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

Suzanne C Dixon-Suen; Sarah J Lewis; Richard M Martin; Dallas R English; Terry Boyle; Graham G Giles; Kyriaki Michailidou; Manjeet K Bolla; Qin Wang; Joe Dennis; Michael Lush; Abctb Investigators; Thomas U Ahearn; Christine B Ambrosone; Irene L Andrulis; Hoda Anton-Culver; Volker Arndt; Kristan J Aronson; Annelie Augustinsson; Päivi Auvinen; Laura E Beane Freeman; Heiko Becher; Matthias W Beckmann; Sabine Behrens; Marina Bermisheva; Carl Blomqvist; Natalia V Bogdanova; Stig E Bojesen; Bernardo Bonanni; Hermann Brenner; Thomas Brüning; Saundra S Buys; Nicola J Camp; Daniele Campa; Federico Canzian; Jose E Castelao; Melissa H Cessna; Jenny Chang-Claude; Stephen J Chanock; Christine L Clarke; Don M Conroy; Fergus J Couch; Angela Cox; Simon S Cross; Kamila Czene; Mary B Daly; Peter Devilee; Thilo Dörk; Miriam Dwek; Henrik Flyger; Breast Cancer Association Consortium

doi:10.1136/bjsports-2021-105132

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

Suzanne C Dixon-Suen, Sarah J Lewis, Richard M Martin, Dallas R English, Terry Boyle, Graham G Giles, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Joe Dennis, Michael Lush, Abctb Investigators, Thomas U Ahearn, Christine B Ambrosone, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J Aronson, Annelie Augustinsson, Päivi AuvinenLaura E Beane Freeman, Heiko Becher, Matthias W Beckmann, Sabine Behrens, Marina Bermisheva, Carl Blomqvist, Natalia V Bogdanova, Stig E Bojesen, Bernardo Bonanni, Hermann Brenner, Thomas Brüning, Saundra S Buys, Nicola J Camp, Daniele Campa, Federico Canzian, Jose E Castelao, Melissa H Cessna, Jenny Chang-Claude, Stephen J Chanock, Christine L Clarke, Don M Conroy, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Mary B Daly, Peter Devilee, Thilo Dörk, Miriam Dwek, Henrik Flyger, Breast Cancer Association Consortium

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.

Original language	English
Journal	British Journal of Sports Medicine
Volume	56
Issue number	20
Pages (from-to)	1157-1170
Number of pages	14
ISSN	0306-3674
DOIs	https://doi.org/10.1136/bjsports-2021-105132
Publication status	Published - Oct 2022

Keywords

Female
Humans
Breast Neoplasms/epidemiology
Exercise
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Risk Factors
Sedentary Behavior

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10.1136/bjsports-2021-105132

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Dixon-Suen, S. C., Lewis, S. J., Martin, R. M., English, D. R., Boyle, T., Giles, G. G., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Lush, M., Investigators, A., Ahearn, T. U., Ambrosone, C. B., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Augustinsson, A., ... Breast Cancer Association Consortium (2022). Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study. British Journal of Sports Medicine, 56(20), 1157-1170. https://doi.org/10.1136/bjsports-2021-105132

Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Investigators, A, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Brenner, H, Brüning, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, Dwek, M, Flyger, H & Breast Cancer Association Consortium 2022, 'Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study', British Journal of Sports Medicine, vol. 56, no. 20, pp. 1157-1170. https://doi.org/10.1136/bjsports-2021-105132

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title = "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.",

keywords = "Female, Humans, Breast Neoplasms/epidemiology, Exercise, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Factors, Sedentary Behavior",

author = "Dixon-Suen, {Suzanne C} and Lewis, {Sarah J} and Martin, {Richard M} and English, {Dallas R} and Terry Boyle and Giles, {Graham G} and Kyriaki Michailidou and Bolla, {Manjeet K} and Qin Wang and Joe Dennis and Michael Lush and Abctb Investigators and Ahearn, {Thomas U} and Ambrosone, {Christine B} and Andrulis, {Irene L} and Hoda Anton-Culver and Volker Arndt and Aronson, {Kristan J} and Annelie Augustinsson and P{\"a}ivi Auvinen and {Beane Freeman}, {Laura E} and Heiko Becher and Beckmann, {Matthias W} and Sabine Behrens and Marina Bermisheva and Carl Blomqvist and Bogdanova, {Natalia V} and Bojesen, {Stig E} and Bernardo Bonanni and Hermann Brenner and Thomas Br{\"u}ning and Buys, {Saundra S} and Camp, {Nicola J} and Daniele Campa and Federico Canzian and Castelao, {Jose E} and Cessna, {Melissa H} and Jenny Chang-Claude and Chanock, {Stephen J} and Clarke, {Christine L} and Conroy, {Don M} and Couch, {Fergus J} and Angela Cox and Cross, {Simon S} and Kamila Czene and Daly, {Mary B} and Peter Devilee and Thilo D{\"o}rk and Miriam Dwek and Henrik Flyger and {Breast Cancer Association Consortium}",

note = "{\textcopyright} Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = oct,

doi = "10.1136/bjsports-2021-105132",

language = "English",

volume = "56",

pages = "1157--1170",

journal = "British Journal of Sports Medicine",

issn = "0306-3674",

publisher = "B M J Group",

number = "20",

}

TY - JOUR

T1 - Physical activity, sedentary time and breast cancer risk

T2 - a Mendelian randomisation study

AU - Dixon-Suen, Suzanne C

AU - Lewis, Sarah J

AU - Martin, Richard M

AU - English, Dallas R

AU - Boyle, Terry

AU - Giles, Graham G

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dennis, Joe

AU - Lush, Michael

AU - Investigators, Abctb

AU - Ahearn, Thomas U

AU - Ambrosone, Christine B

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Aronson, Kristan J

AU - Augustinsson, Annelie

AU - Auvinen, Päivi

AU - Beane Freeman, Laura E

AU - Becher, Heiko

AU - Beckmann, Matthias W

AU - Behrens, Sabine

AU - Bermisheva, Marina

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Bonanni, Bernardo

AU - Brenner, Hermann

AU - Brüning, Thomas

AU - Buys, Saundra S

AU - Camp, Nicola J

AU - Campa, Daniele

AU - Canzian, Federico

AU - Castelao, Jose E

AU - Cessna, Melissa H

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J

AU - Clarke, Christine L

AU - Conroy, Don M

AU - Couch, Fergus J

AU - Cox, Angela

AU - Cross, Simon S

AU - Czene, Kamila

AU - Daly, Mary B

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dwek, Miriam

AU - Flyger, Henrik

AU - Breast Cancer Association Consortium

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Female

KW - Humans

KW - Breast Neoplasms/epidemiology

KW - Exercise

KW - Mendelian Randomization Analysis

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Sedentary Behavior

UR - http://www.scopus.com/inward/record.url?scp=85137660444&partnerID=8YFLogxK

U2 - 10.1136/bjsports-2021-105132

DO - 10.1136/bjsports-2021-105132

M3 - Journal article

C2 - 36328784

SN - 0306-3674

VL - 56

SP - 1157

EP - 1170

JO - British Journal of Sports Medicine

JF - British Journal of Sports Medicine

IS - 20

ER -

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

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