Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

Guo Y, Andersen SW, Shu XO, Michailidou K, Bolla MK, Wang Q, Garcia-Closas M, Milne RL, Schmidt MK, Chang-Claude J, Dunning A, Bojesen SE, Ahsan H, Aittomaki K, Andrulis IL, Anton-Culver H, Arndt V, Beckmann M, Beeghly-Fadiel A, Benitez J, Bogdanova NV, Bonanni B, Borresen-Dale AL, Brand J, Brauch H, Brenner H, Bruening T, Burwinkel B, Casey G, Chenevix-Trench G, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Doerk T, Dumont M, Fasching P, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fostira F, Gammon M, Giles GG, Guenel P, Haiman CA, Hamann U, Hooning MJ, Hopper JL, Jakubowska A, Jasmine F, Jenkins M, John EM, Johnson N, Jones ME, Kabisch M, Kibriya M, Knight JA, Koppert LB, Kosma VM, Kristensen V, Le Marchand L, Lee E, Li J, Lindblom A, Luben R, Lubinski J, Malone KE, Mannermaa A, Margolin S, Marme F, Mclean C, Meijers-Heijboer H, Meindl A, Neuhausen SL, Nevanlinna H, Neven P, Olson JE, Perez JIA, Perkins B, Peterlongo P, Phillips KA, Pylkas K, Rudolph A, Santella R, Sawyer EJ, Schmutzler RK, Seynaeve C, Shah M, Shrubsole MJ, Southey MC, Swerdlow AJ, Toland AE, Tomlinson I, Torres D, Truong T, Ursin G, Van Der Luijt RB, Verhoef S, Whittemore AS, Winqvist R, Zhao H, Zhao S, Hall P, Simard J, Kraft P, Pharoah P, Hunter D, Easton DF, Zheng W (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 13

Journal Issue: 8

DOI: 10.1371/journal.pmed.1002105

Abstract

BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. METHODS: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. RESULTS: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

Authors with CRIS profile

Involved external institutions

University of Cambridge United Kingdom (GB) University of Chicago United States (USA) (US) University of Sheffield United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Antoni van Leeuwenhoek Netherlands (NL) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Karolinska Institute Sweden (SE) Vanderbilt University United States (USA) (US) European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Cancer Council Victoria Australia (AU) The Institute of Cancer Research (ICR) United Kingdom (GB) Stanford University United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) University of Southern California (USC) United States (USA) (US) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of Hawaii (U.H.) United States (USA) (US) Ruprecht-Karls-Universität Heidelberg Germany (DE) Technische Universität München (TUM) Germany (DE) Mayo Clinic United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) University of Oxford United Kingdom (GB) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) The University of Melbourne Australia (AU) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Hospital Monte Naranco Spain (ES) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Copenhagen University Hospital Denmark (DK) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Mount Sinai Hospital (MSH) Canada (CA) Kuopio University Hospital / Pohjois-Savon sairaanhoitopiiri Finland (FI) Universitätsklinikum Köln Germany (DE) Cancer Prevention Institute of California (CPIC) United States (USA) (US) Columbia University United States (USA) (US) Oulun Yliopisto / University of Oulo Finland (FI) The Alfred Hospital Australia (AU) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) King’s College London United Kingdom (GB) Université Laval (UL) Canada (CA) Harvard University United States (USA) (US) University of California Irvine United States (USA) (US) Center for Cancer Biology (CCB) (formerly Vesalius Research Center (VRC)) Belgium (BE) National Centre for Scientific Research (NCSR) "Demokritos" Greece (GR) University of Copenhagen Denmark (DK) Beckman Research Institute of City of Hope (BRI) United States (USA) (US) Helsingin yliopisto / University of Helsinki Finland (FI) Ruhr-Universität Bochum (RUB) Germany (DE) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) University of North Carolina at Chapel Hill United States (USA) (US) Leiden University Netherlands (NL) National Cancer Institute (NCI) United States (USA) (US) Fred Hutchinson Cancer Research Center Canada (CA) Ohio State University United States (USA) (US)

How to cite

APA:

Guo, Y., Andersen, S.W., Shu, X.-O., Michailidou, K., Bolla, M.K., Wang, Q.,... Zheng, W. (2016). Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent. Plos Medicine, 13(8). https://dx.doi.org/10.1371/journal.pmed.1002105

MLA:

Guo, Yan, et al. "Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent." Plos Medicine 13.8 (2016).

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