GBA1 variants and mortality in Parkinson's disease: A systematic review and meta-analysis

Background Variants in the GBA1 gene are a common genetic risk factor for Parkinson's disease (PD). While GBA1 -PD is associated with more rapid motor and cognitive decline, evidence regarding impact on survival remains debatable. Objectives This systematic review and meta-analysis synthesizes longitudinal evidence of GBA1 variants as a prognostic factor for all-cause mortality in PD. Methods We searched MEDLINE, Embase, Cochrane (CENTRAL), ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for studies comparing mortality in GBA1 -PD versus non-carriers from inception to September 2025. Risk of bias was assessed using the Quality in Prognosis Studies tool. Hazard Ratios were pooled using a random-effects meta-analysis. Subgroup analysis was stratified by variant severity. Results Eight studies ( N = 13,690) were included. The primary meta-analysis ( n = 4947) revealed GBA1 variants were associated with significantly increased all-cause mortality risk versus non-carriers (HR 1.53, 95% CI 1.24–1.87; I 2 = 0.7%). A subgroup analysis suggested a possible severity-dependent effect, with severe variants showing higher point estimates (HR 1.87; 95% CI 1.24–2.82) than mild variants (HR 1.38; 95% CI 1.03–1.83), although the test for subgroup differences was not statistically significant. Conclusions GBA1 variants are a significant prognostic marker for reduced survival in PD. This risk may increase with variant severity and persist after adjustment for dementia in the studies that examined this, although the available data is limited. Limitations include heterogeneous screening methods and predominance of European ancestry in study populations. GBA1 status should be considered a significant prognostic factor for stratification in clinical trials and management.