Genome-wide association study of copy number variations in Parkinson's disease.
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Landoulsi Zied, Sreelatha Ashwin Ashok Kumar, Kuznetsov Nicole, Schulte Claudia, Bobbili Dheeraj Reddy, Montanucci Ludovica, Leu Costin, Niestroj Lisa-Marie, Hassanin Emadeldin, Domenighetti Cloé, Sugier Pierre-Emmanuel, Radivojkov-Blagojevic Milena, Lichtner Peter, Portugal Berta, Edsall Connor, Kru Ger Jens, Hernandez Dena G, Blauwendraat Cornelis, Mellick George D, Zimprich Alexander, Pirker Walter, Tan Manuela, Rogaeva Ekaterina, Lang Anthony, 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, Pavelka Lukas, Kolber Pierre, van de Warrenburg Bart Pc, Bloem Bastiaan R, Singleton Andrew B, Vitale Dan, 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, Global Parkinson Genetics Program (GP2), Elbaz Alexis, Gasser Thomas, Krüger Rejko, Sharma Manu, May Patrick
Аннотация
METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings.
RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. 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: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.