Bidirectional Causal Relationship Between Myopia and Neurodegenerative Diseases: Two-Sample Mendelian Randomization Analyses

<b>Aims/Background</b> Myopia is highly prevalent in certain neurodegenerative diseases (NDDs), and both conditions demonstrate genetic susceptibility. This study investigated the potential bidirectional causal relationships between myopia and four NDDs, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), using Mendelian randomization (MR). We aimed to determine whether myopia contributes to the risk of NDDs and vice versa. <b>Methods</b> We analyzed data from two independent, large-scale genome-wide association study (GWAS) cohorts on myopia, comprising 212,571 participants in the first cohort (finn-b-H7_MYOPIA) and 95,619 in the second (GCST009521). GWAS summary statistics for the four NDDs, encompassing 589,439 samples, were also incorporated. Bidirectional MR was employed to investigate causal relationships between myopia and each of the four NDDs. The inverse variance-weighted (IVW) method served as the primary analytical approach. Sensitivity analyses, including MR-Egger regression, weighted median, weighted mode, and simple mode, were conducted to assess the robustness of the findings. Horizontal pleiotropy was evaluated using the MR-Egger regression intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, while heterogeneity was assessed via Cochran's Q test. Leave-one-out analyses were conducted to evaluate the influence of individual single nucleotide polymorphisms (SNPs). Odds ratios (ORs) with 95% confidence intervals (CIs) were reported, and statistical significance was set at <i>p</i> < 0.05. <b>Results</b> MR analyses identified no evidence of a causal relationship between myopia and refractive error and increased risk of any of the four NDDs (all <i>p</i> > 0.05). Similarly, none of the NDDs were associated with an increased risk of myopia or refractive error (all <i>p</i> > 0.05). Sensitivity analyses revealed no SNPs with significant influence on the causal associations (all <i>p</i> > 0.05), supporting the robustness of the findings. <b>Conclusion</b> This study provides no evidence of a bidirectional causal relationship between myopia and the four NDDs among individuals of European ancestry. Future research should extend beyond direct causal inference to investigate potential mediating biological mechanisms.