Dual-Risk axis: GBA1 mutations and occupational pesticide exposure in Parkinson's disease

Background Occupational pesticide (OcP) exposure and pathogenic GBA1 variants are established risk factors for Parkinson's disease (PD). However, whether they interact to influence disease onset or severity remains uncertain. Objective To determine the prevalence of OcP exposure and other lifestyle risks in relation to GBA1 status and their interactions on age of onset (AOO) and clinical scores in a well-characterized PD cohort. Methods We analyzed 505 people with PD (PwP) enrolled in the Ankara Parkinson's Disease Registry (ANPAR). GBA1 variants were identified using next-generation sequencing; benign or uncertain variants were excluded. Structured, face-to-face interviews collected data on history of OcP exposure, history of head trauma, smoking, coffee and tea consumption habits. PwP with and without GBA1 variants were compared using unadjusted and adjusted tests. General linear models assessed gene—environment interactions on AOO, non-motor, and motor scores. Results Fifty-two PwP (10.3%) carried pathogenic GBA1 variants. OcP exposure was more common in carriers than non-carriers (36% vs. 22%; adjusted OR 1.98, 95%CI: 1.07–3.67, p = 0.031). No other risk factor differed between groups. Smoking independently delayed AOO, but there were no significant GBA1 × risk/lifestyle factor interactions for AOO or for motor/non-motor scores. Head trauma, coffee, tea, and OcP exposure showed neither main nor interaction effects on severity indices. Conclusion OcP exposure is reported more often by individuals carrying pathogenic GBA1 variants, supporting a gene—environment “dual-hit” model. However, OcPs did not modify AOO or disease severity once PD was manifest.