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

TY - JOUR

T1 - Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson's disease-associated GBA gene

AU - Toffoli, Marco

AU - Chen, Xiao

AU - Sedlazeck, Fritz J.

AU - Lee, Chiao-Yin

AU - Mullin, Stephen

AU - Higgins, Abigail

AU - Koletsi, Sofia

AU - Garcia-Segura, Monica Emili

AU - Sammler, Esther

AU - Scholz, Sonja W.

AU - Schapira, Anthony H. V.

AU - Eberle, Michael A.

AU - Proukakis, Christos

N1 - © 2022. The Author(s).

PY - 2022/7/6

Y1 - 2022/7/6

N2 - 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.

AB - 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.

KW - Alleles

KW - Glucosylceramidase/genetics

KW - Heterozygote

KW - Humans

KW - Lewy Body Disease/genetics

KW - Parkinson Disease/genetics

UR - https://www.scopus.com/pages/publications/85133623215

U2 - 10.1038/s42003-022-03610-7

DO - 10.1038/s42003-022-03610-7

M3 - Article

C2 - 35794204

SN - 2399-3642

VL - 5

JO - Communications Biology

JF - Communications Biology

M1 - 670

ER -