Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson’s study
Authors: Pachchek Sinthuja , Landoulsi Zied , Pavelka Lukas , Schulte Claudia , Buena-Atienza Elena , Gross Caspar , Hauser Ann-Kathrin , Reddy Bobbili Dheeraj , Casadei Nicolas , May Patrick , Krüger Rejko ,   on behalf of the NCER-PD Consortium, Acharya Geeta , Aguayo Gloria , Alexandre Myriam , Ali Muhammad , Ammerlann Wim , Arena Giuseppe , Balling Rudi , Bassis Michele , Batutu Roxane , Beaumont Katy , Becker Regina , Bellora Camille , Berchem Guy , Berg Daniela , Bisdorff Alexandre , Boussaad Ibrahim , Bouvier David , Brockmann Kathrin , Calmes Jessica , Castillo Lorieza , Contesotto Gessica , De Bremaeker Nancy , Diederich Nico , Dondelinger Rene , E. Ramia Nancy , Esteves Daniela , Fagherazzi Guy , Ferrand Jean-Yves , Frauenknecht Katrin , Gantenbein Manon , Gasser Thomas , Gawron Piotr , Ghosh Soumyabrata , Giraitis Marijus , Glaab Enrico , Goergen Martine , Gómez De Lope Elisa , Graas Jérôme , Graziano Mariella , Groues Valentin , Grünewald Anne , Gu Wei , Hammot Gaël , Hanff Anne-Marie , Hansen Linda , Heneka Michael , Henry Estelle , Herbrink Sylvia , Herzinger Sascha , Heymann Michael , Hu Michele , Hundt Alexander , Jacoby Nadine , Jaroslaw Lebioda Jacek , Jarosz Yohan , Jónsdóttir Sonja , Klopfenstein Quentin , Klucken Jochen , Krüger Rejko , Lambert Pauline , Lentz Roseline , Liepelt Inga , Liszka Robert , Longhino Laura , Lorentz Victoria , Lupu Paula Cristina , Marques Tainá M. , Mackay Clare , Maetzler Walter , Marcus Katrin , Marques Guilherme , Martins Conde Patricia , Mcintyre Deborah , Mediouni Chouaib , Meisch Francoise , Menster Myriam , Minelli Maura , Mittelbronn Michel , Mollenhauer Brit , Mühlschlegel Friedrich , Nati Romain , Nehrbass Ulf , Nickels Sarah , Nicolai Beatrice , Nicolay Jean-Paul , Noor Fozia , Ostaszewski Marek , P. C. Gomes Clarissa , Pauly Claire , Pauly Laure , Pavelka Lukas , Perquin Magali , Ramos Lima Rosalina , Rauschenberger Armin , Rawal Rajesh , Roomp Kirsten , Rosales Eduardo , Rosety Isabel , Sandt Estelle , Sapienza Stefano , Satagopam Venkata , Schmitt Margaux , Schmitz Sabine , Schneider Reinhard , Schwamborn Jens , Severino Raquel , Sharify Amir , Soboleva Ekaterina , Sokolowska Kate , Thien Hermann , Thiry Elodie , Ting Jiin Loo Rebecca , Trefois Christophe , Trouet Johanna , Tsurkalenko Olena , Vaillant Michel , Valenti Mesele , Van Cutsem Gilles , Vega Carlos , Vilas Boas Liliana , Vyas Maharshi , Wade-Martins Richard , Wilmes Paul , Wollscheid-Lengeling Evi , Zelimkhanov Gelani 
Published: November 2023

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.