This systematic review and meta-analysis of 51 studies reports that heterozygous GBA1 L444P carriers have a markedly increased risk of Parkinson's disease (pooled OR ~9.2) across ancestral groups.

By providing robust, mutation-specific evidence that L444P is a high-penetrance PD risk variant, the study strengthens justification for GBA1/GCase- and lysosomal-targeted therapies, informs patient stratification and trial enrichment, and highlights gaps in diverse genetic data.

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 sensitivity analyses. Although overall statistical heterogeneity was negligible, wide confidence intervals in several ancestry subgroups highlight imprecision due to sparse data and internal heterogeneity, underscoring the need for broader and more equitable genetic testing, improved risk estimation in underrepresented populations, and targeted research on severe GBA1 variants to inform genetic counseling and PD risk discussions. REGISTRATION: PROSPERO Registration Number: CRD420251182022. Registration details available at the PROSPERO database.