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

Abstract

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.

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

“…The variable penetrance and phenotypic heterogeneity of PD and LBD patients with GBA mutations is attracting a lot of attention, with lysosomal gene variants acting as genetic modifiers 30 . An effect of common intronic haplotypes was suggested 31 , but not seen by us in the AMP-PD cohort and part of the RAPSODI cohort used here 32 . A possible influence of CNGs has not yet been investigated.…”

“…We only called SNV in GBA coding exons and ten flanking bases. Intronic haplotypes for some of these samples with no coding mutations were recently reported separately 32 . Phasing of SNV was carried out with Whatshap (version 1.0) 45 and data manipulation with Samtools (version 1.10) 46 , Bedtools (version 2.29.1) 47 and Tabix (version 1.7-2).…”