Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study.
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., Eccles DM., Eliassen AH., Engel C., Eriksson M., Evans DG., Fasching PA., Fletcher O., Flyger H., Fritschi L., Gabrielson M., Gago-Dominguez M., García-Closas M., García-Sáenz JA., Goldberg MS., Guénel P., Gündert M., Hahnen E., Haiman CA., Häberle L., Håkansson N., Hall P., Hamann U., Hart SN., Harvie M., Hillemanns P., Hollestelle A., Hooning MJ., Hoppe R., Hopper J., Howell A., Hunter DJ., Jakubowska A., Janni W., John EM., Jung A., Kaaks R., Keeman R., Kitahara CM., Koutros S., Kraft P., Kristensen VN., Kubelka-Sabit K., Kurian AW., Lacey JV., Lambrechts D., Le Marchand L., Lindblom A., Loibl S., Lubiński J., Mannermaa A., Manoochehri M., Margolin S., Martinez ME., Mavroudis D., Menon U., Mulligan AM., Murphy RA., Collaborators N., Nevanlinna H., Nevelsteen I., Newman WG., Offit K., Olshan AF., Olsson H., Orr N., Patel A., Peto J., Plaseska-Karanfilska D., Presneau N., Rack B., Radice P., Rees-Punia E., Rennert G., Rennert HS., Romero A., Saloustros E., Sandler DP., Schmidt MK., Schmutzler RK., Schwentner L., Scott C., Shah M., Shu X-O., Simard J., Southey MC., Stone J., Surowy H., Swerdlow AJ., Tamimi RM., Tapper WJ., Taylor JA., Terry MB., Tollenaar RAEM., Troester MA., Truong T., Untch M., Vachon CM., Joseph V., Wappenschmidt B., Weinberg CR., Wolk A., Yannoukakos D., Zheng W., Ziogas A., Dunning AM., Pharoah PDP., Easton DF., Milne RL., Lynch BM., Breast Cancer Association Consortium .
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.