Yarmolinsky J, Relton CL, Lophatananon A, et al. – Because previous observational epidemiological studies have linked numerous reproductive, lifestyle, and molecular factors to the risk of epithelial ovarian cancer, researchers investigated if these associations represent causal relationships or merely reflect residual confounding, reverse causation, or other forms of bias inherent to conventional epidemiological designs. Performing Mendelian randomization (MR) analysis, they investigated how 12 previously reported risk factors are associated with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumors, in up to 25,509 cases and 40,941 controls in the Ovarian Cancer Association Consortium. The MR analysis revealed a correlation of only 2 of 12 previously reported risk factors (genetic liability to endometriosis and lifetime smoking exposure) with invasive epithelial ovarian cancer risk. When they stratified the analyses with respect to invasive epithelial ovarian cancer histotypes and low malignant potential tumors, an association of eight risk factors with one or more epithelial ovarian cancer subtypes was noted. Correlations that were strongest included positive correlations of height with clear cell carcinoma and age at natural menopause with endometrioid carcinoma, and an inverse association of genetic liability to polycystic ovary syndrome with endometrioid carcinoma. These findings supported that a few of these factors have a role in invasive epithelial ovarian cancer overall and that there are distinct etiologies across histotypes.