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Title: Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent
Authors: Guo Y.
Warren Andersen S.
Shu X.-O.
Michailidou K.
Bolla M.K.
Wang Q.
Garcia-Closas M.
Milne R.L.
Schmidt M.K.
Chang-Claude J.
Dunning A.
Bojesen S.E.
Ahsan H.
Aittom�ki K.
Andrulis I.L.
Anton-Culver H.
Arndt V.
Beckmann M.W.
Beeghly-Fadiel A.
Benitez J.
Bogdanova N.V.
Bonanni B.
B?rresen-Dale A.-L.
Brand J.
Brauch H.
Brenner H.
Br�ning T.
Burwinkel B.
Casey G.
Chenevix-Trench G.
Couch F.J.
Cox A.
Cross S.S.
Czene K.
Devilee P.
D�rk T.
Dumont M.
Fasching P.A.
Figueroa J.
Flesch-Janys D.
Fletcher O.
Flyger H.
Fostira F.
Gammon M.
Giles G.G.
Gu�nel P.
Haiman C.A.
Hamann U.
Hooning M.J.
Hopper J.L.
Jakubowska A.
Jasmine F.
Jenkins M.
John E.M.
Johnson N.
Jones M.E.
Kabisch M.
Kibriya M.
Knight J.A.
Koppert L.B.
Kosma V.-M.
Kristensen V.
Le Marchand L.
Lee E.
Li J. 
Lindblom A.
Luben R.
Lubinski J.
Malone K.E.
Mannermaa A.
Margolin S.
Marme F.
McLean C.
Meijers-Heijboer H.
Meindl A.
Neuhausen S.L.
Nevanlinna H.
Neven P.
Olson J.E.
Perez J.I.A.
Perkins B.
Peterlongo P.
Phillips K.-A.
Pylk�s K.
Rudolph A.
Santella R.
Sawyer E.J.
Schmutzler R.K.
Seynaeve C.
Shah M.
Shrubsole M.J.
Southey M.C.
Swerdlow A.J.
Toland A.E.
Tomlinson I.
Torres D.
Truong T.
Ursin G.
Van Der Luijt R.B.
Verhoef S.
Whittemore A.S.
Winqvist R.
Zhao H.
Zhao S.
Hall P.
Simard J.
Kraft P.
Pharoah P.
Hunter D.
Easton D.F.
Zheng W.
Keywords: adult
body mass
breast cancer
disease association
environmental factor
gene frequency
genetic heterogeneity
genotyping technique
logistic regression analysis
major clinical study
Mendelian randomization analysis
middle aged
single nucleotide polymorphism
weight change
young adult
Breast Neoplasms
genetic predisposition
Mendelian randomization analysis
risk factor
statistical model
statistics and numerical data
Body Mass Index
Breast Neoplasms
European Continental Ancestry Group
Genetic Predisposition to Disease
Mendelian Randomization Analysis
Middle Aged
Models, Statistical
Polymorphism, Single Nucleotide
Risk Factors
Issue Date: 2016
Citation: Guo Y., Warren Andersen S., Shu X.-O., Michailidou K., Bolla M.K., Wang Q., Garcia-Closas M., Milne R.L., Schmidt M.K., Chang-Claude J., Dunning A., Bojesen S.E., Ahsan H., Aittom�ki K., Andrulis I.L., Anton-Culver H., Arndt V., Beckmann M.W., Beeghly-Fadiel A., Benitez J., Bogdanova N.V., Bonanni B., B?rresen-Dale A.-L., Brand J., Brauch H., Brenner H., Br�ning T., Burwinkel B., Casey G., Chenevix-Trench G., Couch F.J., Cox A., Cross S.S., Czene K., Devilee P., D�rk T., Dumont M., Fasching P.A., Figueroa J., Flesch-Janys D., Fletcher O., Flyger H., Fostira F., Gammon M., Giles G.G., Gu�nel P., Haiman C.A., Hamann U., Hooning M.J., Hopper J.L., Jakubowska A., Jasmine F., Jenkins M., John E.M., Johnson N., Jones M.E., Kabisch M., Kibriya M., Knight J.A., Koppert L.B., Kosma V.-M., Kristensen V., Le Marchand L., Lee E., Li J., Lindblom A., Luben R., Lubinski J., Malone K.E., Mannermaa A., Margolin S., Marme F., McLean C., Meijers-Heijboer H., Meindl A., Neuhausen S.L., Nevanlinna H., Neven P., Olson J.E., Perez J.I.A., Perkins B., Peterlongo P., Phillips K.-A., Pylk�s K., Rudolph A., Santella R., Sawyer E.J., Schmutzler R.K., Seynaeve C., Shah M., Shrubsole M.J., Southey M.C., Swerdlow A.J., Toland A.E., Tomlinson I., Torres D., Truong T., Ursin G., Van Der Luijt R.B., Verhoef S., Whittemore A.S., Winqvist R., Zhao H., Zhao S., Hall P., Simard J., Kraft P., Pharoah P., Hunter D., Easton D.F., 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) : e1002105. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. ? 2016 Guo et al.
Source Title: PLoS Medicine
ISSN: 15491277
DOI: 10.1371/journal.pmed.1002105
Rights: Attribution 4.0 International
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