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

• Published in: Communications biology Vol. 5; no. 1; p. 670
• Main Authors: Toffoli, Marco, Chen, Xiao, Sedlazeck, Fritz J., Lee, Chiao-Yin, Mullin, Stephen, Higgins, Abigail, Koletsi, Sofia, Garcia-Segura, Monica Emili, Sammler, Esther, Scholz, Sonja W., Schapira, Anthony H. V., Eberle, Michael A., Proukakis, Christos
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06-07-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 631/208/2489/144; 692/617/375/346/1718; Biology; Biomedical and Life Sciences; Copy number; Data analysis; Dementia disorders; Gaucher's disease; Genetic analysis; Genomes; Glucosylceramidase; Lewy bodies; Life Sciences; Movement disorders; Mutation; Neurodegenerative diseases; Parkinson's disease; Recombinants; Whole genome sequencing
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03610-7

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.
Two methods fully resolve the GBA gene: Gauchian, a tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore sequencing after PCR enrichment. The approach improves our understanding of the relationship between GBA, Gaucher disease and Parkinson disease.