Accurate long-read sequencing identified GBA variants as a major genetic risk factor in the Luxembourg Parkinson extquoterights study 2023.03.29.23287880

Heterozygous variants in the glucocerebrosidase GBA gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the pseudogene GBAP1 that shares 96% sequence homology with the GBA coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA-related PD. We established a novel long-read sequencing technology for assessing the full length of the GBA gene. We used subsequent regression models for genotype-phenotype analyses. We sequenced 752 patients with parkinsonism and 806... Mehr ...

Verfasser: Peiris, Sinthuja
Landoulsi, Zied
Pavelka, Lukas
Schulte, Claudia
Buena-Atienza, Elena
Gross, Caspar
Hauser, Ann-Kathrin
Bobbili, Dheeraj Reddy
Casadei, Nicolas
May, Patrick
Krüger, Rejko
Consortium, The NCER-PD
Dokumenttyp: working paper
Erscheinungsdatum: 2023
Verlag/Hrsg.: Cold Spring Harbor Laboratory Press
Schlagwörter: GBA / Parkinson's disease / Long-read sequencing / Case-control cohort / Life sciences / Genetics & genetic processes / Human health sciences / Neurology / Sciences du vivant / Génétique & processus génétiques / Sciences de la santé humaine / Neurologie
Sprache: Englisch
Permalink: https://search.fid-benelux.de/Record/base-26745391
Datenquelle: BASE; Originalkatalog
Powered By: BASE
Link(s) : https://orbilu.uni.lu/handle/10993/55244

Heterozygous variants in the glucocerebrosidase GBA gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the pseudogene GBAP1 that shares 96% sequence homology with the GBA coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA-related PD. We established a novel long-read sequencing technology for assessing the full length of the GBA gene. We used subsequent regression models for genotype-phenotype analyses. We sequenced 752 patients with parkinsonism and 806 healthy controls of the Luxembourg Parkinson's study. All GBA variants identified showed a 100% true positive rate by Sanger validation. We found 12% of unrelated PD patients carrying GBA variants. Three novel variants of unknown significance (VUS) were identified. Using a structure-based approach, we defined a potential risk prediction method for VUS. This study describes the full landscape of GBA-related parkinsonism in Luxembourg, showing a high prevalence of GBA variants as the major genetic risk for PD. Our approach provides an important advancement for highly accurate GBA variant calling, which is essential for providing access to emerging causative therapies for GBA carriers. ; NCER-PD