Cornelis Blauwendraat1,2, Karl Heilbron3, Costanza L Vallerga4, Sara Bandres-Ciga1, Rainer von Coelln5, Lasse Pihlstrøm6, Javier Simón-Sánchez7,8, Claudia Schulte7,8, Manu Sharma9, Lynne Krohn10,11, Ari Siitonen12,13, Hirotaka Iwaki1,14, Hampton Leonard1, Alastair J Noyce15,16, Manuela Tan16, J Raphael Gibbs1, Dena G Hernandez1, Sonja W Scholz2, Joseph Jankovic17, Lisa M Shulman5, Suzanne Lesage18, Jean-Christophe Corvol18, Alexis Brice18, Jacobus J van Hilten19, Johan Marinus19, Johanna Eerola-Rautio20, Pentti Tienari20, Kari Majamaa12,13, Mathias Toft6,21, Donald G Grosset22,23, Thomas Gasser7,8, Peter Heutink7,8, Joshua M Shulman17,24,25, Nicolas Wood16, John Hardy26, Huw R Morris16, David A Hinds3, Jacob Gratten4,27, Peter M Visscher4,28, Ziv Gan-Or10,11,29, Mike A Nalls1,30, Andrew B Singleton1. 1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. 2. Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. 3. 23andMe, Inc., Mountain View, California, USA. 4. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. 5. Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA. 6. Department of Neurology, Oslo University Hospital, Oslo, Norway. 7. Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 8. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. 9. Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. 10. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. 11. Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. 12. Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. 13. Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. 14. The Michael J Fox Foundation for Parkinson's Research, New York, New York, USA. 15. Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. 16. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. 17. Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. 18. Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. 19. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. 20. Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. 21. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 22. Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom. 23. Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, United Kingdom. 24. Departments of Molecular & Human Genetics and Neuroscience, Baylor College of Medicine, Houston, Texas, USA. 25. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. 26. Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom. 27. Mater Research, Translational Research Institute, Brisbane, Queensland, Australia. 28. Queensland Brain Institute, The University of Queensland, Brisbane, Australia. 29. Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada. 30. Data Tecnica International, Glen Echo, Maryland, USA.
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.
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.
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Authors: Lynne Krohn; Francis P Grenn; Mary B Makarious; Jonggeol Jeffrey Kim; Sara Bandres-Ciga; Dorien A Roosen; Ziv Gan-Or; Mike A Nalls; Andrew B Singleton; Cornelis Blauwendraat Journal: Neurobiol Aging Date: 2020-03-10 Impact factor: 4.673