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Background  To date, variants in the  GBA  gene represent the most frequent large‐effect genetic factor associated with Parkinson's disease (PD). However, the reason why individuals with the same  GBA  variant may or may not develop neurodegeneration and PD is still unclear.    Objectives  Therefore, we evaluated the contribution of rare variants in genes responsible for lysosomal storage disorders (LSDs) to  GBA ‐PD risk, comparing the burden of deleterious variants in LSD genes in PD patients versus asymptomatic subjects, all carriers of deleterious variants in  GBA .    Methods  We used a custom next‐generation sequencing panel, including 50 LSD genes, to screen 305 patients and 207 controls (discovery cohort). Replication and meta‐analysis were performed in two replication cohorts of  GBA ‐variant carriers, of 250 patients and 287 controls, for whom exome or genome data were available.    Results  Statistical analysis in the discovery cohort revealed a significantly increased burden of deleterious variants in LSD genes in patients ( P  = 0.0029). Moreover, our analyses evidenced that the two strongest modifiers of  GBA  penetrance are a second variation in  GBA  (5.6% vs. 1.4%,  P  = 0.023) and variants in genes causing mucopolysaccharidoses (6.9% vs. 1%,  P  = 0.0020). These results were confirmed in the meta‐analysis, where we observed pooled odds ratios of 1.42 (95% confidence interval [CI] = 1.10–1.83,  P  = 0.0063), 4.36 (95% CI = 2.02–9.45,  P  = 0.00019), and 1.83 (95% CI = 1.04–3.22,  P  = 0.038) for variants in LSD genes,  GBA , and mucopolysaccharidosis genes, respectively.    Conclusion  The identification of genetic lesions in lysosomal genes increasing PD risk may have important implications in terms of patient stratification for future therapeutic trials. © 2022 The Authors.  Movement Disorders  published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Role of Lysosomal Gene Variants in Modulating GBA ‐Associated Parkinson's Disease Risk