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Browsing by Author "Pezzoli, Gianni"
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Item Genomewide association study for onset age in Parkinson disease(BioMed Central, 2009-09-22) Latourelle, Jeanne C.; Pankratz, Nathan; Dumitriu, Alexandra; Wilk, Jemma B.; Goldwurm, Stefano; Pezzoli, Gianni; Mariani, Claudio B.; DeStefano, Anita L.; Halter, Cheryl; Gusella, James F.; Nichols, William C.; Myers, Richard H.; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineBackground Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age. Methods Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy. Results Meta-analysis across the three studies detected consistent association (p < 1 × 10-5) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 × 10-7) lies between the genes QSER1 and PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 × 10-6) which lies in an intron of the AAK1 gene. This gene is closely related to GAK, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases. Conclusion Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.Item Role of Lysosomal Gene Variants in Modulating GBA-Associated Parkinson's Disease Risk(Wiley, 2022) Straniero, Letizia; Rimoldi, Valeria; Monfrini, Edoardo; Bonvegna, Salvatore; Melistaccio, Giada; Lake, Julie; Soldà, Giulia; Aureli, Massimo; Shankaracharya; Keagle, Pamela; Foroud, Tatiana; Landers, John E.; Blauwendraat, Cornelis; Zecchinelli, Anna; Cilia, Roberto; Di Fonzo, Alessio; Pezzoli, Gianni; Duga, Stefano; Asselta, Rosanna; Medical and Molecular Genetics, School of MedicineBackground: 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.Item Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease(Springer Nature, 2024) Hop, Paul J.; Lai, Dongbing; Keagle, Pamela J.; Baron, Desiree M.; Kenna, Brendan J.; Kooyman, Maarten; Shankaracharya; Halter, Cheryl; Straniero, Letizia; Asselta, Rosanna; Bonvegna, Salvatore; Soto-Beasley, Alexandra I.; Project MinE ALS Sequencing Consortium; Wszolek, Zbigniew K.; Uitti, Ryan J.; Isaias, Ioannis Ugo; Pezzoli, Gianni; Ticozzi, Nicola; Ross, Owen A.; Veldink, Jan H.; Foroud, Tatiana M.; Kenna, Kevin P.; Landers, John E.; Medical and Molecular Genetics, School of MedicineDespite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified1,2. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32 encodes a small GTPase known to interact with LRRK2 (refs. 3,4). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as indicated by increased autophosphorylation of LRRK2 S1292. Here our results implicate mutant RAB32 in a key pathological mechanism in PD-LRRK2 kinase activity5-7-and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk.