
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.21.24311915
preprint
1
Article
Genome-wide association study of copy number variations in Parkinson’s disease
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
22 8 2024
2024.08.21.24311915https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.08.21.24311915
nihpp-2024.08.21.24311915.pdf
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.
==== Body
pmc
