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

description: 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.