Understanding Causal Relationships Between Imaging-Derived Phenotypes and Parkinson's Disease: A Mendelian Randomization and Observational Study.

Observational studies have suggested a correlation between brain imaging alterations and Parkinson's disease (PD). However, data on causal relationships are still lacking. This study aimed to examine the causal relationship between brain imaging-derived phenotypes (IDPs) and PD. A bidirectional two-sample Mendelian randomization analysis was conducted to explore the causal association between IDPs and PD. Summary-level data for IDPs ( = 39,691), PD ( = 482,730), and PD symptoms ( = 4093) were obtained from genome-wide association studies of European ancestry. Clinical validation was performed in an Asian cohort, which involved healthy controls ( = 81), patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD) ( = 47), and patients with PD ( = 85). We found 13 IDPs with significant causal effects on PD and seven reciprocal effects of PD on IDPs. For instance, increased median T2star in the right caudate (odds ratio = 1.23, 95% confidence interval 1.08-1.40, = 0.0057) and bilateral putamen (left: odds ratio = 1.25, 95% confidence interval 1.09-1.43, = 0.0056; right: odds ratio = 1.25, 95% confidence interval 1.10-1.43, = 0.0056) were associated with PD. Enlargement of the left thalamus (odds ratio = 1.50, 95% confidence interval 1.14-1.96, = 0.016) demonstrated causal links with PD. No reverse causal effects were detected. Observational analyses results in the Asian cohort (healthy controls, iRBD, PD) aligned with the Mendelian randomization results. Our results suggest bidirectional causal links between IDPs and PD, offering insights into disease mechanisms and potential imaging biomarkers for PD.