Genome-wide association study of copy number variations in Parkinson’s disease
Authors: Landoulsi Zied , Sreelatha Ashwin Ashok Kumar , Schulte Claudia , Bobbili Dheeraj Reddy , Montanucci Ludovica , Leu Costin , Niestroj Lisa-Marie , Hassanin Emadeldin , Domenighetti Cloé , Pavelka Lukas , Sugier Pierre-Emmanuel , Radivojkov-Blagojevic Milena , Lichtner Peter , Portugal Berta , Edsall Connor , Kruger Jens , Hernandez Dena G , Blauwendraat Cornelis , Mellick George D , Zimprich Alexander , Pirker Walter , Tan Manuela , Rogaeva Ekaterina , Lang Anthony E. , Koks Sulev , Taba Pille , Lesage Suzanne , Brice Alexis , Corvol Jean-Christophe , Chartier-Harlin Marie-Christine , Mutez Eugenie , Brockmann Kathrin , Deutschländer Angela B , Hadjigeorgiou Georges M , Dardiotis Efthimos , Stefanis Leonidas , Simitsi Athina Maria , Valente Enza Maria , Petrucci Simona , Straniero Letizia , Zecchinelli Anna , Pezzoli Gianni , Brighina Laura , Ferrarese Carlo , Annesi Grazia , Quattrone Andrea , Gagliardi Monica , Burbulla Lena F , Matsuo Hirotaka , Nakayama Akiyoshi , Hattori Nobutaka , Nishioka Kenya , Chung Sun Ju , Kim Yun Joong , Kolber Pierre , van de Warrenburg Bart PC , Bloem Bastiaan R , Singleton Andrew B. , Toft Mathias , Pihlstrom Lasse , Guedes Leonor Correia , Ferreira Joaquim J , Bardien Soraya , Carr Jonathan , Tolosa Eduardo , Ezquerra Mario , Pastor Pau , Wirdefeldt Karin , Pedersen Nancy L , Ran Caroline , Belin Andrea C , Puschmann Andreas , Clarke Carl E , Morrison Karen E , Krainc Dimitri , Farrer Matt J , Lal Dennis , Elbaz Alexis , Gasser Thomas , Krüger Rejko , Sharma Manu , May Patrick 
Published: August 2024

AbstractObjectiveOur 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.MethodsWe 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.ResultsWe 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 genesSNCAandVPS13C, 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 inPRKN. 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), withPRKNshowing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs inPRKNhad an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results.InterpretationThis is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden in EOPD, primarily driven by thePRKNgene, warranting further investigation.