The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis

Ooi BNS, Loh H, Ho PJ, Milne RL, Giles G, Gao C, Kraft P, John EM, Swerdlow A, Brenner H, Wu AH, Haiman C, Evans DG, Zheng W, Fasching P, Castelao JE, Kwong A, Shen X, Czene K, Hall P, Dunning A, Easton D, Hartman M, Li J (2019)

Publication Type: Journal article

Publication year: 2019

Journal

International Journal of Epidemiology Oxford University Press

Book Volume: 48

Pages Range: 781-794

Journal Issue: 3

DOI: 10.1093/ije/dyz124

Abstract

BACKGROUND: Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk. METHODS: Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results. RESULTS: The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P = 1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P = 9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050). CONCLUSION: Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.

Authors with CRIS profile

Peter Fasching Professur für Translationale Frauenheilkunde und Geburtshilfe

Involved external institutions

Genome Institute of Singapore SG Singapore (SG) Cancer Council Victoria AU Australia (AU) Stanford University US United States (USA) (US) Harvard T.H. Chan School of Public Health US United States (USA) (US) Keck School of Medicine of USC US United States (USA) (US) The Institute of Cancer Research (ICR) GB United Kingdom (GB) Vanderbilt University US United States (USA) (US) University of Cambridge GB United Kingdom (GB) University of Manchester GB United Kingdom (GB) Instituto de Investigación Sanitaria Galicia Sur ES Spain (ES) University of Hong Kong (HKU) / 香港大學 HK Hong Kong (HK) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) NUS Yong Loo Lin School of Medicine SG Singapore (SG)

How to cite

APA:

Ooi, B.N.S., Loh, H., Ho, P.J., Milne, R.L., Giles, G., Gao, C.,... Li, J. (2019). The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis. International Journal of Epidemiology, 48(3), 781-794. https://dx.doi.org/10.1093/ije/dyz124

MLA:

Ooi, Brandon Nick Sern, et al. "The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis." International Journal of Epidemiology 48.3 (2019): 781-794.

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