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.

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]

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

L. Straniero
Primo
;
V. Rimoldi
Secondo
;
E. Monfrini;M. Aureli;S. Duga
Penultimo
;
R. Asselta
Ultimo
2022

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.
Parkinson's disease; GBA; lysosomal genes; mutation burden;
Settore MED/26 - Neurologia
Settore BIO/10 - Biochimica
   Molecular and cellular mechanism modulating GBA mutation penetrance in Parkinson’s disease
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   2017228L3J_002
giu-2022
9-mar-2022
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1016509
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