Data di Pubblicazione:
2022
Citazione:
Role of Lysosomal Gene Variants in Modulating GBA-Associated Parkinson's Disease Risk / L. Straniero, V. Rimoldi, E. Monfrini, S. Bonvegna, G. Melistaccio, J. Lake, G. Solda, M. Aureli, Shankaracharya, P. Keagle, T. Foroud, J.E. Landers, C. Blauwendraat, A. Zecchinelli, R. Cilia, A. Di Fonzo, G. Pezzoli, S. Duga, R. Asselta. - In: MOVEMENT DISORDERS. - ISSN 0885-3185. - 37:6(2022 Jun), pp. 1202-1210. [10.1002/mds.28987]
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Parkinson's disease; GBA; lysosomal genes; mutation burden;
Elenco autori:
L. Straniero, V. Rimoldi, E. Monfrini, S. Bonvegna, G. Melistaccio, J. Lake, G. Solda, M. Aureli, Shankaracharya, P. Keagle, T. Foroud, J.E. Landers, C. Blauwendraat, A. Zecchinelli, R. Cilia, A. Di Fonzo, G. Pezzoli, S. Duga, R. Asselta
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