Journal Article

DZNE-2023-01093

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson's study.

Pachchek, S. ; Landoulsi, Z. ; Pavelka, L. ; Schulte, C.DZNE* ; Buena-Atienza, E. ; Gross, C. ; Hauser, A.-K.DZNE* ; Reddy Bobbili, D. ; Casadei, N. ; May, P. ; Krüger, R.Extern* ; Consortium, N.-P. (Collaboration Author) ; Acharya, G. (Contributor) ; Aguayo, G. (Contributor) ; Alexandre, M. (Contributor) ; Ali, M. (Contributor) ; Ammerlann, W. (Contributor) ; Arena, G. (Contributor) ; Balling, R. (Contributor) ; Bassis, M. (Contributor) ; Batutu, R. (Contributor) ; Beaumont, K. (Contributor) ; Becker, R. (Contributor) ; Bellora, C. (Contributor) ; Berchem, G. (Contributor) ; Berg, D. (Contributor) ; Bisdorff, A. (Contributor) ; Boussaad, I. (Contributor) ; Bouvier, D. (Contributor) ; Brockmann, K. (Contributor) ; Calmes, J. (Contributor) ; Castillo, L. (Contributor) ; Contesotto, G. (Contributor) ; De Bremaeker, N. (Contributor) ; Diederich, N. (Contributor) ; Dondelinger, R. (Contributor) ; E Ramia, N. (Contributor) ; Esteves, D. (Contributor) ; Fagherazzi, G. (Contributor) ; Ferrand, J.-Y. (Contributor) ; Frauenknecht, K. (Contributor) ; Gantenbein, M. (Contributor) ; Gasser, T. (Contributor) ; Gawron, P. (Contributor) ; Ghosh, S. (Contributor) ; Giraitis, M. (Contributor) ; Glaab, E. (Contributor) ; Goergen, M. (Contributor) ; Gómez De Lope, E. (Contributor) ; Graas, J. (Contributor) ; Graziano, M. (Contributor) ; Groues, V. (Contributor) ; Grünewald, A. (Contributor) ; Gu, W. (Contributor) ; Hammot, G. (Contributor) ; Hanff, A.-M. (Contributor) ; Hansen, L. (Contributor) ; Heneka, M. (Contributor) ; Henry, E. (Contributor) ; Herbrink, S. (Contributor) ; Herzinger, S. (Contributor) ; Heymann, M. (Contributor) ; Hu, M. (Contributor) ; Hundt, A. (Contributor) ; Jacoby, N. (Contributor) ; Jaroslaw Lebioda, J. (Contributor) ; Jarosz, Y. (Contributor) ; Jónsdóttir, S. (Contributor) ; Klopfenstein, Q. (Contributor) ; Klucken, J. (Contributor) ; Krüger, R. (Contributor) ; Lambert, P. (Contributor) ; Lentz, R. (Contributor) ; Liepelt, I. (Contributor) ; Liszka, R. (Contributor) ; Longhino, L. (Contributor) ; Lorentz, V. (Contributor) ; Lupu, P. C. (Contributor) ; Marques, T. M. (Contributor) ; Mackay, C. (Contributor) ; Maetzler, W. (Contributor) ; Marcus, K. (Contributor) ; Marques, G. (Contributor) ; Martins Conde, P. (Contributor) ; Mcintyre, D. (Contributor) ; Mediouni, C. (Contributor) ; Meisch, F. (Contributor) ; Menster, M. (Contributor) ; Minelli, M. (Contributor) ; Mittelbronn, M. (Contributor) ; Mollenhauer, B. (Contributor) ; Mühlschlegel, F. (Contributor) ; Nati, R. (Contributor) ; Nehrbass, U. (Contributor) ; Nickels, S. (Contributor) ; Nicolai, B. (Contributor) ; Nicolay, J.-P. (Contributor) ; Noor, F. (Contributor) ; Ostaszewski, M. (Contributor) ; P C Gomes, C. (Contributor) ; Pauly, C. (Contributor) ; Pauly, L. (Contributor) ; Pavelka, L. (Contributor) ; Perquin, M. (Contributor) ; Ramos Lima, R. (Contributor) ; Rauschenberger, A. (Contributor) ; Rawal, R. (Contributor) ; Roomp, K. (Contributor) ; Rosales, E. (Contributor) ; Rosety, I. (Contributor) ; Sandt, E. (Contributor) ; Sapienza, S. (Contributor) ; Satagopam, V. (Contributor) ; Schmitt, M. (Contributor) ; Schmitz, S. (Contributor) ; Schneider, R. (Contributor) ; Schwamborn, J. (Contributor) ; Severino, R. (Contributor) ; Sharify, A. (Contributor) ; Soboleva, E. (Contributor) ; Sokolowska, K. (Contributor) ; Thien, H. (Contributor) ; Thiry, E. (Contributor) ; Ting Jiin Loo, R. (Contributor) ; Trefois, C. (Contributor) ; Trouet, J. (Contributor) ; Tsurkalenko, O. (Contributor) ; Vaillant, M. (Contributor) ; Valenti, M. (Contributor) ; Van Cutsem, G. (Contributor) ; Vega, C. (Contributor) ; Vilas Boas, L. (Contributor) ; Vyas, M. (Contributor) ; Wade-Martins, R. (Contributor) ; Wilmes, P. (Contributor) ; Wollscheid-Lengeling, E. (Contributor) ; Zelimkhanov, G. (Contributor)

2023
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41531-023-00595-w

Abstract: Heterozygous variants in the glucocerebrosidase GBA1 gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the GBAP1 pseudogene, which shares 96% sequence homology with the GBA1 coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA1-associated PD. We analyzed 660 patients with PD, 100 patients with Parkinsonism and 808 healthy controls from the Luxembourg Parkinson's study, sequenced using amplicon-based long-read DNA sequencing technology. We found that 12.1% (77/637) of PD patients carried GBA1 variants, with 10.5% (67/637) of them carrying known pathogenic variants (including severe, mild, risk variants). In comparison, 5% (34/675) of the healthy controls carried GBA1 variants, and among them, 4.3% (29/675) were identified as pathogenic variant carriers. We found four GBA1 variants in patients with atypical parkinsonism. Pathogenic GBA1 variants were 2.6-fold more frequently observed in PD patients compared to controls (OR = 2.6; CI = [1.6,4.1]). 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 GBA1-related parkinsonism in Luxembourg, showing a high prevalence of GBA1 variants as the major genetic risk for PD. Although the long-read DNA sequencing technique used in our study may be limited in its effectiveness to detect potential structural variants, our approach provides an important advancement for highly accurate GBA1 variant calling, which is essential for providing access to emerging causative therapies for GBA1 carriers.

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Core ICRU (Core ICRU)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Pachchek, S. ; Landoulsi, Z. ; Pavelka, L. ; et al
Author Correction: Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson's study.
npj Parkinson's Disease 9(1), 168 (2023) [10.1038/s41531-023-00613-x]2023   Files  Fulltext by Pubmed Central BibTeX | EndNote: XML, Text | RIS

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