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

Abstract

AbstractHeterozygous variants in the glucocerebrosidaseGBAgene are an increasingly recognized risk factor for Parkinson’s disease (PD). Due to the pseudogeneGBAP1that shares 96% sequence homology with theGBAcoding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape ofGBA-related PD. We established a novel long-read sequencing technology for assessing the full length of theGBAgene. 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. AllGBAvariants identified showed a 100% true positive rate by Sanger validation. We found 12% of unrelated PD patients carryingGBAvariants. 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 ofGBA-related parkinsonism in Luxembourg, showing a high prevalence ofGBAvariants as the major genetic risk for PD. Our approach provides an important advancement for highly accurateGBAvariant calling, which is essential for providing access to emerging causative therapies forGBAcarriers.