GBA1 in Parkinson’s disease: variant detection and pathogenicity scoring matters

• Published in: BMC genomics Vol. 24; no. 1; pp. 322 - 8
• Main Authors: Gabbert, Carolin, Schaake, Susen, Lüth, Theresa, Much, Christoph, Klein, Christine, Aasly, Jan O., Farrer, Matthew J., Trinh, Joanne
• Format: Journal Article
• Language: English
• Published: London BioMed Central 13.06.2023; BioMed Central Ltd; BMC
• Subjects: Animal Genetics and Genomics; Annotations; Biomedical and Life Sciences; Comparative analysis; Development and progression; DNA sequencing; GBA; Genetic aspects; Genetic variation; Genomics; Health risk assessment; Life Sciences; Literature reviews; Medical research; Medicine, Experimental; Microarrays; Microbial Genetics and Genomics; Movement disorders; Nanopore sequencing; Neurodegenerative diseases; Neurological research; Nucleotide sequencing; Parkinson's disease; Pathogenicity; Pathogens; Plant Genetics and Genomics; Proteomics; Risk factor; Risk factors; Variants; Norway; United Kingdom; Variants; Nanopore sequencing; Parkinson’s disease; Risk factor; GBA
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-023-09417-y

Background GBA1 variants are the strongest genetic risk factor for Parkinson’s disease (PD). However, the pathogenicity of GBA1 variants concerning PD is still not fully understood. Additionally, the frequency of GBA1 variants varies widely across populations. Objectives To evaluate Oxford Nanopore sequencing as a strategy, to determine the frequency of GBA1 variants in Norwegian PD patients and controls, and to review the current literature on newly identified variants that add to pathogenicity determination. Methods We included 462 Norwegian PD patients and 367 healthy controls. We sequenced the full-length GBA1 gene on the Oxford Nanopore GridION as an 8.9 kb amplicon. Six analysis pipelines were compared using two aligners (NGMLR, Minimap2) and three variant callers (BCFtools, Clair3, Pepper-Margin-Deepvariant). Confirmation of GBA1 variants was performed by Sanger sequencing and the pathogenicity of variants was evaluated. Results We found 95.8% (115/120) true-positive GBA1 variant calls, while 4.2% (5/120) variant calls were false-positive, with the NGMLR/Minimap2-BCFtools pipeline performing best. In total, 13 rare GBA1 variants were detected: two were predicted to be (likely) pathogenic and eleven were of uncertain significance. The odds of carrying one of the two common GBA1 variants, p.L483P or p.N409S, in PD patients were estimated to be 4.11 times the odds of carrying one of these variants in controls (OR = 4.11 [1.39, 12.12]). Conclusions In conclusion, we have demonstrated that Oxford long-read Nanopore sequencing, along with the NGMLR/Minimap2-BCFtools pipeline is an effective tool to investigate GBA1 variants. Further studies on the pathogenicity of GBA1 variants are needed to assess their effect on PD.