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, Kru Ger 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
Luxembourg Centre for Systems Biomedicine, University of Luxembourg; L-4367, Esch-sur-Alzette, Luxembourg.
Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg.
medRxiv. 2024 Aug 22:2024.08.21.24311915. doi: 10.1101/2024.08.21.24311915.
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.
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.
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 and , 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 . 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 showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results.
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 gene, warranting further investigation.
我们的研究利用全基因组数据调查拷贝数变异（CNV）对帕金森病（PD）发病机制的影响，旨在揭示新的遗传机制并增进对CNV在散发性PD中作用的理解。
我们应用滑动窗口方法进行CNV全基因组关联研究（CNV-GWAS），并对来自COURAGE-PD联盟的11035例PD患者（包括2731例早发性PD（EOPD））和8901例对照的CNV数据进行全基因组负担分析。
我们鉴定出14个与PD相关的全基因组显著CNV位点，包括1个缺失和13个重复。其中，7q22.1、11q12.3和7q33的重复显示出最高效应。两个显著重复与PD相关基因 和 重叠，但均未与近期基于单核苷酸多态性（SNP）的全基因组关联研究结果重叠。5个重复包含与神经疾病相关的基因，4个重叠基因对剂量敏感且对功能丧失变异不耐受。富集的通路包括神经退行性变、类固醇激素生物合成和脂质代谢。在早发性病例中，4个位点与EOPD显著相关，包括3个已知重复和 中的1个新缺失。CNV负担分析显示，与对照相比，患者中PD相关基因的CNV患病率更高（优势比[OR]=1.56[1.18 - 2.09]，p = 0.0013），其中 负担最高（OR = 1.47[1.10 - 1.98]，p = 0.026）。 中存在CNV的患者疾病发病较早。对照与EOPD患者的负担分析显示出相似结果。
这是基于CNV的最大规模PD全基因组关联研究，鉴定出了新的CNV区域，并证实了EOPD中显著的CNV负担，主要由 基因驱动，值得进一步研究。
