The GBA1-related variant rs12411216 is Associated with Motor and Non-Motor Impairments and Unfavorable Progression in Parkinson's Disease: A Five-Year Longitudinal Study.

We investigated four regulatory single-nucleotide polymorphisms (SNPs) related to genes previously implicated in the autophagy-lysosomal pathway (rs76904798 and rs6581622 (LRRK2), rs356182 (SNCA), and rs12411216 (GBA1)) in order to assess their association with the clinical heterogeneity of Parkinson's disease. In a five-year observational study, 518 patients stratified by genotype were analyzed for cognitive, neuropsychiatric, motor, and other clinical signs.The rs356182 (SNCA) variant showed a modest association with disease traits, including significant associations with anxiety (HAMILTON scale). Conversely, the regulatory GBA1-related variant rs12411216 demonstrated a robust pleiotropic association with earlier disease onset, more severe motor impairment, and a broad spectrum of non-motor impairments, including anxiety, depression, impulsive-compulsive behaviors, and cognitive deficits. Longitudinal analyses revealed that patients homozygous for the rs12411216 AA genotype exhibited the most unfavorable progression across multiple domains, suggesting a faster neurocognitive decline.These findings suggest that the distinct pleiotropic effects of the GBA1-related variant rs12411216 contribute significantly to the clinical heterogeneity of PD by shaping unfavorable motor and neuropsychiatric progression trajectories. While the longitudinal design provides new evidence for genotype-dependent patterns, further functional studies are needed to confirm the proposed mechanistic link.