Association between heterozygous GBA1 L444P carrier status and risk of Parkinson's disease: A systematic review and meta-analysis
Abstract
Introduction and objective: Mutations in the GBA1 gene, particularly the severe L444P variant, are among the strongest known genetic risk factors for Parkinson's disease (PD). Prior meta-analyses published before 2018 included fewer studies and often pooled multiple mutations, prompting this updated, mutation-specific systematic review and meta-analysis.
Methods: Standard systematic review and meta-analytic methods were used, including predefined eligibility criteria, literature search, and pooled analysis of odds ratios (ORs) for PD in GBA1 L444P carriers versus non-carriers.
Results: We included 51 studies comprising 33,752 PD patients and 34,101 controls across multiple continents. In random-effects meta-analysis, heterozygous GBA1 L444P carriers had markedly higher odds of PD than non-carriers (pooled OR 9.19, 95% CI 6.94-12.16), with similar estimates across sensitivity and leave-one-out analyses. Cumulative meta-analysis showed early variability but stable pooled ORs around 7-9 from 2008 to 2010 onward. Ancestry-specific pooled ORs were consistently elevated across populations, with overlapping confidence intervals and no significant subgroup differences. Funnel and Galbraith plots and Egger's test showed no evidence of substantial small-study effects or publication bias.
Conclusions: This updated synthesis demonstrates that heterozygous GBA1 L444P carriage confers a consistently large increase in PD risk across populations, with robust pooled estimates across multiple…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 33,752 participants or records.
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