Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Abstract

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.

Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.

Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).

Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

Metadata

Item Type:	Article
Authors/Creators:	Dixon-Suen, S.C. https://orcid.org/0000-0003-3714-8386 Lewis, S.J. Martin, R.M. English, D.R. Boyle, T. https://orcid.org/0000-0001-6741-330X Giles, G.G. Michailidou, K. Bolla, M.K. Wang, Q. Dennis, J. Lush, M. Investigators, A.B.C.T.B. Ahearn, T.U. Ambrosone, C.B. Andrulis, I.L. Anton-Culver, H. Arndt, V. Aronson, K.J. Augustinsson, A. Auvinen, P. Beane Freeman, L.E. Becher, H. Beckmann, M.W. Behrens, S. Bermisheva, M. Blomqvist, C. Bogdanova, N.V. Bojesen, S.E. Bonanni, B. Brenner, H. Brüning, T. Buys, S.S. Camp, N.J. Campa, D. Canzian, F. Castelao, J.E. Cessna, M.H. Chang-Claude, J. Chanock, S.J. Clarke, C.L. Conroy, D.M. Couch, F.J. Cox, A. https://orcid.org/0000-0002-5138-1099 Cross, S.S. https://orcid.org/0000-0003-2044-1754 Czene, K. Daly, M.B. Devilee, P. Dörk, T. Dwek, M. Eccles, D.M. Eliassen, A.H. Engel, C. Eriksson, M. Evans, D.G. Fasching, P.A. Fletcher, O. Flyger, H. Fritschi, L. Gabrielson, M. Gago-Dominguez, M. García-Closas, M. García-Sáenz, J.A. Goldberg, M.S. Guénel, P. Gündert, M. Hahnen, E. Haiman, C.A. Häberle, L. Håkansson, N. Hall, P. Hamann, U. Hart, S.N. Harvie, M. Hillemanns, P. Hollestelle, A. Hooning, M.J. Hoppe, R. Hopper, J. Howell, A. Hunter, D.J. Jakubowska, A. Janni, W. John, E.M. Jung, A. Kaaks, R. Keeman, R. Kitahara, C.M. Koutros, S. Kraft, P. Kristensen, V.N. Kubelka-Sabit, K. Kurian, A.W. Lacey, J.V. Lambrechts, D. Le Marchand, L. Lindblom, A. Loibl, S. Lubiński, J. Mannermaa, A. Manoochehri, M. Margolin, S. Martinez, M.E. Mavroudis, D. Menon, U. Mulligan, A.M. Murphy, R.A. Collaborators, N.B.C.S. Nevanlinna, H. Nevelsteen, I. Newman, W.G. Offit, K. Olshan, A.F. Olsson, H. Orr, N. Patel, A. Peto, J. Plaseska-Karanfilska, D. Presneau, N. Rack, B. Radice, P. Rees-Punia, E. Rennert, G. Rennert, H.S. Romero, A. https://orcid.org/0000-0002-1634-7397 Saloustros, E. Sandler, D.P. Schmidt, M.K. Schmutzler, R.K. Schwentner, L. Scott, C. Shah, M. Shu, X.-O. Simard, J. Southey, M.C. Stone, J. Surowy, H. Swerdlow, A.J. Tamimi, R.M. Tapper, W.J. Taylor, J.A. Terry, M.B. Tollenaar, R.A.E.M. Troester, M.A. Truong, T. Untch, M. Vachon, C.M. Joseph, V. Wappenschmidt, B. Weinberg, C.R. Wolk, A. Yannoukakos, D. Zheng, W. Ziogas, A. Dunning, A.M. Pharoah, P.D.P. Easton, D.F. Milne, R.L. Lynch, B.M. https://orcid.org/0000-0001-8060-547X
Copyright, Publisher and Additional Information:	© Author(s) (or their employer(s)) 2022. This is an author-produced version of a paper subsequently published in British Journal of Sports Medicine. Uploaded in accordance with the publisher's self-archiving policy. This version is distributed under the terms of the Creative Commons Attribution-NonCommercial Licence (http://creativecommons.org/licenses/by-nc/4.0/). No commercial re-use.
Keywords:	Breast; Genetics; Physical activity; Sedentary Behaviour; Female; Humans; Breast Neoplasms; Exercise; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Factors; Sedentary Behavior
Dates:	Published: October 2022 Published (online): 6 September 2022 Accepted: 29 June 2022
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield)
Funding Information:	Funder Grant number BREAST CANCER CAMPAIGN nan
Depositing User:	Symplectic Sheffield
Date Deposited:	27 Jan 2023 14:38
Last Modified:	27 Jan 2023 14:38
Status:	Published
Publisher:	BMJ
Refereed:	Yes
Identification Number:	10.1136/bjsports-2021-105132
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:195732

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Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

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