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      Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy

      research-article
      1 , 2 , 3 , 4 , 5 , 2 , 3 , 6 , 7 , 8 , 9 , 10 , 11 , 11 , 6 , 12 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , PSP Genetics Study Group, 5 , 5 , 21 , 22 , 6 , 21 , 21 , 6 , 21 , 21 , 23 , 24 , 25 , 26 , 27 , 6 , 6 , 27 , 2 , 4 , 28 , 5
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          Abstract

          Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10 −3. We found significant novel signals (P < 5 × 10 −8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component.

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          Most cited references47

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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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            Principal components analysis corrects for stratification in genome-wide association studies.

            Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.
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              • Record: found
              • Abstract: found
              • Article: not found

              SNAREs--engines for membrane fusion.

              Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nature genetics
                1061-4036
                1546-1718
                15 June 2011
                19 June 2011
                1 January 2012
                : 43
                : 7
                : 699-705
                Affiliations
                [1 ]Department of Neurology, Philipps-Universität, Marburg, Germany.
                [2 ]Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
                [3 ]Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
                [4 ]Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
                [5 ]Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
                [6 ]Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.
                [7 ]Department of Neurology, Division of Movement Disorders, University of Louisville, Louisville, Kentucky, USA.
                [8 ]Department of Neurology, University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA.
                [9 ]Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
                [10 ]Department of Clinical Genetics, VU University Medical Center, Section Medical Genomics, Amsterdam, The Netherlands.
                [11 ]Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
                [12 ]Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.
                [13 ]Center of Neurology, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
                [14 ]German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.
                [15 ]Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy.
                [16 ]Neurology Service, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
                [17 ]Department of Medical and Surgical Sciences, Institute of Neurology, University of Brescia, Brescia, Italy.
                [18 ]CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
                [19 ]Neurogenetics laboratory, Division of Neurosciences, University of Navarra Center for Applied Medical Research, Pamplona, Spain.
                [20 ]Department of Neurology, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain.
                [21 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
                [22 ]Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.
                [23 ]Department of Medical Genetics, CMMT, CRFI, BRC, PPRC, University of British Columbia, Vancouver, British Columbia, Canada.
                [24 ]Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
                [25 ]Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
                [26 ]Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
                [27 ]Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.
                [28 ]Institut for Humangenetik, Justus-Liebig-Universität, Schlangenzahl 14, 35392 Giessen, Germany.
                Author notes
                Correspondence and requests for materials should be addressed to G.D.S. ( gerardsc@ 123456mail.med.upenn.edu ) or U.M. ( Ulrich.Mueller@ 123456humangenetik.med.uni-giessen.de )
                [29]

                A list of PSP Genetics Study Group coauthors and their affiliations appears at the end of the paper.

                [30]

                These authors contributed equally to this work.

                Article
                nihpa297077
                10.1038/ng.859
                3125476
                21685912
                a9cd909a-9fd4-4040-acaa-9b5b0f366462

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                History
                Funding
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U01 HG004603-01 || HG
                Funded by: National Institute on Aging : NIA
                Award ID: R37 AG011762-17 || AG
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS057567-04 || NS
                Funded by: National Institute of Mental Health : NIMH
                Award ID: R01 MH057881-13 || MH
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: P50 NS072187-01 || NS
                Funded by: National Institute of Mental Health : NIMH
                Award ID: K01 MH077930-05 || MH
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                Genetics
                Genetics

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