Screening non-MAPT genes of the Chr17q21 H1 haplotype in Parkinson's disease |
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| Institution: | 11. Department of Biology, College of Arts and Sciences, University of North Florida, Jacksonville, FL, 32224, USA;1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA;2. Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA;3. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA;4. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA;5. Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, USA;6. Department of Radiology, Mayo Clinic, Rochester, MN, USA;7. Department of Neurology, Mayo Clinic, Rochester, MN, USA;8. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;9. Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA;10. Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA;11. Mayo Graduate School, Mayo Clinic, Jacksonville, FL, USA;1. Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada;2. Centre de Recherche, Centre Hospitalier de l’Universite de Montreal, Montreal, Quebec, Canada;3. Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada;4. Department of Human Genetics, McGill University, Montréal, Quebec, Canada;5. Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA;6. Department of Clinical Neurosciences and Department of Radiology, University of Calgary, Calgary, Alberta, Canada;7. Hotchkiss Brain Institute, Cumming School of Medicine, Calgary, Alberta, Canada;8. Department of Neurology, National Reference Center for Narcolepsy, Sleep Unit, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France;9. Department of Neurology, Gardner Family Center for Parkinson''s Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, USA;10. Division of Neurosciences, CHU de Québec, Université Laval, Quebec City, Quebec, Canada;11. Department of Medicine, Faculty of Medicine, Université Laval, Québec, Quebec, Canada;12. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;13. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel;14. The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel;15. Department of Neurology, The Movement Disorders Institute, Sheba Medical Center, Tel Hashomer, Israel;p. Taub Institute for Research on Alzheimer''s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA;1. Department of Human Genetics, McGill University, Montréal, Quebec, Canada;2. Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada;3. Division of Neurology, CHU de Québec, and Faculty of Medicine, Laval University, Quebec City, Quebec, Canada;4. Sleep Unit, National Reference Network for Narcolepsy, Department of Neurology Hôpital-Gui-de Chauliac, CHU Montpellier, INSERM U1061, Montpellier, France;5. Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada;6. GRIP, École de Psychologie, Université Laval, Québec city, Quebec, Canada;7. Institute of Genetic, Neurobiological and Social Foundations of Child Development, Tomsk State University, Tomsk, Russia;1. Faculty of Medicine and Health Sciences, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa;2. University of the Witwatersrand Donald Gordon Medical Centre, Neurology, University of the Witwatersrand, Johannesburg, South Africa;3. Faculty of Health Sciences, Division of Neurology, Department of Medicine, Walter Sisulu University, East London, South Africa;4. Faculty of Health Sciences, School of Medicine, Department of Neurology, University of Pretoria, South Africa;5. Faculty of Medicine and Health Sciences, Division of Neurology, Stellenbosch University, Cape Town, South Africa;6. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA;7. Department of Clinical Genomics, Mayo Clinic College of Medicine, Jacksonville, FL, USA |
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| Abstract: | IntroductionThe microtubule-associated protein tau (MAPT) gene is considered a strong genetic risk factor for Parkinson's disease (PD) in Caucasians. MAPT is located within an inversion region of high linkage disequilibrium designated as H1 and H2 haplotype, and contains eight other genes which have been implicated in neurodegeneration. The aim of the current study was to identify common coding variants in strong linkage disequilibrium (LD) within the associated loci on chr17q21 harboring MAPT.MethodsSanger sequencing of coding exons in 90 Caucasian late-onset PD (LOPD) patients was performed. Specific gene sequencing for LRRC37A, LRRC37A2, ARL17A and ARL17B was not possible given the high homology, presence of pseudogenes and copy number variants that are in the region, and therefore four genes (NSF, KANSL1, SPPL2C, and CRHR1) were included in the analysis. Coding variants from these four genes that did not perfectly tag (r2 = 1) the MAPT H1/H2 haplotype were genotyped in an independent replication series of Caucasian PD cases (N = 851) and controls (N = 730).ResultsIn the 90 LOPD cases we identified 30 coding variants. Eleven non-synonymous variants tagged the MAPT H1/H2 haplotype, including two SPPL2C variants (rs12185233 and rs12373123) that had high pathogenic combined annotation dependent depletion (CADD) scores of >20. In the replication series, the non-synonymous KANSL1 rs17585974 variant was in very strong LD with MAPT H1/H2 and had a high CADD score of 24.7.ConclusionWe have identified several non-synonymous variants across neighboring genes of MAPT that may warrant further genetic and functional investigation within the biological etiology of PD. |
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| Keywords: | H1 haplotype Parkinson's disease |
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