, 95% 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 (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), while there was inconsistent evidence for insomnia symptoms. 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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 05, 2018.
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Investigating causal relationships between sleep traits and risk of breast cancer: a Mendelian randomization study
Rebecca C. Richmond, Emma L. Anderson, Hassan S. Dashti, Samuel E. Jones, Jacqueline M. Lane, Linn Beate Strand, Ben Brumpton, Martin Rutter, Andrew R. Wood, Caroline L. Relton, Marcus Munafò, Timothy M. Frayling, Richard M. Martin, Richa Saxena, Michael N. Weedon, Debbie A. Lawlor, George Davey Smith
bioRxiv 457572; doi: https://doi.org/10.1101/457572
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Investigating causal relationships between sleep traits and risk of breast cancer: a Mendelian randomization study
Rebecca C. Richmond, Emma L. Anderson, Hassan S. Dashti, Samuel E. Jones, Jacqueline M. Lane, Linn Beate Strand, Ben Brumpton, Martin Rutter, Andrew R. Wood, Caroline L. Relton, Marcus Munafò, Timothy M. Frayling, Richard M. Martin, Richa Saxena, Michael N. Weedon, Debbie A. Lawlor, George Davey Smith
bioRxiv 457572; doi: https://doi.org/10.1101/457572

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