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

<b>Background/Objectives:</b> 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. <b>Methods:</b> A bidirectional two-sample Mendelian randomization analysis was conducted to explore the causal association between IDPs and PD. Summary-level data for IDPs (<i>n</i> = 39,691), PD (<i>n</i> = 482,730), and PD symptoms (<i>n</i> = 4093) were obtained from genome-wide association studies of European ancestry. Clinical validation was performed in an Asian cohort, which involved healthy controls (<i>n</i> = 81), patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD) (<i>n</i> = 47), and patients with PD (<i>n</i> = 85). <b>Results:</b> 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, <i>p</i> = 0.0057) and bilateral putamen (left: odds ratio = 1.25, 95% confidence interval 1.09-1.43, <i>p</i> = 0.0056; right: odds ratio = 1.25, 95% confidence interval 1.10-1.43, <i>p</i> = 0.0056) were associated with PD. Enlargement of the left thalamus (odds ratio = 1.50, 95% confidence interval 1.14-1.96, <i>p</i> = 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. <b>Conclusions:</b> Our results suggest bidirectional causal links between IDPs and PD, offering insights into disease mechanisms and potential imaging biomarkers for PD.