Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms
Year: 2019
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. OBJECTIVES: To identify the genetic determinants of PD age at onset. METHODS: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. RESULTS: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. CONCLUSIONS: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society.
Source: Movement Disorders
DOI: 10.1002/mds.27659
Authors: Cornelis Blauwendraat, Karl Heilbron, Costanza L. Vallerga, Sara Bandres‐Ciga, Rainer von Coelln, Lasse Pihlstrøm, Javier Simón‐Sánchez, Claudia Schulte, Manu Sharma, Lynne Krohn, Ari Siitonen, Hirotaka Iwaki, Hampton Leonard, Alastair J. Noyce, Manuela Tan, J. Raphael Gibbs, Dena G. Hernandez, Sonja W. Scholz, Joseph Jankovic, Lisa M. Shulman, Suzanne Lesage, Jean‐Christophe Corvol, Alexis Brice, Jacobus J. van Hilten, Johan Marinus, Johanna Eerola‐Rautio, Pentti Tienari, Kari Majamaa, Mathias Toft, Donald G. Grosset, Thomas Gasser, Peter Heutink, Joshua M. Shulman, Nicolas Wood, John Hardy, Huw R. Morris, David A. Hinds, Jacob Gratten, Peter M. Visscher, Ziv Gan‐Or, Mike A. Nalls, Andrew B. Singleton
Institutions: National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, 23andMe (United States), The University of Queensland, Institute for Molecular Bioscience, University of Maryland, Baltimore, Oslo University Hospital, German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Montreal Neurological Institute and Hospital, McGill University, Oulu University Hospital, University of Oulu, Michael J. Fox Foundation, Queen Mary University of London, UCL Queen Square Institute of Neurology, University College London, Baylor College of Medicine, Inserm, Sorbonne Université, Institut du Cerveau, Université Pierre-et-Marie-Curie, Leiden University Medical Center, University of Helsinki, Helsinki University Hospital, University of Oslo, Queen Elizabeth University Hospital, University of Glasgow, Texas Children's Hospital, Translational Research Institute, Mater Research, Data Tecnica International (United States)
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Michael J. Fox Foundation for Parkinson's Research, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, GlaxoSmithKline, Biogen, Teva Pharmaceutical Industries, American Parkinson Disease Association, Itä-Suomen Yliopisto, Helsingin Yliopisto, Helsingin ja Uudenmaan Sairaanhoitopiiri, McGill University, University of Dundee, Wellcome Trust, EU Joint Programme – Neurodegenerative Disease Research, Consortium canadien en neurodégénérescence associée au vieillissement, Barts Charity, Multiple System Atrophy Coalition, National Institute for Health and Care Research, Parkinson's UK, University College London, Rosetrees Trust, University of Glasgow, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Canada First Research Excellence Fund, Servier, H. Lundbeck A/S, National Institutes of Health, Genentech, Medical Research Council, National Institute on Aging, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Institute of Genetics
Awards: Characterization of Normal Genomic Variability, G1319666062, G1381405788, G1434243473, G1487196722, G1492513106, G149631205, Parkinson Disease Collaborative Study of Genetic Linkage, G1546175775, G1826063430, G1841844222, G1955802110, G20482478, G2131817247, G226565915, WTCCC2 core activities, G2542871354, G2725042310, G2830669520, G2845388095, Prospective studies on Parkinson's disease, G3155125711, G3327757157, G4119534169, JPND Verbundprojekt COURAGE-PD: Umfassende und unabhängige Beurteilung von genetischen und umweltbedingten Risikofaktoren bei der Parkinson Erkrankung, G4265316335, G4315210197, G4721042799, WTCCC Part Two., e:Med - Modul II - Verbundprojekt: MitoPD - Mitochondriale Endophänotypen der Parkinson Krankheit - Teilprojekt A, G5397907424, G5850682332, Understanding the genes for Parkinson's disease, G6256375845, G6265045657, G6307761199, G6535232462, G6552739370, G6579178073, G6671832592, G6804723138, PD GWAS Consortium, G7120366109, Mentorship Program Patient-Oriented Research on Aging, G7297374403, G7309796676, G7310981802, G7553137527, G7616916448, G7752108332, G7955618357, G8027257336, G8083352728, G8098035348, Genetics of Parkonsonism, WTCCC3 core activities., G8716763575, REFUND CHECK AND WAS DE-OBLIGATED IN THE AMOUNT OF $28,044., G8764830727, Genome wide SNP analysis in Parkinson's disease, The genetics of weight, BMI, adiposity and obesity, G9000060582, G9000082987, G9000102915, Genetic characterization of atypical parkinsonism, WTCCC Part Two, G992107779
OpenAlex ID: W2937319110