Two-Sample Mendelian Randomization Estimates of the Effects of Educational Attainment on Osteoporosis

Abstract

Background: Osteoporosis is a complex disorder, with multiple biopsychosocial contributors. As a principal influencing factor of socioeconomic status, education is commonly regarded associated with osteoporosis. However, the associations between education and osteoporosis are inconsistent in different researches, and we aim to investigate it under two-sample Mendelian randomization analysis framework. Methods: A series of quality control steps were taken in our analysis to select eligible instrumental SNPs which were strongly associated with exposure. To make the results more robust and reliable, we utilized several robust analytical methods (inverse-variance weighting, weighted median, MR-Egger regression and MR.RAPS) that based on different assumptions of two-sample Mendelian randomization analysis. MR-Egger intercept test, Cochran’s Q test and “leave-one-out” sensitivity analysis were performed to remove outliers and evaluate the horizontal pleiotropy, heterogeneities and stability of these genetic variants on outcomes. Outlier variants identified by MR-PRESSO outlier test were removed to reduce heterogeneity and the effect of horizontal pleiotropy. Two-sample Mendelian randomization approach was also employed to determine the mechanism by which education affects osteoporosis. Results: Our two-sample Mendelian randomization analyses suggested a causal effect of longer educational attainment on lower risk of osteoporosis and higher heel-BMD, FN-BMD and LS-BMD, but lack of evidence on lower risk of osteoporostic fracture or higher FA-BMD. Our MR analyses also determined the probability of serum lipid level, smoking, magnesium supplements, selenium supplements and physical activity working as mediators in the causal effect of educational attainment on osteoporosis. Interpretation: Our results can be helpful for education policy making to increase BMD, or reminding clinicians of taking integrated biopsychosocial measures and efforts to prevent or intervene with bone loss when patients are high risk population of osteoporosis. Funding Statement: Not applicable Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Our analysis used published study or publicly available GWAS summary data. No original data was collected for this manuscript, and thus, no ethical committee approval was required. Each study included was approved by their institutional ethics review committees, all participants provided written informed consent.