Causal Association of NAFLD with Osteoporosis, Fracture and Falling Risk: a Bidirectional Mendelian Randomization Study

Introduction: The causal association between non-alcoholic fatty liver disease (NAFLD) and osteoporosis remains controversial in previous epidemiological studies. We employed a bidirectional two-sample Mendelian analysis to explore the causal relationship between NAFLD and osteoporosis.

Method: The NAFLD instrumental variables (IVs) were obtained from a large Genome-wide association study (GWAS) meta-analysis dataset of European descent. Two-sample Mendelian randomization (MR) analyses were used to estimate the causal effect of NAFLD on osteoporosis, fracture, and fall. Reverse Mendelian randomization analysis was conducted to estimate the causal effect of osteoporosis on NAFLD. The inverse-variance weighted (IVW) method was the primary analysis in this analysis. We used the MR-Egger method to determine horizontal pleiotropic. The heterogeneity effect of IVs was detected by MR-Egger and IVW analyses.

Results: Five SNPs (rs2980854, rs429358, rs1040196, rs738409, and rs5764430) were chosen as IVs for NAFLD. In forward MR analysis, the IVW-random effect indicated the causal effect of NAFLD on osteoporosis (OR= 1.0021, 95% CI: 1.0006-1.0037, = 0.007) but not on fracture (OR= 1.0016, 95% CI: 0.998-1.0053, = 0.389) and fall (OR= 0.9912, 95% CI: 0.9412-1.0440, = 0.740). Furthermore, the reverse Mendelian randomization did not support a causal effect of osteoporosis on NAFLD (OR= 1.0002, 95% CI: 0.9997-1.0007, = 0.231). No horizontal pleiotropic was detected in all MR analyses.

Conclusions: The results of this study indicate a causal association between NAFLD and osteoporosis. NAFLD patients have a higher risk of osteoporosis but not fracture and falling risk. In addition, our results do not support a causal effect of osteoporosis on NAFLD.