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Evaluating causal associations between previously reported risk factors and epithelial ovarian cancer: a Mendelian randomization analysis
Caroline L Relton,
Woo Yin Ling,
Sue K Park,
George Davey Smith,
Richard M Martin,
Sarah J Lewis
Posted 19 Nov 2018
bioRxiv DOI: 10.1101/472696
Posted 19 Nov 2018
Background: Previously reported observational associations between risk factors and epithelial ovarian cancer (EOC) could reflect residual confounding, reverse causation, or measurement error. Mendelian randomization (MR) uses genetic variants as proxies for modifiable risk factors to strengthen causal inference in observational studies. Methods: We used MR to evaluate the causal role of 13 previously reported risk factors in overall and histotype-specific EOC in up to 25,509 case subjects and 40,941 controls in the Ovarian Cancer Association Consortium. Inverse-variance weighted models were employed to generate effect estimates and MR-Egger, weighted median, and weighted mode were performed to examine evidence of horizontal pleiotropy. A Bonferroni-corrected P-value threshold was used to establish "strong evidence" (P<0.0038) and "suggestive evidence" (0.0038<P<0.05) for associations. Results: There was strong or suggestive evidence that 9 of 13 risk factors were causally associated with overall or histotype-specific EOC. Genetic liability to endometriosis was strongly associated with EOC (OR per log odds higher liability: 1.27, 95%CI: 1.16-1.40; P=6.94x10-7) and lifetime smoking exposure was suggestively associated with EOC (OR per unit increase in smoking score: 1.36, 95%CI: 1.04-1.78; P=0.02). In histotype-stratified analyses, the strongest associations found were between: height and clear cell carcinoma (OR per SD increase: 1.36, 95%CI: 1.15-1.61; P=0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI: 1.02-1.16; P=0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per log odds higher liability: 0.74, 95% CI: 0.62-0.90; P=0.002). There was little evidence that genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone-binding globulin were associated with ovarian cancer or its subtypes. Conclusions: Our comprehensive examination of possible etiological drivers of ovarian carcinogenesis supports a causal role for few of these factors in epithelial ovarian cancer and suggests distinct etiologies across histotypes.
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