Phenotypic effect of GBA1 variants in individuals with and without Parkinson's disease: The RAPSODI study.

BACKGROUND: Variants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype. The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes. OBJECTIVES: To compare the motor and non-motor phenotype of GBA1 carriers and non-carriers. METHODS: We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included. RESULTS: A total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1-positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1-negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups. CONCLUSIONS: Our results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.

Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson's disease-associated GBA gene.

GBA variants carriers are at increased risk of Parkinson's disease (PD) and Lewy body dementia (LBD). The presence of pseudogene GBAP1 predisposes to structural variants, complicating genetic analysis. We present two methods to resolve recombinant alleles and other variants in GBA: Gauchian, a tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore sequencing after PCR enrichment. Both methods were concordant for 42 samples carrying a range of recombinants and GBAP1-related mutations, and Gauchian outperformed the GATK Best Practices pipeline. Applying Gauchian to sequencing of over 10,000 individuals shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls. Gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects more GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA analysis in these patients.

The remote assessment of parkinsonism supporting the ongoing development of interventions in Gaucher disease.

Mutations in GBA which are causative of Gaucher disease in their biallelic form, are the most common genetic risk factor for Parkinson's disease (PD). The diagnosis of PD relies upon clinically defined motor features which appear after irreversible neurodegeneration. Prodromal symptoms of PD may provide a means to predict latent pathology, years before the onset of motor features. Previous work has reported prodromal features of PD in GBA mutation carriers, however this has been insufficiently sensitive to identify those that will develop PD. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI GD) study assesses a large cohort of GBA mutation carriers, to aid development of procedures for earlier diagnosis of PD.

Lay abstract Changes in a gene called GBA cause a rare condition called Gaucher disease and are the most common genetic risk factor for Parkinson's disease (PD). To diagnose PD, patients must show symptoms of disordered movement which only occur after irreversible brain cell loss. Earlier symptoms may allow for the prediction of PD, years before movement symptoms occur. Previous work has reported earlier symptoms of PD occurring in people with GBA changes, however these studies have not been able to identify those at risk of developing PD. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI GD) study assesses a large group of people with GBA changes, to help develop a way to diagnose PD earlier.

Intronic Haplotypes in the GBA Gene Do Not Predict Age at Diagnosis of Parkinson's Disease.

BACKGROUND: GBA mutations are a common risk factor for Parkinson's disease (PD). A recent study has suggested that GBA haplotypes, identified by intronic variants, can affect age at diagnosis of PD. OBJECTIVES: In this study, we assess this hypothesis using long reads across a large cohort and the publicly available Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) cohort. METHODS: We recruited a PD cohort through the Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease study (RAPSODI) and sequenced GBA using Oxford Nanopore technology. Genetic and clinical data on the full AMP-PD cohort were obtained from the online portal of the consortium. RESULTS: A total of 1417 participants were analyzed. There was no significant difference in age at PD diagnosis between the two main haplotypes of the GBA gene. CONCLUSIONS: GBA haplotypes do not affect age at diagnosis of PD in the two independent cohorts studied. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.