Genetic landscape of Parkinson’s disease and related diseases in Luxembourg

[en] Objectives: To explore the genetic architecture of PD in the Luxembourg Parkinson’s Study including cohorts of healthy people and patients with Parkinson’s disease (PD) and atypical parkinsonism (AP).Methods: 809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened and validated rare single nucleotide variants (SNVs) and copy number variants (CNVs) within seven PD-causing genes (LRRK2, SNCA, VPS35, PRKN, PARK7, PINK1 and ATP13A2). Polygenic risk scores (PRSs) were generated using the latest genome-wide association study for PD. We then estimated the role of common variants in PD risk by applying gene-set-specific PRSs.Results: We identified 60 rare SNVs in seven PD-causing genes, nine of which were pathogenic in LRRK2, PINK1 and PRKN. Eleven rare CNVs were detected in PRKN including seven duplications and four deletions. The majority of PRKN SNVs and CNVs carriers were heterozygous and not differentially distributed between cases and controls. The PRSs were significantly associated with PD and identified specific molecular pathways related to protein metabolism and signal transduction as drivers of PD risk.Conclusion: We performed a comprehensive genetic characterization of the deep-phenotyped individuals of the Luxembourgish Parkinson’s Study. Heterozygous SNVs and CNVs in PRKN were not associated with higher PD risk. In particular, we reported novel digenic variants in PD related genes and rare LRRK2 SNVs in AP patients. Our findings will help future studies to unravel the genetic complexity of PD.

Centre de recherche :

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
LIH - Luxembourg Institute of Health
ULHPC - University of Luxembourg: High Performance Computing

Disciplines :

Génétique & processus génétiques
Neurologie

Auteur, co-auteur :

LANDOULSI, Zied ^✱; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core

PACHCHEK, Sinthuja ^✱; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience

BOBBILI, Dheeraj Reddy ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core

PAVELKA, Lukas ; University of Luxembourg

MAY, Patrick ^✱; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core

KRÜGER, Rejko ^✱; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Centre Hospitalier de Luxembourg (CHL) > Parkinson Research Clinic ; Luxembourg Institute of Health (LIH) > Transversal Translational Medicine

NCER-PD consortium

^✱ Ces auteurs ont contribué de façon équivalente à la publication.

Co-auteurs externes :

Langue du document :

Anglais

Titre :

Genetic landscape of Parkinson’s disease and related diseases in Luxembourg

Date de publication/diffusion :

20 décembre 2023

Titre du périodique :

Frontiers in Aging Neuroscience

eISSN :

1663-4365

Maison d'édition :

Frontiers Media SA

Volume/Tome :

Peer reviewed :

Peer reviewed vérifié par ORBi

Focus Area :

Systems Biomedicine

Objectif de développement durable (ODD) :

3. Bonne santé et bien-être

URL complémentaire :

https://www.frontiersin.org/articles/10.3389/fnagi.2023.1282174/full

Projet FnR :

FNR11264123 - Ncer-pd, 2015 (01/01/2015-30/11/2020) - Rejko Krüger

Organisme subsidiant :

FNR - Fonds National de la Recherche

N° du Fonds :

FNR/P13/6682797; C17/BM/11676395; FNR11250962; PRIDE17/12244779/PARK-QC

Subventionnement (détails) :

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123), the PEARL program (FNR/P13/6682797 to RK), MotaSYN (12719684 to RK), MAMaSyn (to RK), MiRisk-PD (C17/BM/11676395 to RK and PM), the FNR/DFG Core INTER (ProtectMove, FNR11250962 to PM and ZL), and the PARK-QC DTU (PRIDE17/12244779/PARK-QC to RK and SP).

Commentaire :

NCER-PD consortium member Geeta Acharya, Gloria Aguayo, Myriam Alexandre, Wim Ammerlann, Katy Beaumont, Camille Bellora, Jessica Calmes, Lorieza Castillo, Gessica Contesotto, Daniela Esteves, Guy Fagherazzi, Jean-Yves Ferrand, Manon Gantenbein, Marijus Giraitis, Jérôme Graas, Gaël Hammot, Anne-Marie Hanff, Estelle Henry, Michael Heymann, Alexander Hundt, Sonja Jónsdóttir, Jochen Klucken, Rejko Krüger, Pauline Lambert, Victoria Lorentz, Paula Cristina Lupu, Guilherme Marques, Deborah Mcintyre, Chouaib Mediouni, Myriam Menster, Maura Minelli, Ulf Nehrbass, Fozia Noor, Magali Perquin, Rosalina Ramos Lima, Eduardo Rosales, Estelle Sandt, Margaux Schmitt, Amir Sharify, Kate Sokolowska, Hermann Thien, Johanna Trouet, Olena Tsurkalenko, Michel Vaillant, Mesele Valenti, Luxembourg Institute of Health, Strassen, Luxembourg; Muhammad Ali, Giuseppe Arena, Rudi Balling, Michele Bassis, Regina Becker, Ibrahim Boussaad, Kathrin Brockmann, Piotr Gawron, Soumyabrata Ghosh, Enrico Glaab, Elisa Gómez De Lope, Valentin Groues, Anne Grünewald, Wei Gu, Linda Hansen, Michael Heneka, Sascha Herzinger, Jacek Jaroslaw Lebioda, Yohan Jaroz, Quentin Klopfenstein, Jochen Klucken, Rejko Krüger, Zied Landoulsi, Tainá M. Marques, Patricia Martins Conde, Patrick May, Francoise Meisch, Michel Mittelbronn, Michel Mittelbronn, Sarah Nickels, Marek Ostaszewski, Clarissa P. C. Gomes, Sinthuja Pachchek, Claire Pauly, Laure Pauly, Lukas Pavelka, Armin Rauschenberger, Rajesh Rawal, Dheeraj Reddy Bobbili, Kirsten Roomp, Isabel Rosety, Stefano Sapienza, Venkata Satagopam, Sabine Schmitz, Reinhard Schneider, Jens Schwamborn, Ekaterina Soboleva, Rebecca Ting Jiin Loo, Christophe Trefois, Carlos Vega, Maharshi Vyas, Paul Wilmes, Evi Wollscheid-Lengeling, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg; Guy Berchem, Nico Diederich, Marijus Giraitis, Linda Hansen, Jochen Klucken, Rejko Krüger, Laura Longhino, Romain Nati, Beatrice Nicolai, Claire Pauly, Lukas Pavelka, Elodie Thiry, Liliana Vilas Boas, Gelani Zelimkhanov, Centre Hospitalier de Luxembourg, Strassen, Luxembourg; Michel Mittelbronn, Friedrich Mühlschlegel, Laboratoire National de Santé, Dudelange, Luxembourg; Alexandre Bisdorff, Rene Dondelinger, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg; Sylvia Herbrink, Centre Hospitalier du Nord, Ettelbrück, Luxembourg; Roseline Lentz, Parkinson Luxembourg Association, Leudelange, Luxembourg; Michele Hu, Oxford Parkinson’s Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom; Richard Wade-Martins, Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; Clare Mackay, Oxford Centre for Human Brain Activity, Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Oxford, United Kingdom; Daniela Berg, Kathrin Brockmann, Thomas Gasser, Inga Liepelt, Center of Neurology and Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University Hospital Tübingen, Tübingen, Germany; Brit Mollenhauer, Paracelsus-Elena-Klinik, Kassel, Germany; Katrin Marcus, Ruhr-University of Bochum, Bochum, Germany; Robert Liszka, Westpfalz-Klinikum GmbH, Kaiserslautern, Germany; Walter Maetzler, Department of Neurology, University Medical Center Schleswig-Holstein, Kiel, Germany; Mariella Graziano, Association of Physiotherapists in Parkinson’s Disease Europe, Esch-sur-Alzette, Luxembourg; Nadine Jacoby, Private Practice, Ettelbruck, Luxembourg; Jean-Paul Nicolay, Private Practice, Luxembourg, Luxembourg.

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