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Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer
Open accessAbstract
BACKGROUND: Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers. METHODS: We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium. RESULTS: We found an inverse association between the genetic score for childhood BMI and risk of breast cancer [odds ratio (OR) = 0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P = 6.5 × 10(-5)). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR = 0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P = 2.5 × 10(-7)), and positively associated with ovarian cancer (OR = 1.35; 95% CI: 1.05, 1.72; P = 0.017), lung cancer (OR = 1.27; 95% CI: 1.09, 1.49; P = 2.9 × 10(-3)) and colorectal cancer (OR = 1.39; 95% CI: 1.06, 1.82, P = 0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression. CONCLUSIONS: Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status.
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“Gao and colleagues do not provide any information on the strength of the different instrumental variables, such as the F-statistic or R 2 for the genetic instrument-adiposity trait associations.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [1]
In the citing paper
“They are unable with the summary data available to test differences in effect between pre- and postmenopausal breast cancer, as GWAS separated by these sub-phenotypes are not presented by the breast cancer consortia.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [1]
In the citing paper
“Greater adult BMI, but not waist-hip ratio (WHR), is concluded to decrease breast cancer and increase ovarian, lung and colorectal cancer risk.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [1]
In the citing paper
“The paper by Gao and colleagues illustrates this with the large numbers of cancer cases that they analyse: 15 748, 5100, 12 160, 4369 and 14 160, respectively, for breast, colorectal, lung, ovarian and prostate cancer.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [1]
In the citing paper
“but Gao and colleagues are able to examine effects with estrogen receptor-positive cancers and they find the same inverse association with these as seen for all breast cancer cases combined.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [1]
In the citing paper
“Gao and colleagues explore the causal effect of adiposity on several cancers using two-sample Mendelian randomization (MR), and find some evidence that greater adult body mass index (BMI) causally reduces the risk of breast cancer while increasing ovarian, lung and colorectal cancer.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [1]
In the citing paper
“but for the sex-specific cancers in the paper by Gao et al. , this does not seem to be the case.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [1]
In the citing paper
“According to data presented by Gao in their Supplementary Table 1, it seems that the association of the genetic instrumental variable with each adiposity trait has been taken from samples that combine females and males, whereas for the association of the genetic instrument with breast and ovarian cancer, females only are included and with prostate cancer males only are included.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [1]
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Metadata
- Authors
- Gao, C., Patel, C. J., Michailidou, K., Peters, U., Gong, J., Schildkraut, J., Schumacher, F. R., Zheng, W., Boffetta, P., Stucker, I., Willett, W., Gruber, S., Easton, D. F., Hunter, D. J., Sellers, T. A., Haiman, C., Henderson, B. E., Hung, R. J., Amos, C., Pierce, B. L., Lindström, S., & Kraft, P.
- Affiliations
- Harvard University (US)
- University of Cambridge (GB)
- Fred Hutch Cancer Center (US)
- Duke University (US)
- USC Norris Comprehensive Cancer Center (US)
- Vanderbilt University (US)
- Tisch Cancer Institute (US)
- University of Southern California (US)
- Moffitt Cancer Center (US)
- Mount Sinai Hospital (CA)
- Dartmouth College (US)
- University of Chicago (US)
- Corresponding author
- Kraft, Peter
- ORCID
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-06
- Volume
- 45
- Issue
- 3
- Pages
- 896-908
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- PMC
- PMC6372135
- OpenAlex
- W2483210912
- Cited by
- 163
- References
- 59
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 7 · 2023: 10 · 2022: 28 · 2021: 21 · 2020: 18 · 2019: 15 · 2018: 16 · 2017: 17 · 2016: 9
- FWCI
- 15.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Epidemiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Mayo Clinic
- Wellcome Trust (085475, 076113)
- Cancer Research UK (U19 CA148065, U19 CA148112, C1287, C1178/A3947, C150/A5660, 16563, U19 CA148537, A16563, C490/A8339, C1287‐A16563)
- National Institute for Health and Care Research (U19 CA148065, C1287/A16563)
- European Commission (U19-CA148112, U19 CA148065, C1287/A16563)
- ZonMw (050-060-810)
- Erasmus Medisch Centrum (014-93-015)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (050.060.810, 911-03-012, 175.010.200, 175.010.2005.011)
- National Institutes of Health (C1287/A16563, CA15083, CA148127)
- National Cancer Institute (R03CA165131, U19CA148107, U19CA148065, U19CA148537, CA148065, U19CA148127, U19CA148112, C1287/A16563, CA 15083, R01CA114343, P30CA15083, P30CA023108, P30CA015083)
- National Institute of Environmental Health Sciences (ES025052, R21ES025052, K99ES023504, R00ES023504, C1287/A16563)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Keywords
- adiposity, body mass index, childhood BMI, birth weight, waist-to-hip ratio, breast cancer, ovarian cancer, prostate cancer, lung cancer, colorectal cancer, cancer risk, causal inference, polygenic risk score, pleiotropy, menopausal status, smoking status
- MeSH terms
- Breast Neoplasms, Female, Humans, Lung Neoplasms, Male, Neoplasms, Ovarian Neoplasms, Phenotype, Prostatic Neoplasms, Regression Analysis, Risk Factors, Colorectal Neoplasms, Body Mass Index, Odds Ratio, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Adiposity, Mendelian Randomization Analysis
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