Abstract
BACKGROUND: The catechol-O-methyltransferase (COMT) gene is involved in brain catecholamine metabolism, but its association with Parkinson's disease (PD) risk remains unclear. OBJECTIVE: To investigate the relationship between COMT genetic variants and PD risk across diverse ancestries. METHODS: We analyzed COMT variants in 2,251 PD patients and 2,835 controls of European descent using whole-genome sequencing from the Accelerating Medicines Partnership-Parkinson Disease (AMP-PD), along with 20,427 PD patients and 11,837 controls from 10 ancestries using genotyping data from the Global Parkinson's Genetics Program (GP2). RESULTS: Utilizing the largest case-control datasets to date, no significant enrichment of COMT risk alleles in PD patients was observed across any ancestry group after correcting for multiple testing. Among Europeans, no correlations with cognitive decline, motor function, motor complications, or time to LID onset were observed. CONCLUSIONS: These findings emphasize the need for larger, diverse cohorts to confirm the role of COMT in PD development and progression.