LCSB R³
Responsible and Reproducible Research

Genome-wide association study of copy number variations in Parkinson’s disease#

Authors#

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

Abstract#

Objective:#

Our study investigates the impact of copy number variations (CNVs) on Parkinson’s disease (PD) pathogenesis using genome-wide data, with the aim of uncovering novel genetic mechanisms and improving the understanding of the role of CNVs in sporadic PD.

Methods:#

We applied a sliding window approach to perform CNV-GWAS and performed genome-wide burden analyses on CNV data from 11,035 PD patients (including 2,731 early-onset 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. Two significant duplications overlapped with PD-related genes SNCA and VPS13C, but none overlapped with significant recent SNP-based GWAS findings. Four 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, three of which were previously identified 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 these CNVs had an earlier disease onset. EOPD burden analysis confirmed an increased prevalence of CNVs in PD-related genes (OR=2.43 [1.64-3.59], p=2.8e-05), with PRKN showing the highest burden (OR=2.32 [1.54-3.46], p=1.1e-04).

Interpretation:#

This is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden on EOPD, primarily driven by the PRKN gene, warranting further investigation.

Data and code availability#

Genome-wide CNV association summary statistics are available in the Supplementary Data. Individual-level CNVs and genotyping data are available on request from the COURAGE-PD consortium. Relevant scripts used in the present work are available on GitHub (https://gitlab.lcsb.uni.lu/genomeanalysis/cnv_gwas_courage-pd). For the sliding window association method, we used the code available under the Talkowski Laboratory (Massachusetts General Hospital & The Broad Institute) repository in Zenodo (https://github.com/talkowski-lab/rCNV2/tree/v1.0, with https://zenodo.org/records/6647918).