Lipids, Anthropometric Measures, Smoking and Physical Activity Mediate the Causal Pathway from Education to Breast Cancer in Women: A Mendelian Randomization Study

Abstract Background Our objective is to investigate whether obtaining a higher level of education was causally associated with lower breast cancer risk and to identify the causal mechanism linking them. Methods Firstly, we performed a meta-analysis for educational attainment on breast cancer using 33 MR studies, including 15 case-control studies, 10 cross-sectional studies, and 8 cohort studies. Secondly, the main data analysis used publicly available summary-level data from two large GWAS consortia (Breast Cancer Association Consortium [BCAC] and the Social Science Genetic Association Consortium [SSGAC]). Mendelian randomization (MR) analysis used 65 genetic variants derived from the SSGAC as instrumental variables for years of schooling. The outcomes were the overall breast cancer risk (122,977 cases/105,974 controls in women) and its two subtypes: estrogen receptor (ER)-positive breast cancer (ER+: 69,501 cases) and ER-negative breast cancer (ER-: 21,468 cases). Furthermore, six additional consortia were analyzed to investigate the causal pathways from education to breast cancer. The fixed and random effects inverse variance weighted methods were used to estimate the causal effects, along with other additional MR methods as sensitivity analyses. Results The results showed that each additional standard deviation of 4.2 years of education was causally associated with a 27% lower risk of ER- (OR 0.73, 95% CI [0.64, 0.84]; P-value < 0.001). However, very weak causal relationship was found with overall breast cancer and no causal association with ER + risk, consistent with the sensitivity analyses. A genetic predisposition for higher education was causally associated with lower ER- risk and was found to be partially related to hip circumference, body mass index, triglyceride and HDL levels, smoking, and physical activity. Conclusion A low level of education is a causal risk factor in the development of ER- as it is associated with a poor lipid profile, anthropometric measurements, smoking, and types of physical activity.