Genome-wide association study of copy number variations in Parkinson's disease.
Journal: medRxiv : the preprint server for health sciences
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Affiliated Institutions:
Luxembourg Centre for Systems Biomedicine, University of Luxembourg; L-, Esch-sur-Alzette, Luxembourg.
Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany.
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tubingen, Germany.
Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK.
Cologne Center for Genomics (CCG), Medical Faculty of the University of Cologne, Cologne, Germany.
Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, , Villejuif, France.
Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg.
Institute of Human Genetics, Helmholtz Zentrum Munchen, Neuherberg, Germany.
Department of Precision Health, Luxembourg Institute of Health, Strassen, Luxembourg.
Molecular Genetics Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD , USA.
Group of Applied Bioinformatics, University of Tubingen, Tubingen, Germany.
Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland, Australia.
Department of Neurology, Medical University of Vienna, Austria.
Department of Neurology, Klinik Ottakring, Vienna Austria.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Australia.
Department of Neurology and Neurosurgery, University of Tartu, Estonia.
Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Paris, France.
Univ. Lille, Inserm, CHU Lille, UMR-S - JPArc - Centre de Recherche Lille Neurosciences & Cognition, F- Lille, France.
Department of Neurology, Ludwig Maximilians University of Munich, Germany.
Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus.
Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.
Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
UOC Medical Genetics and Advanced Cell Diagnostics, S. Andrea University Hospital, Rome, Italy.
Department of Biomedical Sciences - Humanitas University, Milan, Italy.
Parkinson Institute, Azienda Socio Sanitaria Territoriale (ASST) Gaetano Pini/CTO, Milano, Italia.
Department of Neurology, San Gerardo Hospital, Milan, Italy.
Institute for Biomedical Research and Innovation, National Research Council, Cosenza, Italy.
Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
Department of Medical and Surgical Sciences, Neuroscience Research Center, Magna Graecia University, Catanzaro, Italy.
German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany.
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama -, Japan.
Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo -, Japan.
Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.
Centre Hospitalier du Luxembourg, Parkinson Research Clinic, Luxembourg, Luxembourg.
Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, The Netherlands.
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
Parkinson's disease &Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, ES- Barcelona, Catalonia.
Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain.
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Getingevägen , , Lund, Sweden.
University of Birmingham and Sandwell and West Birmingham Hospitals NHS Trust, United Kingdom.
Faculty of Medicine, Health and Life Sciences, Queens University, Belfast, United Kingdom.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois , United States.
Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Abstract summary
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.
Authors & Co-authors:
Landoulsi Zied Z
Sreelatha Ashwin Ashok Kumar AAK
Schulte Claudia C
Bobbili Dheeraj Reddy DR
Montanucci Ludovica L
Leu Costin C
Niestroj Lisa-Marie LM
Hassanin Emadeldin E
Domenighetti Cloé C
Pavelka Lukas L
Sugier Pierre-Emmanuel PE
Radivojkov-Blagojevic Milena M
Lichtner Peter P
Portugal Berta B
Edsall Connor C
Kru Ger Jens J
Hernandez Dena G DG
Blauwendraat Cornelis C
Mellick George D GD
Zimprich Alexander A
Pirker Walter W
Tan Manuela M
Rogaeva Ekaterina E
Lang Anthony E AE
Koks Sulev S
Taba Pille P
Lesage Suzanne S
Brice Alexis A
Corvol Jean-Christophe JC
Chartier-Harlin Marie-Christine MC
Mutez Eugenie E
Brockmann Kathrin K
Deutschländer Angela B AB
Hadjigeorgiou Georges M GM
Dardiotis Efthimos E
Stefanis Leonidas L
Simitsi Athina Maria AM
Valente Enza Maria EM
Petrucci Simona S
Straniero Letizia L
Zecchinelli Anna A
Pezzoli Gianni G
Brighina Laura L
Ferrarese Carlo C
Annesi Grazia G
Quattrone Andrea A
Gagliardi Monica M
Burbulla Lena F LF
Matsuo Hirotaka H
Nakayama Akiyoshi A
Hattori Nobutaka N
Nishioka Kenya K
Chung Sun Ju SJ
Kim Yun Joong YJ
Kolber Pierre P
van de Warrenburg Bart Pc BP
Bloem Bastiaan R BR
Singleton Andrew B AB
Toft Mathias M
Pihlstrom Lasse L
Guedes Leonor Correia LC
Ferreira Joaquim J JJ
Bardien Soraya S
Carr Jonathan J
Tolosa Eduardo E
Ezquerra Mario M
Pastor Pau P
Wirdefeldt Karin K
Pedersen Nancy L NL
Ran Caroline C
Belin Andrea C AC
Puschmann Andreas A
Clarke Carl E CE
Morrison Karen E KE
Krainc Dimitri D
Farrer Matt J MJ
Lal Dennis D
Elbaz Alexis A
Gasser Thomas T
Krüger Rejko R
Sharma Manu M
May Patrick P
Study Outcome
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