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Preprint
Genome-wide association study of copy number variations in Parkinson's disease
medRxiv: the preprint server for health sciences
Cold Spring Harbor Laboratory
2024
PMCID: PMC11370542
PMID: 39228715
Abstract
Objective
Our study investigates the impact of copy number variations (CNVs) on Parkinson’s disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD.
Methods
We applied a sliding window approach to perform CNV-GWAS and conducted genome-wide burden analyses on CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium.
Results
We identified 14 genome-wide significant CNV loci associated with PD, including one deletion and 13 duplications. Among these, duplications in 7q22.1, 11q12.3 and 7q33 displayed the highest effect. Two significant duplications overlapped with PD-related genes SNCA and VPS13C, but none overlapped with recent significant SNP-based GWAS findings. Five duplications included genes associated with neurological disease, and four overlapping genes were dosage-sensitive and intolerant to loss-of-function variants. Enriched pathways included neurodegeneration, steroid hormone biosynthesis, and lipid metabolism. In early-onset cases, four loci were significantly associated with EOPD, including three known duplications and one novel deletion in PRKN. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results.
Interpretation
This is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden in EOPD, primarily driven by the PRKN gene, warranting further investigation.
Details
- Title
- Genome-wide association study of copy number variations in Parkinson's disease
- Authors/Creators
- Zied Landoulsi - Luxembourg Institute of HealthAshwin Ashok Kumar Sreelatha - University of TübingenClaudia Schulte - Hertie Institute for Clinical Brain ResearchDheeraj Reddy Bobbili - University of LuxembourgLudovica Montanucci - The University of Texas Health Science Center at HoustonCostin Leu - University College LondonLisa-Marie Niestroj - University of CologneEmadeldin Hassanin - ArbedCloé Domenighetti - InsermLukas Pavelka - Luxembourg Institute of HealthPierre-Emmanuel SugierMilena Radivojkov-BlagojevicPeter Lichtner - Helmholtz Zentrum MünchenBerta Portugal - Luxembourg Institute of HealthConnor Edsall - National Institutes of HealthJens Kruger - University of TübingenDena G Hernandez - National Institutes of HealthCornelis Blauwendraat - National Institutes of HealthGeorge D Mellick - Griffith UniversityAlexander Zimprich - Medical University of ViennaWalter PirkerManuela Tan - University College LondonEkaterina Rogaeva - Occupational Cancer Research CentreAnthony E Lang - Toronto Western HospitalSulev Koks - Murdoch UniversityPille Taba - Tartu University HospitalSuzanne LesageAlexis BriceJean-Christophe CorvolMarie-Christine Chartier-HarlinEugenie Mutez - InsermKathrin Brockmann - Hertie Institute for Clinical Brain ResearchAngela B Deutschländer - Ludwig-Maximilians-Universität MünchenGeorges M HadjigeorgiouEfthimos Dardiotis - University Hospital of LarissaLeonidas StefanisAthina Maria SimitsiEnza Maria Valente - University of PaviaSimona Petrucci - Sapienza University of RomeLetizia Straniero - Humanitas UniversityAnna Zecchinelli - Azienda Socio Sanitaria Territoriale LarianaGianni Pezzoli - Grigioni Foundation for Parkinson's diseaseLaura Brighina - University of Milano-BicoccaCarlo Ferrarese - University of Milano-BicoccaGrazia Annesi - Institute for Biomedical Research and InnovationAndrea Quattrone - Magna Graecia UniversityMonica Gagliardi - Magna Graecia UniversityLena F Burbulla - German Center for Neurodegenerative DiseasesHirotaka Matsuo - National Defense Medical CollegeAkiyoshi Nakayama - National Defense Medical CollegeNobutaka HattoriKenya Nishioka - Juntendo UniversitySun Ju Chung - University of UlsanYun Joong Kim - Yonsei UniversityPierre Kolber - Centre Hospitalier de LuxembourgBart Pc van de Warrenburg - Radboud University NijmegenBastiaan R Bloem - Radboud University NijmegenAndrew B SingletonMathias Toft - Oslo University HospitalLasse PihlstromLeonor Correia Guedes - University of LisbonJoaquim J Ferreira - University of LisbonSoraya Bardien - Stellenbosch UniversityJonathan Carr - Stellenbosch UniversityEduardo TolosaMario Ezquerra - Universitat de BarcelonaPau Pastor - University Hospital Mútua de TerrassaKarin Wirdefeldt - Karolinska InstitutetNancy L Pedersen - Karolinska InstitutetCaroline Ran - Karolinska InstitutetAndrea C Belin - Karolinska InstitutetAndreas Puschmann - Lund UniversityCarl E Clarke - Sandwell & West Birmingham Hospitals NHS TrustKaren E Morrison - Queen's University BelfastDimitri Krainc - Northwestern UniversityMatt J FarrerDennis Lal - Cleveland ClinicAlexis Elbaz - InsermThomas Gasser - Hertie Institute for Clinical Brain ResearchRejko Krüger - University of LuxembourgManu Sharma - University of TübingenPatrick May - University of Luxembourg
- Publication Details
- medRxiv: the preprint server for health sciences
- Publisher
- Cold Spring Harbor Laboratory
- Identifiers
- 991005701367107891
- Copyright
- The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Preprint
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