Journal of molecular neuroscience : MNOct 22, 2026

GBA1 gene variant rs12411216 linked to movement and non-movement problems and worse progression in Parkinson's disease over five years

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 23, 2026

Abstract

In a five-year observational study of 518 Parkinson's disease patients, the GBA1-related variant rs12411216 was associated with earlier disease onset and more severe clinical symptoms.

The rs356182 (SNCA) variant showed a modest association with anxiety as measured by the HAMILTON scale.
Patients with the rs12411216 AA genotype experienced a more severe progression of motor symptoms and neuropsychiatric issues.
The GBA1 variant rs12411216 is associated with a broad range of non-motor impairments, including anxiety, depression, and cognitive deficits.
Longitudinal analysis indicated that those homozygous for the rs12411216 variant exhibited a faster neurocognitive decline.
Distinct effects of the GBA1 variant may contribute to the clinical variability observed in Parkinson's disease.

Simplified

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.

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GBA1 gene variant rs12411216 linked to movement and non-movement problems and worse progression in Parkinson's disease over five years

Abstract

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