| Abstract Objective: To explore the potential causal relationship between the degree of brain functional connectivity and some neurological diseases by conducting two-sample bidirectional Mendelian randomization (MR), provide genetic evidence to support the association of the disease onset risks between them, and offer references for the prevention and treatment of some neurological diseases. Methods: Two-sample MR analysis was conducted with verification using an independent dataset. The exposure data was derived from Michael""s research on UK Biobank participants, while the outcome data came from the Finnish database FinnGen R10 and the verification group data from the IEU Open GWAS. SNPs related to brain connectivity were carefully selected as instrumental variables. Multiple MR methods, including inverse variance weighting (IVW), were applied, along with sensitivity analyses for heterogeneity and pleiotropy. All analyses were performed using R software. Results: Using the IVW method with FDR correction, significant associations between brain connectivity and various diseases were observed in both the outcome and verification datasets. After taking the intersection of datasets, specific white matter structural connections were found to have causal relationships with diseases. For Alzheimer""s disease, the left hemisphere visual network and left hemisphere limbic network white matter connection (P_IVW=0.031, P_FDR=0.0451, OR= 1.282) and the left hemisphere somatomotor network and left hemisphere control network white matter connection (P_IVW=0.034, P_FDR=0.037, OR=1.237) showed a positive causal relationship. For epilepsy, the left hemisphere visual network and left hemisphere limbic network white matter connection (P_IVW < 0.000, P_FDR=0.0002, OR=1.497) demonstrated a positive causal relationship. For multiple sclerosis, the right hemisphere limbic network and caudate nucleus white matter connection (P_IVW<0.046, P_FDR= 0.046, OR=0.708) showed a negative causal relationship. For Parkinson""s disease, the left hemisphere somatomotor network and left hemisphere somatomotor network white matter connection (P_IVW=0.034, P_FDR=0.047, OR=1.273), left hemisphere somatomotor network and left hemisphere control network white matter connection (P_IVW=0.028, P_FDR=0.044, OR=1.365), and right hemisphere white matter connection (P_IVW=0.038, P_FDR=0.047, OR=1.309) showed a positive causal relationship. These results remained significant after FDR correction. Sensitivity analyses revealed that no horizontal pleiotropy or heterogeneity existed in some datasets, and leave-one-out analysis confirmed the stability of results. Reverse MR analysis indicated no reverse causal relationships. Conclusion: This study identified significant causal relationships between specific brain white matter functional connections and four neurological diseases, confirming the pivotal role of brain white matter in these diseases. While the study boasts advantages such as strong causal inference, effective data utilization, and scientific methodology, it is limited by genetic pleiotropy. Future studies should integrate multimodal technologies to explore these connections further, offering insights for early diagnosis, treatment, and prognosis, while considering the study""s limitations in its applications. |