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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy</title><author><name sortKey="Hoglinger, Gunter U" sort="Hoglinger, Gunter U" uniqKey="Hoglinger G" first="Günter U." last="Höglinger">Günter U. Höglinger</name><affiliation><nlm:aff id="A1">Department of Neurology, Philipps-Universität, Marburg, Germany.</nlm:aff></affiliation></author><author><name sortKey="Melhem, Nadine M" sort="Melhem, Nadine M" uniqKey="Melhem N" first="Nadine M." last="Melhem">Nadine M. Melhem</name><affiliation><nlm:aff id="A2">Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Dickson, Dennis W" sort="Dickson, Dennis W" uniqKey="Dickson D" first="Dennis W." last="Dickson">Dennis W. Dickson</name><affiliation><nlm:aff id="A3">Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Sleiman, Patrick M A" sort="Sleiman, Patrick M A" uniqKey="Sleiman P" first="Patrick M. A." last="Sleiman">Patrick M. A. Sleiman</name><affiliation><nlm:aff id="A4">Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Wang, Li San" sort="Wang, Li San" uniqKey="Wang L" first="Li-San" last="Wang">Li-San Wang</name><affiliation><nlm:aff id="A5">Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Klei, Lambertus" sort="Klei, Lambertus" uniqKey="Klei L" first="Lambertus" last="Klei">Lambertus Klei</name><affiliation><nlm:aff id="A2">Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name><affiliation><nlm:aff id="A3">Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="De Silva, Rohan" sort="De Silva, Rohan" uniqKey="De Silva R" first="Rohan" last="De Silva">Rohan De Silva</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Litvan, Irene" sort="Litvan, Irene" uniqKey="Litvan I" first="Irene" last="Litvan">Irene Litvan</name><affiliation><nlm:aff id="A7">Department of Neurology, Division of Movement Disorders, University of Louisville, Louisville, Kentucky, USA.</nlm:aff></affiliation></author><author><name sortKey="Riley, David E" sort="Riley, David E" uniqKey="Riley D" first="David E." last="Riley">David E. Riley</name><affiliation><nlm:aff id="A8">Department of Neurology, University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA.</nlm:aff></affiliation></author><author><name sortKey="Van Swieten, John C" sort="Van Swieten, John C" uniqKey="Van Swieten J" first="John C." last="Van Swieten">John C. Van Swieten</name><affiliation><nlm:aff id="A9">Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Heutink, Peter" sort="Heutink, Peter" uniqKey="Heutink P" first="Peter" last="Heutink">Peter Heutink</name><affiliation><nlm:aff id="A10">Department of Clinical Genetics, VU University Medical Center, Section Medical Genomics, Amsterdam, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Wszolek, Zbigniew K" sort="Wszolek, Zbigniew K" uniqKey="Wszolek Z" first="Zbigniew K." last="Wszolek">Zbigniew K. Wszolek</name><affiliation><nlm:aff id="A11">Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Uitti, Ryan J" sort="Uitti, Ryan J" uniqKey="Uitti R" first="Ryan J." last="Uitti">Ryan J. Uitti</name><affiliation><nlm:aff id="A11">Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Vandrovcova, Jana" sort="Vandrovcova, Jana" uniqKey="Vandrovcova J" first="Jana" last="Vandrovcova">Jana Vandrovcova</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Hurtig, Howard I" sort="Hurtig, Howard I" uniqKey="Hurtig H" first="Howard I." last="Hurtig">Howard I. Hurtig</name><affiliation><nlm:aff id="A12">Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Gross, Rachel G" sort="Gross, Rachel G" uniqKey="Gross R" first="Rachel G." last="Gross">Rachel G. Gross</name><affiliation><nlm:aff id="A12">Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Maetzler, Walter" sort="Maetzler, Walter" uniqKey="Maetzler W" first="Walter" last="Maetzler">Walter Maetzler</name><affiliation><nlm:aff id="A13">Center of Neurology, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.</nlm:aff></affiliation><affiliation><nlm:aff id="A14">German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.</nlm:aff></affiliation></author><author><name sortKey="Goldwurm, Stefano" sort="Goldwurm, Stefano" uniqKey="Goldwurm S" first="Stefano" last="Goldwurm">Stefano Goldwurm</name><affiliation><nlm:aff id="A15">Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy.</nlm:aff></affiliation></author><author><name sortKey="Tolosa, Eduardo" sort="Tolosa, Eduardo" uniqKey="Tolosa E" first="Eduardo" last="Tolosa">Eduardo Tolosa</name><affiliation><nlm:aff id="A16">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.</nlm:aff></affiliation></author><author><name sortKey="Borroni, Barbara" sort="Borroni, Barbara" uniqKey="Borroni B" first="Barbara" last="Borroni">Barbara Borroni</name><affiliation><nlm:aff id="A17">Department of Medical and Surgical Sciences, Institute of Neurology, University of Brescia, Brescia, Italy.</nlm:aff></affiliation></author><author><name sortKey="Pastor, Pau" sort="Pastor, Pau" uniqKey="Pastor P" first="Pau" last="Pastor">Pau Pastor</name><affiliation><nlm:aff id="A18">CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.</nlm:aff></affiliation><affiliation><nlm:aff id="A19">Neurogenetics laboratory, Division of Neurosciences, University of Navarra Center for Applied Medical Research, Pamplona, Spain.</nlm:aff></affiliation><affiliation><nlm:aff id="A20">Department of Neurology, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain.</nlm:aff></affiliation></author><author><name sortKey="Cantwell, Laura B" sort="Cantwell, Laura B" uniqKey="Cantwell L" first="Laura B." last="Cantwell">Laura B. Cantwell</name><affiliation><nlm:aff id="A5">Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Han, Mi Ryung" sort="Han, Mi Ryung" uniqKey="Han M" first="Mi Ryung" last="Han">Mi Ryung Han</name><affiliation><nlm:aff id="A5">Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Dillman, Allissa" sort="Dillman, Allissa" uniqKey="Dillman A" first="Allissa" last="Dillman">Allissa Dillman</name><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Van Der Brug, Marcel P" sort="Van Der Brug, Marcel P" uniqKey="Van Der Brug M" first="Marcel P." last="Van Der Brug">Marcel P. Van Der Brug</name><affiliation><nlm:aff id="A22">Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Gibbs, J Raphael" sort="Gibbs, J Raphael" uniqKey="Gibbs J" first="J Raphael" last="Gibbs">J Raphael Gibbs</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R." last="Cookson">Mark R. Cookson</name><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Hernandez, Dena G" sort="Hernandez, Dena G" uniqKey="Hernandez D" first="Dena G." last="Hernandez">Dena G. Hernandez</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Singleton, Andrew B" sort="Singleton, Andrew B" uniqKey="Singleton A" first="Andrew B." last="Singleton">Andrew B. Singleton</name><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><affiliation><nlm:aff id="A23">Department of Medical Genetics, CMMT, CRFI, BRC, PPRC, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:aff></affiliation></author><author><name sortKey="Yu, Chang En" sort="Yu, Chang En" uniqKey="Yu C" first="Chang-En" last="Yu">Chang-En Yu</name><affiliation><nlm:aff id="A24">Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A25">Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.</nlm:aff></affiliation></author><author><name sortKey="Golbe, Lawrence I" sort="Golbe, Lawrence I" uniqKey="Golbe L" first="Lawrence I." last="Golbe">Lawrence I. Golbe</name><affiliation><nlm:aff id="A26">Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.</nlm:aff></affiliation></author><author><name sortKey="Revesz, Tamas" sort="Revesz, Tamas" uniqKey="Revesz T" first="Tamas" last="Revesz">Tamas Revesz</name><affiliation><nlm:aff id="A27">Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Lees, Andrew J" sort="Lees, Andrew J" uniqKey="Lees A" first="Andrew J." last="Lees">Andrew J. Lees</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A27">Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name><affiliation><nlm:aff id="A2">Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name><affiliation><nlm:aff id="A4">Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Muller, Ulrich" sort="Muller, Ulrich" uniqKey="Muller U" first="Ulrich" last="Müller">Ulrich Müller</name><affiliation><nlm:aff id="A28">Institut for Humangenetik, Justus-Liebig-Universität, Schlangenzahl 14, 35392 Giessen, Germany.</nlm:aff></affiliation></author><author><name sortKey="Schellenberg, Gerard D" sort="Schellenberg, Gerard D" uniqKey="Schellenberg G" first="Gerard D." last="Schellenberg">Gerard D. Schellenberg</name><affiliation><nlm:aff id="A5">Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21685912</idno><idno type="pmc">3125476</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125476</idno><idno type="RBID">PMC:3125476</idno><idno type="doi">10.1038/ng.859</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000B56</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B56</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy</title><author><name sortKey="Hoglinger, Gunter U" sort="Hoglinger, Gunter U" uniqKey="Hoglinger G" first="Günter U." last="Höglinger">Günter U. Höglinger</name><affiliation><nlm:aff id="A1">Department of Neurology, Philipps-Universität, Marburg, Germany.</nlm:aff></affiliation></author><author><name sortKey="Melhem, Nadine M" sort="Melhem, Nadine M" uniqKey="Melhem N" first="Nadine M." last="Melhem">Nadine M. Melhem</name><affiliation><nlm:aff id="A2">Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Dickson, Dennis W" sort="Dickson, Dennis W" uniqKey="Dickson D" first="Dennis W." last="Dickson">Dennis W. Dickson</name><affiliation><nlm:aff id="A3">Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Sleiman, Patrick M A" sort="Sleiman, Patrick M A" uniqKey="Sleiman P" first="Patrick M. A." last="Sleiman">Patrick M. A. Sleiman</name><affiliation><nlm:aff id="A4">Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Wang, Li San" sort="Wang, Li San" uniqKey="Wang L" first="Li-San" last="Wang">Li-San Wang</name><affiliation><nlm:aff id="A5">Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Klei, Lambertus" sort="Klei, Lambertus" uniqKey="Klei L" first="Lambertus" last="Klei">Lambertus Klei</name><affiliation><nlm:aff id="A2">Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Rademakers, Rosa" sort="Rademakers, Rosa" uniqKey="Rademakers R" first="Rosa" last="Rademakers">Rosa Rademakers</name><affiliation><nlm:aff id="A3">Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="De Silva, Rohan" sort="De Silva, Rohan" uniqKey="De Silva R" first="Rohan" last="De Silva">Rohan De Silva</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Litvan, Irene" sort="Litvan, Irene" uniqKey="Litvan I" first="Irene" last="Litvan">Irene Litvan</name><affiliation><nlm:aff id="A7">Department of Neurology, Division of Movement Disorders, University of Louisville, Louisville, Kentucky, USA.</nlm:aff></affiliation></author><author><name sortKey="Riley, David E" sort="Riley, David E" uniqKey="Riley D" first="David E." last="Riley">David E. Riley</name><affiliation><nlm:aff id="A8">Department of Neurology, University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA.</nlm:aff></affiliation></author><author><name sortKey="Van Swieten, John C" sort="Van Swieten, John C" uniqKey="Van Swieten J" first="John C." last="Van Swieten">John C. Van Swieten</name><affiliation><nlm:aff id="A9">Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Heutink, Peter" sort="Heutink, Peter" uniqKey="Heutink P" first="Peter" last="Heutink">Peter Heutink</name><affiliation><nlm:aff id="A10">Department of Clinical Genetics, VU University Medical Center, Section Medical Genomics, Amsterdam, The Netherlands.</nlm:aff></affiliation></author><author><name sortKey="Wszolek, Zbigniew K" sort="Wszolek, Zbigniew K" uniqKey="Wszolek Z" first="Zbigniew K." last="Wszolek">Zbigniew K. Wszolek</name><affiliation><nlm:aff id="A11">Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Uitti, Ryan J" sort="Uitti, Ryan J" uniqKey="Uitti R" first="Ryan J." last="Uitti">Ryan J. Uitti</name><affiliation><nlm:aff id="A11">Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Vandrovcova, Jana" sort="Vandrovcova, Jana" uniqKey="Vandrovcova J" first="Jana" last="Vandrovcova">Jana Vandrovcova</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Hurtig, Howard I" sort="Hurtig, Howard I" uniqKey="Hurtig H" first="Howard I." last="Hurtig">Howard I. Hurtig</name><affiliation><nlm:aff id="A12">Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Gross, Rachel G" sort="Gross, Rachel G" uniqKey="Gross R" first="Rachel G." last="Gross">Rachel G. Gross</name><affiliation><nlm:aff id="A12">Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Maetzler, Walter" sort="Maetzler, Walter" uniqKey="Maetzler W" first="Walter" last="Maetzler">Walter Maetzler</name><affiliation><nlm:aff id="A13">Center of Neurology, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.</nlm:aff></affiliation><affiliation><nlm:aff id="A14">German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.</nlm:aff></affiliation></author><author><name sortKey="Goldwurm, Stefano" sort="Goldwurm, Stefano" uniqKey="Goldwurm S" first="Stefano" last="Goldwurm">Stefano Goldwurm</name><affiliation><nlm:aff id="A15">Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy.</nlm:aff></affiliation></author><author><name sortKey="Tolosa, Eduardo" sort="Tolosa, Eduardo" uniqKey="Tolosa E" first="Eduardo" last="Tolosa">Eduardo Tolosa</name><affiliation><nlm:aff id="A16">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.</nlm:aff></affiliation></author><author><name sortKey="Borroni, Barbara" sort="Borroni, Barbara" uniqKey="Borroni B" first="Barbara" last="Borroni">Barbara Borroni</name><affiliation><nlm:aff id="A17">Department of Medical and Surgical Sciences, Institute of Neurology, University of Brescia, Brescia, Italy.</nlm:aff></affiliation></author><author><name sortKey="Pastor, Pau" sort="Pastor, Pau" uniqKey="Pastor P" first="Pau" last="Pastor">Pau Pastor</name><affiliation><nlm:aff id="A18">CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.</nlm:aff></affiliation><affiliation><nlm:aff id="A19">Neurogenetics laboratory, Division of Neurosciences, University of Navarra Center for Applied Medical Research, Pamplona, Spain.</nlm:aff></affiliation><affiliation><nlm:aff id="A20">Department of Neurology, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain.</nlm:aff></affiliation></author><author><name sortKey="Cantwell, Laura B" sort="Cantwell, Laura B" uniqKey="Cantwell L" first="Laura B." last="Cantwell">Laura B. Cantwell</name><affiliation><nlm:aff id="A5">Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Han, Mi Ryung" sort="Han, Mi Ryung" uniqKey="Han M" first="Mi Ryung" last="Han">Mi Ryung Han</name><affiliation><nlm:aff id="A5">Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Dillman, Allissa" sort="Dillman, Allissa" uniqKey="Dillman A" first="Allissa" last="Dillman">Allissa Dillman</name><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Van Der Brug, Marcel P" sort="Van Der Brug, Marcel P" uniqKey="Van Der Brug M" first="Marcel P." last="Van Der Brug">Marcel P. Van Der Brug</name><affiliation><nlm:aff id="A22">Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Gibbs, J Raphael" sort="Gibbs, J Raphael" uniqKey="Gibbs J" first="J Raphael" last="Gibbs">J Raphael Gibbs</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R." last="Cookson">Mark R. Cookson</name><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Hernandez, Dena G" sort="Hernandez, Dena G" uniqKey="Hernandez D" first="Dena G." last="Hernandez">Dena G. Hernandez</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Singleton, Andrew B" sort="Singleton, Andrew B" uniqKey="Singleton A" first="Andrew B." last="Singleton">Andrew B. Singleton</name><affiliation><nlm:aff id="A21">Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</nlm:aff></affiliation></author><author><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><affiliation><nlm:aff id="A23">Department of Medical Genetics, CMMT, CRFI, BRC, PPRC, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:aff></affiliation></author><author><name sortKey="Yu, Chang En" sort="Yu, Chang En" uniqKey="Yu C" first="Chang-En" last="Yu">Chang-En Yu</name><affiliation><nlm:aff id="A24">Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A25">Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.</nlm:aff></affiliation></author><author><name sortKey="Golbe, Lawrence I" sort="Golbe, Lawrence I" uniqKey="Golbe L" first="Lawrence I." last="Golbe">Lawrence I. Golbe</name><affiliation><nlm:aff id="A26">Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.</nlm:aff></affiliation></author><author><name sortKey="Revesz, Tamas" sort="Revesz, Tamas" uniqKey="Revesz T" first="Tamas" last="Revesz">Tamas Revesz</name><affiliation><nlm:aff id="A27">Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Lees, Andrew J" sort="Lees, Andrew J" uniqKey="Lees A" first="Andrew J." last="Lees">Andrew J. Lees</name><affiliation><nlm:aff id="A6">Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation><affiliation><nlm:aff id="A27">Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.</nlm:aff></affiliation></author><author><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name><affiliation><nlm:aff id="A2">Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Hakonarson, Hakon" sort="Hakonarson, Hakon" uniqKey="Hakonarson H" first="Hakon" last="Hakonarson">Hakon Hakonarson</name><affiliation><nlm:aff id="A4">Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author><author><name sortKey="Muller, Ulrich" sort="Muller, Ulrich" uniqKey="Muller U" first="Ulrich" last="Müller">Ulrich Müller</name><affiliation><nlm:aff id="A28">Institut for Humangenetik, Justus-Liebig-Universität, Schlangenzahl 14, 35392 Giessen, Germany.</nlm:aff></affiliation></author><author><name sortKey="Schellenberg, Gerard D" sort="Schellenberg, Gerard D" uniqKey="Schellenberg G" first="Gerard D." last="Schellenberg">Gerard D. Schellenberg</name><affiliation><nlm:aff id="A5">Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</nlm:aff></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="ISSN">1061-4036</idno><idno type="eISSN">1546-1718</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P3">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<sup>−3</sup>. We found significant novel signals (P < 5 × 10<sup>−8</sup>) associated with PSP risk at <italic>STX6</italic>, <italic>EIF2AK3</italic>, and <italic>MOBP</italic>. We confirmed two independent variants in <italic>MAPT</italic> affecting risk for PSP, one of which influences <italic>MAPT</italic> 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hoppitt, T" uniqKey="Hoppitt T">T Hoppitt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Litvan, I" uniqKey="Litvan I">I Litvan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dickson, Dw" uniqKey="Dickson D">DW Dickson</name></author><author><name sortKey="Rademakers, R" uniqKey="Rademakers R">R Rademakers</name></author><author><name sortKey="Hutton, Ml" uniqKey="Hutton M">ML Hutton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stamelou, M" uniqKey="Stamelou M">M Stamelou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mckee, Ac" uniqKey="Mckee A">AC McKee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Golbe, Li" uniqKey="Golbe L">LI Golbe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stefansson, H" uniqKey="Stefansson H">H Stefansson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baker, M" uniqKey="Baker M">M Baker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cruchaga, C" uniqKey="Cruchaga C">C Cruchaga</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Houlden, H" uniqKey="Houlden H">H Houlden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sundar, Pd" uniqKey="Sundar P">PD Sundar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Simon Sanchez, J" uniqKey="Simon Sanchez J">J Simon-Sanchez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chanock, Sj" uniqKey="Chanock S">SJ Chanock</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Skol, Ad" uniqKey="Skol A">AD Skol</name></author><author><name sortKey="Scott, Lj" uniqKey="Scott L">LJ Scott</name></author><author><name sortKey="Abecasis, Gr" uniqKey="Abecasis G">GR Abecasis</name></author><author><name sortKey="Boehnke, M" uniqKey="Boehnke M">M Boehnke</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zody, Mc" uniqKey="Zody M">MC Zody</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tian, C" uniqKey="Tian C">C Tian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Litvan, I" uniqKey="Litvan I">I Litvan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Osaki, Y" uniqKey="Osaki Y">Y Osaki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Duffy, Dl" uniqKey="Duffy D">DL Duffy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Farrer, La" uniqKey="Farrer L">LA Farrer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rademakers, R" uniqKey="Rademakers R">R Rademakers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Caffrey, Tm" uniqKey="Caffrey T">TM Caffrey</name></author><author><name sortKey="Joachim, C" uniqKey="Joachim C">C Joachim</name></author><author><name sortKey="Paracchini, S" uniqKey="Paracchini S">S Paracchini</name></author><author><name sortKey="Esiri, Mm" uniqKey="Esiri M">MM Esiri</name></author><author><name sortKey="Wademartins, R" uniqKey="Wademartins R">R WadeMartins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Myers, Aj" uniqKey="Myers A">AJ Myers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harold, D" uniqKey="Harold D">D Harold</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lambert, Jc" uniqKey="Lambert J">JC Lambert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Seshadri, S" uniqKey="Seshadri S">S Seshadri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Naj, Ac" uniqKey="Naj A">AC Naj</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hollingworth, P" uniqKey="Hollingworth P">P Hollingworth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nalls, Ma" uniqKey="Nalls M">MA Nalls</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Unterberger, U" uniqKey="Unterberger U">U Unterberger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoozemans, Jjm" uniqKey="Hoozemans J">JJM Hoozemans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoozemans, Jj" uniqKey="Hoozemans J">JJ Hoozemans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jahn, R" uniqKey="Jahn R">R Jahn</name></author><author><name sortKey="Scheller, Rh" uniqKey="Scheller R">RH Scheller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wendler, F" uniqKey="Wendler F">F Wendler</name></author><author><name sortKey="Tooze, S" uniqKey="Tooze S">S Tooze</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Montague, P" uniqKey="Montague P">P Montague</name></author><author><name sortKey="Mccallion, As" uniqKey="Mccallion A">AS McCallion</name></author><author><name sortKey="Davies, Rw" uniqKey="Davies R">RW Davies</name></author><author><name sortKey="Griffiths, Ir" uniqKey="Griffiths I">IR Griffiths</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scheper, W" uniqKey="Scheper W">W Scheper</name></author><author><name sortKey="Hoozemans, Jjm" uniqKey="Hoozemans J">JJM Hoozemans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Paschen, W" uniqKey="Paschen W">W Paschen</name></author><author><name sortKey="Mengesdorf, T" uniqKey="Mengesdorf T">T Mengesdorf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, J" uniqKey="Wu J">J Wu</name></author><author><name sortKey="Devlin, B" uniqKey="Devlin B">B Devlin</name></author><author><name sortKey="Ringquist, S" uniqKey="Ringquist S">S Ringquist</name></author><author><name sortKey="Trucco, M" uniqKey="Trucco M">M Trucco</name></author><author><name sortKey="Roeder, K" uniqKey="Roeder K">K Roeder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hauw, Jj" uniqKey="Hauw J">JJ Hauw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dickson, Dw" uniqKey="Dickson D">DW Dickson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Ab" uniqKey="Lee A">AB Lee</name></author><author><name sortKey="Luca, D" uniqKey="Luca D">D Luca</name></author><author><name sortKey="Klei, L" uniqKey="Klei L">L Klei</name></author><author><name sortKey="Devlin, B" uniqKey="Devlin B">B Devlin</name></author><author><name sortKey="Roeder, K" uniqKey="Roeder K">K Roeder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crossett, A" uniqKey="Crossett A">A Crossett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tian, C" uniqKey="Tian C">C Tian</name></author><author><name sortKey="Plenge, Rm" uniqKey="Plenge R">RM Plenge</name></author><author><name sortKey="Ransom, M" uniqKey="Ransom M">M Ransom</name></author><author><name sortKey="Lee, A" uniqKey="Lee A">A Lee</name></author><author><name sortKey="Villoslada, P" uniqKey="Villoslada P">P Villoslada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Price, Al" uniqKey="Price A">AL Price</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Luca, D" uniqKey="Luca D">D Luca</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gibbs, Jr" uniqKey="Gibbs J">JR Gibbs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Purcell, S" uniqKey="Purcell S">S Purcell</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9216904</journal-id><journal-id journal-id-type="pubmed-jr-id">2419</journal-id><journal-id journal-id-type="nlm-ta">Nat Genet</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Genet.</journal-id><journal-title-group><journal-title>Nature genetics</journal-title></journal-title-group><issn pub-type="ppub">1061-4036</issn><issn pub-type="epub">1546-1718</issn></journal-meta><article-meta><article-id pub-id-type="pmid">21685912</article-id><article-id pub-id-type="pmc">3125476</article-id><article-id pub-id-type="doi">10.1038/ng.859</article-id><article-id pub-id-type="manuscript">NIHMS297077</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Höglinger</surname><given-names>Günter U.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FN2">30</xref></contrib><contrib contrib-type="author"><name><surname>Melhem</surname><given-names>Nadine M.</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="author-notes" rid="FN2">30</xref></contrib><contrib contrib-type="author"><name><surname>Dickson</surname><given-names>Dennis W.</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref ref-type="author-notes" rid="FN2">30</xref></contrib><contrib contrib-type="author"><name><surname>Sleiman</surname><given-names>Patrick M.A.</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="author-notes" rid="FN2">30</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Li-San</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Klei</surname><given-names>Lambertus</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Rademakers</surname><given-names>Rosa</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>de Silva</surname><given-names>Rohan</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Litvan</surname><given-names>Irene</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Riley</surname><given-names>David E.</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>van Swieten</surname><given-names>John C.</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Heutink</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Wszolek</surname><given-names>Zbigniew K.</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Uitti</surname><given-names>Ryan J.</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Vandrovcova</surname><given-names>Jana</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Hurtig</surname><given-names>Howard I.</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Gross</surname><given-names>Rachel G.</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Maetzler</surname><given-names>Walter</given-names></name><xref ref-type="aff" rid="A13">13</xref><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Goldwurm</surname><given-names>Stefano</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Tolosa</surname><given-names>Eduardo</given-names></name><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><name><surname>Borroni</surname><given-names>Barbara</given-names></name><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><name><surname>Pastor</surname><given-names>Pau</given-names></name><xref ref-type="aff" rid="A18">18</xref><xref ref-type="aff" rid="A19">19</xref><xref ref-type="aff" rid="A20">20</xref></contrib><contrib contrib-type="author"><collab>PSP Genetics Study Group</collab><xref ref-type="author-notes" rid="FN1">29</xref></contrib><contrib contrib-type="author"><name><surname>Cantwell</surname><given-names>Laura B.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Han</surname><given-names>Mi Ryung</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Dillman</surname><given-names>Allissa</given-names></name><xref ref-type="aff" rid="A21">21</xref></contrib><contrib contrib-type="author"><name><surname>van der Brug</surname><given-names>Marcel P.</given-names></name><xref ref-type="aff" rid="A22">22</xref></contrib><contrib contrib-type="author"><name><surname>Gibbs</surname><given-names>J Raphael</given-names></name><xref ref-type="aff" rid="A6">6</xref><xref ref-type="aff" rid="A21">21</xref></contrib><contrib contrib-type="author"><name><surname>Cookson</surname><given-names>Mark R.</given-names></name><xref ref-type="aff" rid="A21">21</xref></contrib><contrib contrib-type="author"><name><surname>Hernandez</surname><given-names>Dena G.</given-names></name><xref ref-type="aff" rid="A6">6</xref><xref ref-type="aff" rid="A21">21</xref></contrib><contrib contrib-type="author"><name><surname>Singleton</surname><given-names>Andrew B.</given-names></name><xref ref-type="aff" rid="A21">21</xref></contrib><contrib contrib-type="author"><name><surname>Farrer</surname><given-names>Matthew J.</given-names></name><xref ref-type="aff" rid="A23">23</xref></contrib><contrib contrib-type="author"><name><surname>Yu</surname><given-names>Chang-En</given-names></name><xref ref-type="aff" rid="A24">24</xref><xref ref-type="aff" rid="A25">25</xref></contrib><contrib contrib-type="author"><name><surname>Golbe</surname><given-names>Lawrence I.</given-names></name><xref ref-type="aff" rid="A26">26</xref></contrib><contrib contrib-type="author"><name><surname>Revesz</surname><given-names>Tamas</given-names></name><xref ref-type="aff" rid="A27">27</xref></contrib><contrib contrib-type="author"><name><surname>Hardy</surname><given-names>John</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Lees</surname><given-names>Andrew J.</given-names></name><xref ref-type="aff" rid="A6">6</xref><xref ref-type="aff" rid="A27">27</xref></contrib><contrib contrib-type="author"><name><surname>Devlin</surname><given-names>Bernie</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hakonarson</surname><given-names>Hakon</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Müller</surname><given-names>Ulrich</given-names></name><xref ref-type="aff" rid="A28">28</xref><xref ref-type="author-notes" rid="FN2">30</xref></contrib><contrib contrib-type="author"><name><surname>Schellenberg</surname><given-names>Gerard D.</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="author-notes" rid="FN2">30</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Neurology, Philipps-Universität, Marburg, Germany.</aff><aff id="A2"><label>2</label>Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.</aff><aff id="A3"><label>3</label>Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.</aff><aff id="A4"><label>4</label>Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.</aff><aff id="A5"><label>5</label>Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.</aff><aff id="A6"><label>6</label>Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK.</aff><aff id="A7"><label>7</label>Department of Neurology, Division of Movement Disorders, University of Louisville, Louisville, Kentucky, USA.</aff><aff id="A8"><label>8</label>Department of Neurology, University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA.</aff><aff id="A9"><label>9</label>Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.</aff><aff id="A10"><label>10</label>Department of Clinical Genetics, VU University Medical Center, Section Medical Genomics, Amsterdam, The Netherlands.</aff><aff id="A11"><label>11</label>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.</aff><aff id="A12"><label>12</label>Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.</aff><aff id="A13"><label>13</label>Center of Neurology, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.</aff><aff id="A14"><label>14</label>German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.</aff><aff id="A15"><label>15</label>Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy.</aff><aff id="A16"><label>16</label>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.</aff><aff id="A17"><label>17</label>Department of Medical and Surgical Sciences, Institute of Neurology, University of Brescia, Brescia, Italy.</aff><aff id="A18"><label>18</label>CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.</aff><aff id="A19"><label>19</label>Neurogenetics laboratory, Division of Neurosciences, University of Navarra Center for Applied Medical Research, Pamplona, Spain.</aff><aff id="A20"><label>20</label>Department of Neurology, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain.</aff><aff id="A21"><label>21</label>Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.</aff><aff id="A22"><label>22</label>Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.</aff><aff id="A23"><label>23</label>Department of Medical Genetics, CMMT, CRFI, BRC, PPRC, University of British Columbia, Vancouver, British Columbia, Canada.</aff><aff id="A24"><label>24</label>Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.</aff><aff id="A25"><label>25</label>Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.</aff><aff id="A26"><label>26</label>Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.</aff><aff id="A27"><label>27</label>Department of Molecular Neuroscience, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.</aff><aff id="A28"><label>28</label>Institut for Humangenetik, Justus-Liebig-Universität, Schlangenzahl 14, 35392 Giessen, Germany.</aff><author-notes><corresp id="cor1">Correspondence and requests for materials should be addressed to G.D.S. (<email>gerardsc@mail.med.upenn.edu</email>) or U.M. (<email>Ulrich.Mueller@humangenetik.med.uni-giessen.de</email>)</corresp><fn id="FN1"><label>29</label><p id="P1">A list of PSP Genetics Study Group coauthors and their affiliations appears at the end of the paper.</p></fn><fn id="FN2" fn-type="equal"><label>30</label><p id="P2">These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>15</day><month>6</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>19</day><month>6</month><year>2011</year></pub-date><pub-date pub-type="collection"><month>7</month><year>2011</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>1</month><year>2012</year></pub-date><volume>43</volume><issue>7</issue><fpage>699</fpage><lpage>705</lpage><pmc-comment>elocation-id from pubmed: 10.1038/ng.859</pmc-comment>
<permissions><license><license-p>Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: <uri xlink:type="simple" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri></license-p></license></permissions><abstract><p id="P3">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<sup>−3</sup>. We found significant novel signals (P < 5 × 10<sup>−8</sup>) associated with PSP risk at <italic>STX6</italic>, <italic>EIF2AK3</italic>, and <italic>MOBP</italic>. We confirmed two independent variants in <italic>MAPT</italic> affecting risk for PSP, one of which influences <italic>MAPT</italic> 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.</p></abstract></article-meta></front><body><p id="P4">PSP is a rare neurodegenerative movement disorder clinically characterized by falls, axial rigidity, vertical supranuclear gaze palsy, bradykinesia, and cognitive decline. Though PSP is rare (prevalence is 3.1–6.5/100,000<sup><xref rid="R1" ref-type="bibr">1</xref></sup>), after Parkinson’s disease (PD), PSP is the second most common cause of degenerative parkinsonism<sup><xref rid="R2" ref-type="bibr">2</xref></sup>. PSP is a tauopathy with abnormal accumulation of tau protein within neurons as neurofibrillary tangles (NFTs), primarily in the basal ganglia, diencephalon, and brainstem, with neuronal loss in globus pallidus, subthalamic nucleus and substantia nigra. Abnormal tau also accumulates within oligodendroglia and astrocytes<sup><xref rid="R3" ref-type="bibr">3</xref></sup>. In Alzheimer’s disease (AD), even though all cases have NFTs, Aβ plaques are closely tied to the primary disease process, and thus AD is a secondary tauopathy. PSP is a primary tauopathy because tau is the major abnormal protein observed. Both environmental insults and inherited factors contribute to the risk of developing tauopathies<sup><xref rid="R4" ref-type="bibr">4</xref></sup>. Repetitive brain trauma, associated with certain sports, can cause chronic traumatic encephalopathy associated with tau deposits<sup><xref rid="R5" ref-type="bibr">5</xref></sup>. Viral encephalitis, associated with subsequent parkinsonism, is also associated with tau neuropathology. In PSP, neurotoxins<sup><xref rid="R4" ref-type="bibr">4</xref></sup> and low education levels<sup><xref rid="R6" ref-type="bibr">6</xref></sup> may also contribute to risk. Genetic risk for PSP is in part determined by variants at a 1 Mb inversion polymorphism that contains a number of genes including <italic>MAPT</italic>, the gene that encodes tau<sup><xref rid="R7" ref-type="bibr">7</xref></sup>. The inversion variants are called H1 and H2 “haplotypes”, with H1 conferring risk for PSP<sup><xref rid="R8" ref-type="bibr">8</xref></sup>. H1 also contributes to risk for corticobasal degeneration<sup><xref rid="R9" ref-type="bibr">9</xref>,<xref rid="R10" ref-type="bibr">10</xref></sup> and Guam amyotrophic lateral sclerosis/parkinsonism dementia complex<sup><xref rid="R11" ref-type="bibr">11</xref></sup>, both rare tauopathies. H1 does not contribute to risk for AD. Surprisingly, H1 is also a risk factor for PD<sup><xref rid="R12" ref-type="bibr">12</xref></sup>, a movement disorder with clinical features that overlap those of PSP, yet in PD there are no neuropathologically recognizable tau containing lesions.</p><p id="P5">We performed a genome wide association (GWA) study of PSP to identify genes that modify risk for this primary tauopathy. We performed a two-stage analysis to maximize efficiency while maintaining power<sup><xref rid="R13" ref-type="bibr">13</xref>,<xref rid="R14" ref-type="bibr">14</xref></sup>. For Stage 1 we used only autopsied cases (n = 1,114), thereby essentially eliminating incorrect diagnoses. These were contrasted with 3,287 controls; 96% of cases and 90% of controls were of European ancestry (<xref ref-type="table" rid="T1">Table 1</xref>, <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>). We assessed association between genotypes at 531,451 single nucleotide polymorphisms (SNPs) and PSP status among subjects of all ancestries (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 2</xref>) and those of only European ancestry (<xref ref-type="table" rid="T2">Table 2</xref>) using an additive model. Results from both ancestry groups were similar. Because our control samples were younger than cases, we compared their allele frequencies at significant and strongly suggestive SNPs to those of older controls (N = 3,816) from three datasets from the NIH repository Database for Genotypes and Phenotypes (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 3</xref>). Only SNPs with no significant differences in allele frequencies between old and young controls are presented in <xref ref-type="table" rid="T2">Table 2</xref>.</p><p id="P6">Stage 1 P-values (P<sub>1</sub>) for SNPs in three regions crossed the significance threshold of P < 5 × 10<sup>−8</sup> (<xref ref-type="table" rid="T2">Table 2</xref>, <xref ref-type="fig" rid="F1">Fig. 1</xref>). At 1q25.3, a SNP in <italic>STX6</italic> crossed this threshold (P<sub>1</sub> = 1.8 × 10<sup>−9</sup>). Another SNP at 3p22.1 in <italic>MOBP</italic> crosses this threshold (P<sub>1</sub> = 1.0 × 10<sup>−9</sup>). The third region was 17q21.31, in which 58 SNPs had P<sub>1</sub> < 5 × 10<sup>−8</sup> (<xref ref-type="table" rid="T2">Table 2</xref>, <xref ref-type="fig" rid="F2">Fig. 2a</xref>). This focus of association is the approximately 1 Mb H1/H2 inversion polymorphism containing <italic>MAPT</italic><sup><xref rid="R15" ref-type="bibr">15</xref></sup>.</p><p id="P7">SNPs for Stage 2 were selected from the original set if they yielded a P<sub>1</sub> < 10<sup>−3</sup>. We assessed 4,099 SNPs for association in 1,051 cases, mostly living subjects clinically diagnosed with PSP (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 4</xref>) and 3,560 control subjects, all of European ancestry. We also included 197 ancestry informative markers<sup><xref rid="R16" ref-type="bibr">16</xref></sup> to evaluate population substructure. Clinically diagnosed PSP<sup><xref rid="R17" ref-type="bibr">17</xref></sup> is reasonably concordant with autopsy results<sup><xref rid="R18" ref-type="bibr">18</xref></sup>. We estimated the diagnostic misclassification rate as 12%, which has only a small impact on power (<xref ref-type="supplementary-material" rid="SD3">Online Methods</xref>).</p><p id="P8">All three loci associated in Stage 1, were replicated by joint analysis (<xref ref-type="table" rid="T2">Table 2</xref>, <xref ref-type="fig" rid="F1">Figs. 1</xref> and <xref ref-type="fig" rid="F2">2</xref>). Joint analysis revealed two new loci with joint P-values (P<sub>J</sub>) below the genome-wide significant threshold. One was at 2p11.2, within <italic>EIF2AK3</italic> (P<sub>J</sub> = 3.2 × 10<sup>−13</sup>). Another, rs12203592 (P<sub>J</sub> = 6.2 × 10<sup>−15</sup>), at 6p25.3, highlighted <italic>IRF4</italic>, with a neighboring SNP in <italic>EXOC2</italic>, rs2493013 (P<sub>J</sub> = 6.0 × 10<sup>−7</sup>); rs2493013 was significant after controlling for rs12203592 at P < 1 × 10<sup>−3</sup> (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 5</xref>). However, allele frequencies for rs12203592 and rs2493013 in older controls were significantly different from those of our controls (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 3</xref>). Curiously, the older control data sets were all significantly different from each other. While rs12203592 alleles frequencies vary widely across Europe<sup><xref rid="R19" ref-type="bibr">19</xref></sup>, we could not ascribe these fluctuations amongst controls to either ancestry or genotyping artifacts. In the joint analysis, 3 other loci reached suggestive association (an intergenic region at 1q41, P<sub>J</sub> = 2.8 × 10<sup>−7</sup>; <italic>BMS1</italic>, P<sub>J</sub> = 4.9 × 10<sup>−7</sup>; <italic>SLCO1A2</italic>, P<sub>J</sub> = 1.9 × 10<sup>−7</sup>; <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 6 and Figure 5</xref>).</p><p id="P9">In the <italic>MAPT</italic> region, most of the PSP-associated SNPs mapped directly or closely onto H1/H2, producing very small P-values (<italic>e.g.</italic>, for rs8070723, P<sub>1</sub> = 2.1 × 10<sup>−51</sup>, P<sub>J</sub> = 1.5 × 10<sup>−116</sup>). H1 confers risk and 95% of PSP subject chromosomes are H1 compared to 77.5% of control chromosomes. In the Stage 1 autopsy cases, the odds ratio (OR) is 5.5 [confidence interval (C.I.) 4.4 – 6.86, <xref ref-type="table" rid="T2">Table 2</xref>], which is stronger than the OR for the <italic>APOE</italic> ε3/ε4 genotype as a risk locus for AD<sup><xref rid="R20" ref-type="bibr">20</xref></sup>. The OR for the Stage 2 PSP samples was comparable to the Stage 1 OR, evidence that the clinically and autopsy-diagnosed cohorts are similar in composition.</p><p id="P10">If all of the risk from 17q21.31 were associated with H1/H2, controlling for H1/H2 (using rs8070723 as a proxy) should be sufficient to make association at all other loci in this region non-significant. That is not the case; instead certain SNPs remained associated, with the maximum falling in <italic>MAPT</italic> (rs242557) (<xref ref-type="table" rid="T2">Table 2</xref>, <xref ref-type="fig" rid="F2">Figure 2</xref>, <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 5</xref>). No other 17q21.31 SNPs showed association after controlling for rs8070723 and rs242557 genotypes. SNP rs242557 was previously identified as a key regulatory polymorphism influencing <italic>MAPT</italic> expression<sup><xref rid="R21" ref-type="bibr">21</xref></sup>. Note that rs242557 accounts for only part of the total risk associated with H1/H2 (<xref ref-type="table" rid="T2">Table 2</xref>).</p><p id="P11">The SNPs used to detect a GWA signal are not necessarily the risk-causing variants. For <italic>STX6</italic> and <italic>EIF2AK3</italic>, there are non-synonymous SNPs in close proximity to and highly correlated with the top GWA SNPs (<xref ref-type="supplementary-material" rid="SD2">Supplementary Table 7</xref>) making these coding changes candidates for the pathogenic change. To evaluate the possibility that some risk-variants regulate gene expression, we analyzed the correlations between gene expression levels from two brain regions of 387 normal subjects and SNP genotypes for the regions listed in <xref ref-type="table" rid="T2">Table 2</xref>. Two regions showed strong genotype-expression associations (<xref ref-type="fig" rid="F3">Fig. 3</xref>). SNPs falling in or near <italic>MOBP</italic> have some effect on <italic>MOBP</italic> expression, but are more strongly correlated with <italic>SLC25A38</italic> expression, which is 70 kb from <italic>MOBP</italic> (<xref ref-type="fig" rid="F3">Fig. 3a</xref>). This effect on <italic>SLC25A38</italic> is seen in cerebellum but is weaker in the frontal cortex.</p><p id="P12">The second region showing a strong genotype-expression correlation is the <italic>MAPT</italic> inversion region. SNP alleles across the entire H1/H2 inversion and flanking regions show strong correlation with not only <italic>MAPT</italic> expression (p = 8.71 × 10<sup>−28</sup> for multiple SNPs), but also with <italic>ARL17A</italic> (P = 9.2 × 10<sup>−22</sup>), <italic>PLEKHM1</italic> (P = 1.0 × 10<sup>−9</sup>), and <italic>LRRC37A4</italic> (P = 2.2 × 10<sup>−35</sup>)<sup><xref rid="R12" ref-type="bibr">12</xref></sup>. Note that while <italic>MAPT</italic> expression is correlated with SNPs across the entire inversion region, the SNPs influencing <italic>ARL17A</italic> are associated with a subset of regional SNPs and these are not identical to the SNPs affecting <italic>MAPT</italic> expression. Expression of <italic>CRHR1</italic> and <italic>KIAA1267</italic>, genes that are in the inversion region and that flank <italic>MAPT</italic>, is not correlated with H1/H2 SNPs.</p><p id="P13">To distinguish between the effects on gene expression of the inversion <italic>versus</italic> other independent effects, we controlled for H1/H2 as was done for association with PSP (<xref ref-type="table" rid="T2">Table 2</xref>). After controlling for H1/H2, all significant genotype-expression correlation for <italic>MAPT</italic> and <italic>LRRC37A4</italic> disappears (<xref ref-type="fig" rid="F3">Fig. 3c</xref>) showing that either the orientation of this region or a polymorphism that maps onto H1/H2, determines <italic>MAPT</italic> expression. In contrast, controlling for H1/H2 has no effect on genotype-expression correlations for <italic>ARL17A</italic>. Potential eSNPs for <italic>ARL17A</italic> include rs242557 (<xref ref-type="table" rid="T2">Table 2</xref>), which is highly associated with PSP but more modestly correlated with <italic>ARL17A</italic> expression, and rs8079215, which is highly correlated with <italic>ARL17A</italic> expression but not as strongly with risk for PSP. Statistical modeling of these data produce the following conclusions: haplotypes involving H1 and rs242557 alleles predict a highly significant portion of the variability of <italic>ARL17A</italic> expression; however, essentially all of that variance can be explained by alleles at rs8079215, which are correlated with H1/H2 and rs242557 alleles; and that alleles at rs8079215 cannot predict risk for PSP independent of H1/H2 status even though they are excellent predictors of <italic>ARL17A</italic> expression. In sum, risk for PSP does not rise and fall with <italic>ARL17A</italic> expression. The global <italic>MAPT</italic> brain region expression analyzed here does not explain how rs242557 alleles confer risk to PSP. Yet this SNP or a correlated polymorphism is assumed to have a regulatory effect because there are no coding variants in <italic>MAPT</italic> brain isoforms that are candidate pathogenic variants. One possible explanation is that rs242557 alleles could affect alternative splicing without altering total <italic>MAPT</italic> expression levels<sup><xref rid="R22" ref-type="bibr">22</xref>,<xref rid="R23" ref-type="bibr">23</xref></sup>.</p><p id="P14">Because AD and PSP are tauoptahies, and because H1 is a shared risk factor for PSP and PD, we determined whether any confirmed AD<sup><xref rid="R24" ref-type="bibr">24</xref>–<xref rid="R28" ref-type="bibr">28</xref></sup> or PD<sup><xref rid="R29" ref-type="bibr">29</xref></sup> loci also produced suggestive evidence for PSP association (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 8</xref>). Besides the overlap between PD and PSP at <italic>MAPT</italic>, the single noteworthy result was from rs2075650 in <italic>TOMM40</italic> that yielded P<sub>J</sub> = 1.28 × 10<sup>−5</sup> for association with PSP. <italic>TOMM40</italic> is adjacent to <italic>APOE</italic> and rs2075650 tags the AD risk allele, e4, in <italic>APOE</italic>. The effect in PSP is opposite that seen in AD: e4 frequency is elevated in AD and diminished in PSP (for rs2075650, the estimated MAF in cases is 0.11 <italic>versus</italic> 0.15 in both our young and older controls; r<sup>2</sup> between rs2075650 and e4 is 0.33).</p><p id="P15">Our work suggests a number of intriguing insights into PSP. One comes from <italic>EIF2AK3</italic>, a gene that encodes PERK, a component of the endoplasmic reticulum (ER) unfolded protein response (UPR). When excess unfolded proteins accumulate in the ER, PERK is activated and protein synthesis is inhibited allowing the ER to clear mis-folded proteins and return to homeostasis. The UPR is active in PSP<sup><xref rid="R30" ref-type="bibr">30</xref></sup>, AD<sup><xref rid="R31" ref-type="bibr">31</xref></sup>, and PD<sup><xref rid="R32" ref-type="bibr">32</xref></sup>. In PSP, activated PERK is in neurons, oligodendrocytes, and astrocytes<sup><xref rid="R30" ref-type="bibr">30</xref></sup>. In AD, activated UPR components are found in pre-tangle neurons in a number of brain regions<sup><xref rid="R31" ref-type="bibr">31</xref></sup>. In PD, UPR activation occurs in neuromelanin containing dopaminergic neurons in the substantia nigra<sup><xref rid="R32" ref-type="bibr">32</xref></sup>. How the UPR contributes to PSP pathogenesis is unclear because the primary mis-folded protein in PSP, tau, is not a secreted protein and thus is not expected to traffic through the ER.</p><p id="P16">The PSP susceptibility gene <italic>STX6</italic> encodes syntaxin 6 (Stx6), a SNARE class protein. SNARE proteins are part of the cellular machinery that catalyzes the fusion of vesicles with membranes<sup><xref rid="R33" ref-type="bibr">33</xref></sup>. Stx6 is localized to the <italic>trans</italic>-Golgi network and endosomal structures<sup><xref rid="R34" ref-type="bibr">34</xref></sup>. Since our work implicates ER-stress in PSP pathogenesis, genetic variation at <italic>STX6</italic> could influence movement of mis-folded proteins from the ER to lysosomes <italic>via</italic> the endosomal system.</p><p id="P17"><italic>MOBP</italic> (P<sub>J</sub> = 1 × 10<sup>−16</sup>), like the myelin basic protein gene (<italic>MBP</italic>), encodes a protein (MOBP) that is produced by oligodendrocytes and is present in the major dense line of CNS myelin. MOBP is highly expressed in the white matter of the medulla, pons, cerebellum, and midbrain<sup><xref rid="R35" ref-type="bibr">35</xref></sup>, regions affected in PSP. Our findings suggest that myelin dysfunction or oligodendrocyte mis-function contributes to PSP pathogenesis.</p><p id="P18">Our work generates a testable translational hypothesis based on the results for <italic>EIK2AK3</italic>. Our work suggests that perturbation of the UPR can influence PSP risk, and that the UPR is not just a downstream consequence of neurodegeneration. Thus pharmacologic modulation of the UPR is a potential therapeutic strategy for PSP<sup><xref rid="R36" ref-type="bibr">36</xref>,<xref rid="R37" ref-type="bibr">37</xref></sup>.</p><sec sec-type="supplementary-material" id="SM"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><label>1</label><media xlink:href="NIHMS297077-supplement-1.pdf" mimetype="application" mime-subtype="pdf" orientation="portrait" xlink:type="simple" id="d37e1181" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD2"><label>2</label><media xlink:href="NIHMS297077-supplement-2.xlsx" mimetype="application" mime-subtype="octet-stream" orientation="portrait" xlink:type="simple" id="d37e1185" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD3"><label>3</label><media xlink:href="NIHMS297077-supplement-3.pdf" mimetype="application" mime-subtype="pdf" orientation="portrait" xlink:type="simple" id="d37e1189" position="anchor"></media></supplementary-material></sec></body><back><ack id="S1"><title>Acknowledgements</title><p id="P21">We thank the patients and their families that participated in this study. This work was funded by grants from the CurePSP Foundation, the Peebler <italic>PSP</italic> Research Foundation, and National Institutes on Health (NIH) grants R37 AG 11762, R01 PAS-03-092, P50 NS72187, P01 AG17216 [National Institute on Aging(NIA)/NIH], MH057881 and MH077930 [National Institute of Mental Health (NIMH)]. Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS08136-4) and the Deutsche Forschungsgemeinschaft (HO 2402/6-1), Prinses Beatrix Fonds (JCvS, 01–0128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and by a grant from the Alzheimer’s Society and Alzheimer’s Research Trust as part of the Brains for Dementia Resarch Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the 'Human Genetic Bank of Patients affected by Parkinson Disease and parkinsonism' (<ext-link ext-link-type="uri" xlink:href="http://www.parkinson.it/dnabank.html">http://www.parkinson.it/dnabank.html</ext-link>) of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project n. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Brain-Net-Germany is supported by BMBF (01GI0505). RdS, AJL and JAH are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. RdS is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF)Research Committee CR programs (MCF #90052030 and MCF #90052030), and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). The Mayo Clinic College of Medicine would like to acknowledge Matt Baker, Richard Crook, Mariely DeJesus-Hernandez and Nicola Rutherford for their preparation of samples. PP was supported by a grant from the Government of Navarra ("Ayudas para la Realización de Proyectos de Investigación" 2006–2007) and acknowledges the "Iberian Atypical Parkinsonism Study Group Researchers", i.e. Maria A. Pastor, Maria R. Luquin, Mario Riverol, Jose A. Obeso and Maria C Rodriguez-Oroz (Department of Neurology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain), Marta Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), Adolfo Lopez de Munain, Begoña Indakoetxea, Javier Olaskoaga, Javier Ruiz, José Félix Martí Massó (Servicio de Neurología, Hospital Donostia, San Sebastián, Spain), Victoria Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), Teresa Tuñon (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), Fermin Moreno (Servicio de Neurología, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), Ainhoa Alzualde (Neurogenétics Department, Hospital Donostia, San Sebastián, Spain).</p><p id="P22">The datasets used for older controls were obtained from Database for Genotypes and Phenotypes (dbGap) at <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/gap">http://www.ncbi.nlm.nih.gov/gap</ext-link>. Funding support for the “Genetic Consortium for Late Onset Alzheimer’s Disease” was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer’s Disease (Study accession number: phs000168.v1.p1) includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late Onset Alzheimer’s Disease. Funding support for the “CIDR Visceral Adiposity Study” (Study accession number: phs000169.v1.p1) was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The CIDR Visceral Adiposity Study includes a genome-wide association study funded as part of the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Heath ABC Study Investigators. Funding support for the Personalized Medicine Research Project (PMRP) was provided through a cooperative agreement (U01HG004608) with the National Human Genome Research Institute (NHGRI), with additional funding from the National Institute for General Medical Sciences (NIGMS) The samples used for PMRP analyses were obtained with funding from Marshfield Clinic, Health Resources Service Administration Office of Rural Health Policy grant number D1A RH00025, and Wisconsin Department of Commerce Technology Development Fund contract number TDF FYO10718. Funding support for genotyping, which was performed at Johns Hopkins University, was provided by the NIH (U01HG004438). Assistance with phenotype harmonization and genotype cleaning was provided by the eMERGE Administrative Coordinating Center (U01HG004603) and the National Center for Biotechnology Information (NCBI). The datasets used for the analyses described in this manuscript were obtained from dbGaP at <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/gap">http://www.ncbi.nlm.nih.gov/gap</ext-link> through dbGaP accession number phs000170.v1.p1.</p></ack><fn-group><fn id="FN3" fn-type="con"><p id="P23"><bold>Author Contributions</bold> Co-first authors G.U.H., N.M.M., D.W.D., and P.M.A.S. and senior authors U.M. and G.D.S., contributed equally to this project. G.U.H. and U.M. initiated this study and consortium, drafted the first grant and protocol, coordinated the European sample acquisition and preparation, contributed to data interpretation, and contributed to the preparation of the manuscript. N.M.M. conducted the analyses and contributed to the preparation of the manuscript. D.W.D. contributed to study design, data interpretation, and contributed to the preparation of the manuscript. P.M.A.S. contributed in the selection of controls for both phases of the experiment, data QC, data analysis and content curation for the replication phase custom array. L.S.W. participated in the initial association analysis, eSNP and pathway analysis, and functional annotation of SNPs in top genes. L.K. participated in genotype QC and analysis. R.R and R.DeSilva participated in study design, sample preparation and revising the manuscript for content. I.Litvan, D.E.R., J.C.V., P.H., Z.K.W., R.J.U., J.V., H.I.H., R.G.G., W.M., S.G., E.T., B.B., P.P., and the PSP Genetics Study Group (R.L.A., E.A., A.A., M.A., S.E.A., J.A., T.B., S.B., D.B., T.D.B., N.B., A.J.W.B., Y.B., A.B., H.B., M.C., W.Z.C., R.C., C.C., P.P.D., J.G.D., L.D.K., R.Duara, A.Durr, S.E., G.F., N.A.F., R.F., M.P.F., C.G., D.R.G., T.G., M.Gearing, E.T.G., B.G., N.R.G.R., M.Grossman, D.A.H., L.H., M.H., J.J., J.L.J., A.K., H.A.K., I.Leber, V.M.L., A.P.L., K.L., C.Mariani, E.M., L.A.M., C.A.M., N.M., B.L.M., B.M., J.C.M., H.R.M., C.Morris, S.S.O., W.H.O., D.O., A.P., R.P., G.P., S.P.B., W.P., A.Rabano, A.Rajput, S.G.R., G.R., S.R., J.D.R., O.A.R., M.N.R., G.S., W.W.S., K.Seppi, L.S.M., S.S., K.Srulijes, P.S.G., M.S., D.G.S., S.T., W.W.T., C.Trenkwalder, C.Troakes, J.Q.T., J.C.T., V.M.V., J.P.G.V., G.K.W., C.L.W., P.W., C.Z., and A.L.Z.) participated in characterization, preparation and contribution of samples from patients with PSP. L.B.C. coordinated project, sample acquisition and selection, and managed phenotypes. M.R.H. conducted eSNP and pathway analysis. A.Dillman performed mRNA expression experiments in human brain. M.P.V. and D.G.H. performed mRNA expression experiments in human brain, contributed to the design of eQTL experiments. J.R.G. performed computational and statistical analysis of the expression QTL data, contributed to the design of eQTL experiments. M.R.C. and A.B.S. were responsible for overall supervision, design and analysis of eQTL experiments. J.C.V., M.J.F., L.I.G., J.H., A.J.L., participated in study design, and data analysis discussions. C.E.Y. and T.R. participated in the initial design of experiments. B.D. supervised analyses and contributed to the writing of the manuscript. H.H. supervised genotyping and platform and sample selection, participated in analyses, and reviewed the manuscript. G.D.S. led the consortium, supervised study design, coordinated the United States sample acquisition and preparation, contributed to data interpretation, and wrote and coordinated assembly of the manuscript.</p></fn><fn id="FN4"><p id="P24"><bold>Competing Financial Interests</bold> T.G. serves as an editorial board member of <italic>Movement Disorders and Parkinsonism and Related Disorders</italic> and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).</p></fn></fn-group><app-group><app id="APP1"><title>PSP Genetics Study Group coauthors</title><p id="P19">Roger L. Albin<sup>31,32</sup>, Elena Alonso<sup>33,34</sup>, Angelo Antonini<sup>35,36</sup>, Manuela Apfelbacher<sup>37</sup>, Steven E. Arnold<sup>38</sup>, Jesus Avila<sup>39</sup>, Thomas G. Beach<sup>40</sup>, Sherry Beecher<sup>41</sup>, Daniela Berg<sup>42</sup>, Thomas D. Bird<sup>43</sup>, Nenad Bogdanovic<sup>44</sup>, Agnita J.W. Boon<sup>45</sup>, Yvette Bordelon<sup>46</sup>, Alexis Brice<sup>47,48,49</sup>, Herbert Budka<sup>50</sup>, Margherita Canesi<sup>35</sup>, Wang Zheng Chiu<sup>45</sup>, Roberto Cilia<sup>35</sup>, Carlo Colosimo<sup>51</sup>, Peter P. De Deyn<sup>52</sup>, Justo García de Yebenes<sup>53</sup>, Laura Donker Kaat<sup>45</sup>, Ranjan Duara<sup>54</sup>, Alexandra Durr<sup>47,48,49</sup>, Sebastiaan Engelborghs<sup>52</sup>, Giovanni Fabbrini<sup>51</sup>, NiCole A. Finch<sup>55</sup>, Robyn Flook<sup>56</sup>, Matthew P. Frosch<sup>57</sup>, Carles Gaig<sup>58</sup>, Douglas R. Galasko<sup>59</sup>, Thomas Gasser<sup>42</sup>, Marla Gearing<sup>60</sup>, Evan T. Geller<sup>41</sup>, Bernardino Ghetti<sup>61</sup>, Neill R. Graff-Radford<sup>62</sup>, Murray Grossman<sup>63</sup>, Deborah A. Hall<sup>64</sup>, Lili-Naz Hazrati<sup>65</sup>, Matthias Höllerhage<sup>66</sup>, Joseph Jankovic<sup>67</sup>, Jorge L. Juncos<sup>68</sup>, Anna Karydas<sup>69</sup>, Hans A. Kretzschmar<sup>70</sup>, Isabelle Leber<sup>47,48,49</sup>, Virginia M. Lee<sup>41</sup>, Andrew P. Lieberman<sup>71</sup>, Kelly E. Lyons<sup>72</sup>, Claudio Mariani<sup>35</sup>, Eliezer Masliah<sup>59,73</sup>, Luke A. Massey<sup>74</sup>, Catriona A. McLean<sup>75</sup>, Nicoletta Meucci<sup>35</sup>, Bruce L. Miller<sup>69</sup>, Brit Mollenhauer<sup>76,77</sup>, Jens C. Möller<sup>66</sup>, Huw R. Morris<sup>78</sup>, Chris Morris<sup>79</sup>, Sean S. O’Sullivan<sup>74</sup>, Wolfgang H. Oertel<sup>66</sup>, Donatella Ottaviani<sup>51</sup>, Alessandro Padovani<sup>80</sup>, Rajesh Pahwa<sup>72</sup>, Gianni Pezzoli<sup>35</sup>, Stuart Pickering-Brown<sup>81</sup>, Werner Poewe<sup>82</sup>, Alberto Rabano<sup>83</sup>, Alex Rajput<sup>84</sup>, Stephen G Reich<sup>85</sup>, Gesine Respondek<sup>66</sup>, Sigrun Roeber<sup>70</sup>, Jonathan D. Rohrer<sup>86</sup>, Owen A. Ross<sup>55</sup>, Martin N. Rossor<sup>86</sup>, Giorgio Sacilotto<sup>35</sup>, William W. Seeley<sup>69</sup>, Klaus Seppi<sup>82</sup>, Laura Silveira-Moriyama<sup>74</sup>, Salvatore Spina<sup>61</sup>, Karin Srulijes<sup>42</sup>, Peter St. George-Hyslop<sup>65,87</sup>, Maria Stamelou<sup>66</sup>, David G. Standaert<sup>88</sup>, Silvana Tesei<sup>35</sup>, Wallace W. Tourtellotte<sup>89</sup>, Claudia Trenkwalder<sup>77</sup>, Claire Troakes<sup>90</sup>, John Q. Trojanowski<sup>41</sup>, Juan C. Troncoso<sup>91</sup>, Vivianna M. Van Deerlin<sup>41</sup>, Jean Paul G. Vonsattel<sup>92</sup>, Gregor K. Wenning<sup>82</sup>, Charles L. White<sup>93</sup>, Pia Winter<sup>94</sup>, Chris Zarow<sup>95</sup>, Anna L. Zecchinelli<sup>35</sup></p><p id="P20"><bold>PSP Genetics Study Group coauthor affiliations</bold><sup>31</sup>Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. <sup>32</sup>Geriatrics Research, Education, and Clinical Center, VA Ann Arbor Health System, Ann Arbor, Michigan, USA. <sup>33</sup>Neurogenetics laboratory, Division of Neurosciences, University of Navarra Center for Applied Medical Research, Pamplona, Spain. <sup>34</sup>Neurogenetics laboratory, Division of Neurosciences, University of Navarra Center for Applied Medical Research, Pamplona, Spain. <sup>35</sup>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. <sup>36</sup>Department for Parkinson's Disease, IRCCS San Camillo, Venice, Italy. <sup>37</sup>Institute of Legal Medicine, University of Würzburg, Würzburg, Germany. <sup>38</sup>Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. <sup>39</sup>Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Campus Cantoblanco, Universidad Autonoma de Madrid, Madrid, Spain. <sup>40</sup>Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA. <sup>41</sup>Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. <sup>42</sup>Center of Neurology, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen and German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany. <sup>43</sup>Departments of Medicine, Neurology, and Medical Genetics, University of Washington, Seattle, Washington, USA. <sup>44</sup>Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Hudding University Hospital, Stockholm, Sweden. <sup>45</sup>Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands. <sup>46</sup>Department of Neurology, University of California Los Angeles, Los Angeles, California, USA. <sup>47</sup>Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Université Pierre et Marie Curie, Paris, France. <sup>48</sup>Institut National de la Santé et de la Recherche Médicale, Paris, France. <sup>49</sup>Centre National de la Recherche Scientifique, Paris, France. <sup>50</sup>Institute of Neurology, Medical University Vienna, Vienna, Austria. <sup>51</sup>Dipartimento di Scienze Neurologiche e Psichiatriche, Sapienza Università di Roma, Rome, Italy. <sup>52</sup>Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. <sup>53</sup>Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain. <sup>54</sup>Wien Center for Alzheimer's Disease and Memory Disorders, Mt Sinai Medical Center, Miami Beach, Florida, USA. <sup>55</sup>Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. <sup>56</sup>Centre for Neuroscience, Flinders University and Australian Brain Bank Network, Victoria, Australia. <sup>57</sup>C.S. Kubik Laboratory for Neuropathology and Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. <sup>58</sup>Neurology Service, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain. <sup>59</sup>Department of Neurosciences, University of California San Diego, La Jolla, California, USA. <sup>60</sup>Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. <sup>61</sup>Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. <sup>62</sup>Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA. <sup>63</sup>Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA. <sup>64</sup>Department of Neurological Sciences, Rush University, Chicago, IL, USA. <sup>65</sup>Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada. <sup>66</sup>Department of Neurology, Philipps University, Marburg, Germany. <sup>67</sup>Department of Neurology, Baylor College of Medicine, Houston, TX, USA. <sup>68</sup>Depratment of Neurology, Emory University, Atlanta, GA, USA. <sup>69</sup>Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA. <sup>70</sup>Institut für Neuropathologie, Ludwig-Maximilians-Universität and Brain Net Germany, Munich, Germany. <sup>71</sup>Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. <sup>72</sup>Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA. <sup>73</sup>Department of Pathology, University of California San Diego, La Jolla, CA, USA. <sup>74</sup>Reta Lila Weston Institute, UCL Institute of Neurology, University College London, London, UK. <sup>75</sup>Victorian Brain Bank Network, Mental Health Research Institute, Victoria, Australia. <sup>76</sup>Department of Neurology, Georg-August University, Goettingen, Germany. <sup>77</sup>Paracelsus-Elena-Klinik, University of Goettingen, Kassel, Germany. <sup>78</sup>MRC Centre for Neuropsychiatric Genetics and Department of Neurology, School of Medicine, Cardiff University, Cardiff, UK. <sup>79</sup>Newcastle Brain Tissue Resource, Newcastle University, Institute for Ageing and Health, Newcastle upon Tyne, UK. <sup>80</sup>Department of Medical and Surgical Sciences, Institute of Neurology, University of Brescia, Brescia, Italy. <sup>81</sup>Neurodegeneration and Mental Health Research Group, Faculty of Human and Medical Sciences, University of Manchester, Manchester, UK. <sup>82</sup>Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. <sup>83</sup>Department of Neuropathology and Tissue Bank Fundación CIEN, Instituto de Salud Carlos III, Madrid, Spain. <sup>84</sup>Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatchewan, Canada. <sup>85</sup>Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. <sup>86</sup>Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, University College London, London, UK. <sup>87</sup>Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. <sup>88</sup>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA. <sup>89</sup>Human Brain and Spinal Fluid Resource Center, Veterans Affairs West Los Angeles Healthcare Center, Los Angeles, CA, USA. <sup>90</sup>Department of Clinical Neuroscience, MRC Centre for Neurodegeneration Research, King's College London, London, UK. <sup>91</sup>Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. <sup>92</sup>Department of Pathology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York City, NY, USA. <sup>93</sup>Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. <sup>94</sup>Institute of Human Genetics, Justus-Liebig University, Giessen, Germany. <sup>95</sup>Rancho Los Amigos National Rehabilitation Center, University of Southern California, Downey, CA, USA.</p></app></app-group><ref-list><title>References</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hoppitt</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>A Systematic Review of the Incidence and Prevalence of Long-Term Neurological Conditions in the UK</article-title><source>Neuroepidemiology</source><year>2011</year><volume>36</volume><fpage>19</fpage><lpage>28</lpage><pub-id pub-id-type="pmid">21088431</pub-id></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Litvan</surname><given-names>I</given-names></name></person-group><article-title>Update on progressive supranuclear palsy</article-title><source>Curr Neurol Neurosci Rep</source><year>2004</year><volume>4</volume><fpage>296</fpage><lpage>302</lpage><pub-id pub-id-type="pmid">15217544</pub-id></element-citation></ref><ref id="R3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dickson</surname><given-names>DW</given-names></name><name><surname>Rademakers</surname><given-names>R</given-names></name><name><surname>Hutton</surname><given-names>ML</given-names></name></person-group><article-title>Progressive supranuclear palsy: Pathology and genetics</article-title><source>Brain Pathology</source><year>2007</year><volume>17</volume><fpage>74</fpage><lpage>82</lpage><pub-id pub-id-type="pmid">17493041</pub-id></element-citation></ref><ref id="R4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stamelou</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Rational therapeutic approaches to progressive supranuclear palsy</article-title><source>Brain</source><year>2010</year><volume>133</volume><fpage>1578</fpage><lpage>1590</lpage><pub-id pub-id-type="pmid">20472654</pub-id></element-citation></ref><ref id="R5"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McKee</surname><given-names>AC</given-names></name><etal></etal></person-group><article-title>TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy</article-title><source>J Neuropathol Exp Neurol</source><year>2010</year><volume>69</volume><fpage>918</fpage><lpage>929</lpage><pub-id pub-id-type="pmid">20720505</pub-id></element-citation></ref><ref id="R6"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Golbe</surname><given-names>LI</given-names></name><etal></etal></person-group><article-title>Follow-up study of risk factors in progressive supranuclear palsy</article-title><source>Neurology</source><year>1996</year><volume>47</volume><fpage>148</fpage><lpage>154</lpage><pub-id pub-id-type="pmid">8710069</pub-id></element-citation></ref><ref id="R7"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stefansson</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>A common inversion under selection in Europeans</article-title><source>Nat. Genet</source><year>2005</year><volume>37</volume><fpage>129</fpage><lpage>137</lpage><pub-id pub-id-type="pmid">15654335</pub-id></element-citation></ref><ref id="R8"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Baker</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Association of an extended haplotype in the tau gene with progressive supranuclear palsy</article-title><source>Hum. Mol. Genet</source><year>1999</year><volume>8</volume><fpage>711</fpage><lpage>715</lpage><pub-id pub-id-type="pmid">10072441</pub-id></element-citation></ref><ref id="R9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cruchaga</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>5'-Upstream variants of CRHR1 and MAPT genes associated with age at onset in progressive supranuclear palsy and cortical basal degeneration</article-title><source>Neurobiol Dis</source><year>2009</year><volume>33</volume><fpage>164</fpage><lpage>170</lpage><pub-id pub-id-type="pmid">19022385</pub-id></element-citation></ref><ref id="R10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Houlden</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype</article-title><source>Neurology</source><year>2001</year><volume>56</volume><fpage>1702</fpage><lpage>1706</lpage><pub-id pub-id-type="pmid">11425937</pub-id></element-citation></ref><ref id="R11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sundar</surname><given-names>PD</given-names></name><etal></etal></person-group><article-title>Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia</article-title><source>Hum. Molec. Genet</source><year>2007</year><volume>16</volume><fpage>295</fpage><lpage>306</lpage><pub-id pub-id-type="pmid">17185385</pub-id></element-citation></ref><ref id="R12"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Simon-Sanchez</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Genome-wide association study reveals genetic risk underlying Parkinson's disease</article-title><source>Nat Genet</source><year>2009</year><volume>41</volume><fpage>1308</fpage><lpage>1312</lpage><pub-id pub-id-type="pmid">19915575</pub-id></element-citation></ref><ref id="R13"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chanock</surname><given-names>SJ</given-names></name><etal></etal></person-group><article-title>Replicating genotype-phenotype associations</article-title><source>Nature</source><year>2007</year><volume>447</volume><fpage>655</fpage><lpage>660</lpage><pub-id pub-id-type="pmid">17554299</pub-id></element-citation></ref><ref id="R14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Skol</surname><given-names>AD</given-names></name><name><surname>Scott</surname><given-names>LJ</given-names></name><name><surname>Abecasis</surname><given-names>GR</given-names></name><name><surname>Boehnke</surname><given-names>M</given-names></name></person-group><article-title>Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies</article-title><source>Nat. Genet</source><year>2006</year><volume>38</volume><fpage>209</fpage><lpage>213</lpage><pub-id pub-id-type="pmid">16415888</pub-id></element-citation></ref><ref id="R15"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zody</surname><given-names>MC</given-names></name><etal></etal></person-group><article-title>Evolutionary toggling of the MAPT 17q21.31 inversion region</article-title><source>Nat Genet</source><year>2008</year><volume>40</volume><fpage>1076</fpage><lpage>1083</lpage><pub-id pub-id-type="pmid">19165922</pub-id></element-citation></ref><ref id="R16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tian</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Analysis and application of European genetic substructure using 300 K SNP information</article-title><source>PLoS Genet</source><year>2008</year><volume>4</volume><fpage>e4</fpage><pub-id pub-id-type="pmid">18208329</pub-id></element-citation></ref><ref id="R17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Litvan</surname><given-names>I</given-names></name><etal></etal></person-group><article-title>Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): Report of the NINDS-SPSP international workshop</article-title><source>Neurology</source><year>1996</year><volume>47</volume><fpage>1</fpage><lpage>9</lpage><pub-id pub-id-type="pmid">8710059</pub-id></element-citation></ref><ref id="R18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Osaki</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Accuracy of clinical diagnosis of progressive supranuclear palsy</article-title><source>Movement Disorders</source><year>2004</year><volume>19</volume><fpage>181</fpage><lpage>189</lpage><pub-id pub-id-type="pmid">14978673</pub-id></element-citation></ref><ref id="R19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Duffy</surname><given-names>DL</given-names></name><etal></etal></person-group><article-title>Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma</article-title><source>J Invest Dermatol</source><year>2010</year><volume>130</volume><fpage>520</fpage><lpage>528</lpage><pub-id pub-id-type="pmid">19710684</pub-id></element-citation></ref><ref id="R20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Farrer</surname><given-names>LA</given-names></name><etal></etal></person-group><article-title>Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium</article-title><source>JAMA</source><year>1997</year><volume>278</volume><fpage>1349</fpage><lpage>1356</lpage><pub-id pub-id-type="pmid">9343467</pub-id></element-citation></ref><ref id="R21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rademakers</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy</article-title><source>Hum. Mol. Genet</source><year>2005</year><volume>14</volume><fpage>3281</fpage><lpage>3292</lpage><pub-id pub-id-type="pmid">16195395</pub-id></element-citation></ref><ref id="R22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Caffrey</surname><given-names>TM</given-names></name><name><surname>Joachim</surname><given-names>C</given-names></name><name><surname>Paracchini</surname><given-names>S</given-names></name><name><surname>Esiri</surname><given-names>MM</given-names></name><name><surname>WadeMartins</surname><given-names>R</given-names></name></person-group><article-title>Haplotype-specific expression of exon 10 at the human MAPT locus</article-title><source>Human Molecular Genetics</source><year>2006</year><volume>15</volume><fpage>3529</fpage><lpage>3537</lpage><pub-id pub-id-type="pmid">17085483</pub-id></element-citation></ref><ref id="R23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Myers</surname><given-names>AJ</given-names></name><etal></etal></person-group><article-title>The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts</article-title><source>Neurobiol. Dis</source><year>2007</year><volume>25</volume><fpage>561</fpage><lpage>570</lpage><pub-id pub-id-type="pmid">17174556</pub-id></element-citation></ref><ref id="R24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Harold</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease</article-title><source>Nat Genet</source><year>2009</year><volume>41</volume><comment>1088-U61</comment></element-citation></ref><ref id="R25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lambert</surname><given-names>JC</given-names></name><etal></etal></person-group><article-title>Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease</article-title><source>Nat Genet</source><year>2009</year><volume>41</volume><fpage>1094</fpage><lpage>1099</lpage><pub-id pub-id-type="pmid">19734903</pub-id></element-citation></ref><ref id="R26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Seshadri</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Genome-wide analysis of genetic loci associated with Alzheimer disease</article-title><source>JAMA</source><year>2010</year><volume>303</volume><fpage>1832</fpage><lpage>1840</lpage><pub-id pub-id-type="pmid">20460622</pub-id></element-citation></ref><ref id="R27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Naj</surname><given-names>AC</given-names></name><etal></etal></person-group><article-title>Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease</article-title><source>Nature Genetics</source><year>2011</year><volume>43</volume><fpage>436</fpage><lpage>441</lpage><pub-id pub-id-type="pmid">21460841</pub-id></element-citation></ref><ref id="R28"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hollingworth</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease</article-title><source>Nature Genetics</source><year>2011</year><volume>43</volume><fpage>429</fpage><lpage>435</lpage><pub-id pub-id-type="pmid">21460840</pub-id></element-citation></ref><ref id="R29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nalls</surname><given-names>MA</given-names></name><etal></etal></person-group><article-title>Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies</article-title><source>Lancet</source><year>2011</year><volume>377</volume><fpage>641</fpage><lpage>649</lpage><pub-id pub-id-type="pmid">21292315</pub-id></element-citation></ref><ref id="R30"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Unterberger</surname><given-names>U</given-names></name><etal></etal></person-group><article-title>Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo</article-title><source>Journal of Neuropathology and Experimental Neurology</source><year>2006</year><volume>65</volume><fpage>348</fpage><lpage>357</lpage><pub-id pub-id-type="pmid">16691116</pub-id></element-citation></ref><ref id="R31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hoozemans</surname><given-names>JJM</given-names></name><etal></etal></person-group><article-title>The Unfolded Protein Response Is Activated in Pretangle Neurons in Alzheimer's Disease Hippocampus</article-title><source>Amer J Pathol</source><year>2009</year><volume>174</volume><fpage>1241</fpage><lpage>1251</lpage><pub-id pub-id-type="pmid">19264902</pub-id></element-citation></ref><ref id="R32"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hoozemans</surname><given-names>JJ</given-names></name><etal></etal></person-group><article-title>Activation of the unfolded protein response in Parkinson's disease</article-title><source>Biochem Biophys Res Commun</source><year>2007</year><volume>354</volume><fpage>707</fpage><lpage>711</lpage><pub-id pub-id-type="pmid">17254549</pub-id></element-citation></ref><ref id="R33"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jahn</surname><given-names>R</given-names></name><name><surname>Scheller</surname><given-names>RH</given-names></name></person-group><article-title>SNAREs--engines for membrane fusion</article-title><source>Nat Rev Mol Cell Biol</source><year>2006</year><volume>7</volume><fpage>631</fpage><lpage>643</lpage><pub-id pub-id-type="pmid">16912714</pub-id></element-citation></ref><ref id="R34"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wendler</surname><given-names>F</given-names></name><name><surname>Tooze</surname><given-names>S</given-names></name></person-group><article-title>Syntaxin 6: the promiscuous behaviour of a SNARE protein</article-title><source>Traffic</source><year>2001</year><volume>2</volume><fpage>606</fpage><lpage>611</lpage><pub-id pub-id-type="pmid">11555414</pub-id></element-citation></ref><ref id="R35"><label>35</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Montague</surname><given-names>P</given-names></name><name><surname>McCallion</surname><given-names>AS</given-names></name><name><surname>Davies</surname><given-names>RW</given-names></name><name><surname>Griffiths</surname><given-names>IR</given-names></name></person-group><article-title>Myelin-associated oligodendrocytic basic protein: a family of abundant CNS myelin proteins in search of a function</article-title><source>Dev Neurosci</source><year>2006</year><volume>28</volume><fpage>479</fpage><lpage>487</lpage><pub-id pub-id-type="pmid">17028425</pub-id></element-citation></ref><ref id="R36"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Scheper</surname><given-names>W</given-names></name><name><surname>Hoozemans</surname><given-names>JJM</given-names></name></person-group><article-title>Endoplasmic Reticulum Protein Quality Control in Neurodegenerative Disease: The Good, the Bad and the Therapy</article-title><source>Curr Medicinal Chem</source><year>2009</year><volume>16</volume><fpage>615</fpage><lpage>626</lpage></element-citation></ref><ref id="R37"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Paschen</surname><given-names>W</given-names></name><name><surname>Mengesdorf</surname><given-names>T</given-names></name></person-group><article-title>Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease - therapeutic potential</article-title><source>Pharmacology & Therapeutics</source><year>2005</year><volume>108</volume><fpage>362</fpage><lpage>375</lpage><pub-id pub-id-type="pmid">16140387</pub-id></element-citation></ref><ref id="R38"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>J</given-names></name><name><surname>Devlin</surname><given-names>B</given-names></name><name><surname>Ringquist</surname><given-names>S</given-names></name><name><surname>Trucco</surname><given-names>M</given-names></name><name><surname>Roeder</surname><given-names>K</given-names></name></person-group><article-title>Screen and clean: a tool for identifying interactions in genome-wide association studies</article-title><source>Genet Epidemiol</source><year>2010</year><volume>34</volume><fpage>275</fpage><lpage>285</lpage><pub-id pub-id-type="pmid">20088021</pub-id></element-citation></ref><ref id="R39"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hauw</surname><given-names>JJ</given-names></name><etal></etal></person-group><article-title>Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy)</article-title><source>Neurology</source><year>1994</year><volume>44</volume><fpage>2015</fpage><lpage>2019</lpage><pub-id pub-id-type="pmid">7969952</pub-id></element-citation></ref><ref id="R40"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dickson</surname><given-names>DW</given-names></name><etal></etal></person-group><article-title>Office of rare diseases neuropathologic criteria for corticobasal degeneration</article-title><source>Journal of Neuropathology and Experimental Neurology</source><year>2002</year><volume>61</volume><fpage>935</fpage><lpage>946</lpage><pub-id pub-id-type="pmid">12430710</pub-id></element-citation></ref><ref id="R41"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>AB</given-names></name><name><surname>Luca</surname><given-names>D</given-names></name><name><surname>Klei</surname><given-names>L</given-names></name><name><surname>Devlin</surname><given-names>B</given-names></name><name><surname>Roeder</surname><given-names>K</given-names></name></person-group><article-title>Discovering genetic ancestry using spectral graph theory</article-title><source>Genet Epidemiol</source><year>2010</year><volume>34</volume><fpage>51</fpage><lpage>59</lpage><pub-id pub-id-type="pmid">19455578</pub-id></element-citation></ref><ref id="R42"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Crossett</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Using ancestry matching to combine family-based and unrelated samples for genome-wide association studies</article-title><source>Stat Med</source><year>2010</year><volume>29</volume><fpage>2932</fpage><lpage>2945</lpage><pub-id pub-id-type="pmid">20862653</pub-id></element-citation></ref><ref id="R43"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tian</surname><given-names>C</given-names></name><name><surname>Plenge</surname><given-names>RM</given-names></name><name><surname>Ransom</surname><given-names>M</given-names></name><name><surname>Lee</surname><given-names>A</given-names></name><name><surname>Villoslada</surname><given-names>P</given-names></name></person-group><article-title>Analysis and application of European genetic substructure using 300K SNP information</article-title><source>PLoS Genet</source><year>2008</year><volume>4</volume><fpage>e4</fpage><pub-id pub-id-type="pmid">18208329</pub-id></element-citation></ref><ref id="R44"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Price</surname><given-names>AL</given-names></name><etal></etal></person-group><article-title>Principal components analysis corrects for stratification in genome-wide association studies</article-title><source>Nat. Genet</source><year>2006</year><volume>38</volume><fpage>904</fpage><lpage>909</lpage><pub-id pub-id-type="pmid">16862161</pub-id></element-citation></ref><ref id="R45"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Luca</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>On the use of general control samples for genome-wide association studies: genetic matching highlights causal variants</article-title><source>Am. J. Hum. Genet</source><year>2008</year><comment>(in press)</comment></element-citation></ref><ref id="R46"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gibbs</surname><given-names>JR</given-names></name><etal></etal></person-group><article-title>Abundant quantitative trait Loci exist for DNA methylation and gene expression in human brain</article-title><source>PLoS Genet</source><year>2010</year><volume>6</volume><fpage>e1000952</fpage><pub-id pub-id-type="pmid">20485568</pub-id></element-citation></ref><ref id="R47"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Purcell</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>PLINK: A tool set for whole-genome association and population-based linkage analysis</article-title><source>Am. J. Hum. Genet</source><year>2007</year><volume>81</volume><fpage>559</fpage><lpage>575</lpage><pub-id pub-id-type="pmid">17701901</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><p id="P25">(a) Association results for 1q25.3 <italic>STX6</italic>. (b) Association results for 2p11.2 <italic>EIF2AK3</italic>. (c) Association results for 3p22.1 <italic>MOBP</italic> regions. –log10 P values are shown for Stages 1 and 2 and the joint analyses. Recombination rate, calculated from the linkage disequilibrium (LD) structure of the region, is derived from Hapmap3 data. LD, encoded by intensity of the colors, is the pairwise LD of the most highly associated SNP at Stage 1 with each of the SNPs in the region. Transcript positions are shown below each graph.</p></caption><graphic xlink:href="nihms297077f1"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><p id="P26">(a) Association results for the 17q21.31 H1/H2 inversion polymorphism (40,974,015 – 41,926,692 Kb) and flanking segments. (b) Association results for 17q21.31 controlling for H1/H2. Results are shown for Stages 1 and 2 and the joint analyses. Recombination rate, calculated from the linkage disequilibrium (LD) structure of the region, is derived from Hapmap3 data. LD, encoded by intensity of the colors, is the pairwise LD of the most highly associated SNP at Stage 1 with each of the SNPs in the region.</p></caption><graphic xlink:href="nihms297077f2"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><p id="P27"><bold>(a)</bold> Association results for the relationship between SNP genotypes and mRNA transcripts from the cerebellum and frontal cortex for the <italic>SLC25S38/MOBP</italic> region. (b) Association results for the relationship between SNP genotypes and mRNA transcripts from the cerebellum and frontal cortex for the H1/H2 inversion polymorphism region. (c) Association results for the relationship between SNP genotypes and mRNA transcripts from the cerebellum and frontal cortex for the H1/H2 inversion polymorphism region controlling for H1/H2. The color of the circle corresponds to the color assigned each gene and each SNP is tested against multiple <italic>cis</italic> transcripts. The data presented here are independent samples from those used previously by Simon-Sanchez <italic>et al.</italic><sup><xref rid="R12" ref-type="bibr">12</xref></sup>.</p></caption><graphic xlink:href="nihms297077f3"></graphic></fig><table-wrap id="T1" position="float" orientation="landscape"><label>Table 1</label><caption><p id="P28">Characteristics of the samples<xref ref-type="table-fn" rid="TFN1">a</xref></p></caption><table frame="box" rules="all"><thead><tr><th align="center" rowspan="2" valign="middle" colspan="1">Cohort</th><th align="center" rowspan="2" valign="middle" colspan="1">Total<break></break>sample<break></break>analyzed</th><th align="center" colspan="2" valign="top" rowspan="1">Gender (male)</th><th align="center" colspan="4" valign="top" rowspan="1">Onset Age</th><th align="center" colspan="4" valign="top" rowspan="1">Age-at-death</th><th align="center" colspan="4" valign="top" rowspan="1">Disease Duration</th></tr><tr><th align="center" valign="top" rowspan="1" colspan="1">Percent</th><th align="center" valign="top" rowspan="1" colspan="1">n<xref ref-type="table-fn" rid="TFN2">b</xref></th><th align="center" valign="top" rowspan="1" colspan="1">Mean<break></break>age</th><th align="center" valign="top" rowspan="1" colspan="1">Range</th><th align="center" valign="top" rowspan="1" colspan="1">SD<break></break>(±)</th><th align="center" valign="top" rowspan="1" colspan="1">n</th><th align="center" valign="top" rowspan="1" colspan="1">Mean<break></break>age</th><th align="center" valign="top" rowspan="1" colspan="1">range</th><th align="center" valign="top" rowspan="1" colspan="1">SD<break></break>(±)</th><th align="center" valign="top" rowspan="1" colspan="1">n</th><th align="center" valign="top" rowspan="1" colspan="1">Mean<break></break>duration<break></break>(years)</th><th align="center" valign="top" rowspan="1" colspan="1">range</th><th align="center" valign="top" rowspan="1" colspan="1">SD<break></break>(±)</th><th align="center" valign="top" rowspan="1" colspan="1">n</th></tr></thead><tbody><tr><td align="center" rowspan="1" colspan="1">PSP stage 1<xref ref-type="table-fn" rid="TFN3">c</xref></td><td align="center" rowspan="1" colspan="1">1,114</td><td align="center" rowspan="1" colspan="1">55 </td><td align="center" rowspan="1" colspan="1">599</td><td align="center" rowspan="1" colspan="1">68</td><td align="center" rowspan="1" colspan="1">(41–93)</td><td align="center" rowspan="1" colspan="1">8.2</td><td align="center" rowspan="1" colspan="1">827</td><td align="center" rowspan="1" colspan="1">75</td><td align="center" rowspan="1" colspan="1">45–99</td><td align="center" rowspan="1" colspan="1">8.0</td><td align="center" rowspan="1" colspan="1">1,070</td><td align="center" rowspan="1" colspan="1">7.4</td><td align="center" rowspan="1" colspan="1">1–21</td><td align="center" rowspan="1" colspan="1">3.2</td><td align="center" rowspan="1" colspan="1">827</td></tr><tr><td align="center" rowspan="1" colspan="1">PSP stage 1 European Ancestry</td><td align="center" rowspan="1" colspan="1">1,069</td><td align="center" rowspan="1" colspan="1">55</td><td align="center" rowspan="1" colspan="1">570</td><td align="center" rowspan="1" colspan="1">68</td><td align="center" rowspan="1" colspan="1">(41–93)</td><td align="center" rowspan="1" colspan="1">8.3</td><td align="center" rowspan="1" colspan="1">794</td><td align="center" rowspan="1" colspan="1">75</td><td align="center" rowspan="1" colspan="1">45–99</td><td align="center" rowspan="1" colspan="1">8.0</td><td align="center" rowspan="1" colspan="1">1,025</td><td align="center" rowspan="1" colspan="1">7.4</td><td align="center" rowspan="1" colspan="1">1–21</td><td align="center" rowspan="1" colspan="1">3.1</td><td align="center" rowspan="1" colspan="1">794</td></tr><tr><td align="center" rowspan="1" colspan="1">PSP stage 2<xref ref-type="table-fn" rid="TFN4">d</xref></td><td align="center" rowspan="1" colspan="1">1,051</td><td align="center" rowspan="1" colspan="1">53</td><td align="center" rowspan="1" colspan="1">530</td><td align="center" rowspan="1" colspan="1">65</td><td align="center" rowspan="1" colspan="1">(40–91)</td><td align="center" rowspan="1" colspan="1">7.3</td><td align="center" rowspan="1" colspan="1">913</td><td align="center" rowspan="1" colspan="1">75</td><td align="center" rowspan="1" colspan="1">57–94</td><td align="center" rowspan="1" colspan="1">7.4</td><td align="center" rowspan="1" colspan="1">118</td><td align="center" rowspan="1" colspan="1">8.0</td><td align="center" rowspan="1" colspan="1"><1–18</td><td align="center" rowspan="1" colspan="1">3.3</td><td align="center" rowspan="1" colspan="1">42</td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><label>a</label><p id="P29">Controls were young normal subjects recruited from the Children's Hospital of Philadelphia Health Care Network (See <xref ref-type="supplementary-material" rid="SD3">Online Methods</xref> for details). These were 3,287 controls for Stage 1 and 3,560 for Stage 2;</p></fn><fn id="TFN2"><label>b</label><p id="P30">n, number of samples with available data. Values of n for each type of analysis do not add up to the total samples used because of missing values;</p></fn><fn id="TFN3"><label>c</label><p id="P31">Stage 1 consisted of autopsy-confirmed cases.</p></fn><fn id="TFN4"><label>d</label><p id="P32">The stage 2 dataset included 130 cases with autopsies. All stage 2 samples (cases and controls) were independent of stage 1 samples.</p></fn></table-wrap-foot></table-wrap><table-wrap id="T2" position="float" orientation="landscape"><label>Table 2</label><caption><p id="P33">Results from Stage 1, Stage 2, and joint analysis among subjects of European Ancestry: SNPs Significant at P < 5 × 10<sup>−8</sup> in the joint analysis</p></caption><table frame="box" rules="all"><thead><tr><th align="center" rowspan="2" valign="middle" colspan="1">Chr band</th><th align="center" rowspan="2" valign="middle" colspan="1">SNP<break></break>Location<break></break>(bp)</th><th align="center" rowspan="2" valign="middle" colspan="1">Gene or<break></break>nearby<break></break>gene</th><th align="center" colspan="4" valign="top" rowspan="1">Stage 1</th><th align="center" colspan="4" valign="top" rowspan="1">Stage 2</th><th align="center" colspan="2" valign="top" rowspan="1">Joint P</th></tr><tr><th align="center" valign="top" rowspan="1" colspan="1">MAF<xref ref-type="table-fn" rid="TFN5">a</xref><break></break>Case</th><th align="center" valign="top" rowspan="1" colspan="1">MAF<break></break>Cont<xref ref-type="table-fn" rid="TFN6">b</xref></th><th align="center" valign="bottom" rowspan="1" colspan="1">OR<xref ref-type="table-fn" rid="TFN7">c</xref>/CI</th><th align="center" valign="bottom" rowspan="1" colspan="1">P<sub>1</sub></th><th align="center" valign="top" rowspan="1" colspan="1">MAF<break></break>Case</th><th align="center" valign="top" rowspan="1" colspan="1">MAF<break></break>Cont</th><th align="center" valign="bottom" rowspan="1" colspan="1">OR / CI</th><th align="center" valign="bottom" rowspan="1" colspan="1">P<sub>2</sub></th><th align="center" valign="bottom" rowspan="1" colspan="1">OR/CI</th><th align="center" valign="bottom" rowspan="1" colspan="1">P<sub>J</sub></th></tr></thead><tbody><tr><td align="center" rowspan="1" colspan="1">1q25.3</td><td align="center" rowspan="1" colspan="1">rs1411478<break></break>179,229,155</td><td align="center" rowspan="1" colspan="1"><italic>STX6</italic></td><td align="center" rowspan="1" colspan="1">0.50</td><td align="center" rowspan="1" colspan="1">0.42</td><td align="center" rowspan="1" colspan="1">0.73<break></break>0.65 – 0.81</td><td align="center" valign="top" rowspan="1" colspan="1">1.8 × 10<sup>−9</sup></td><td align="center" rowspan="1" colspan="1">0.46</td><td align="center" rowspan="1" colspan="1">0.43</td><td align="center" rowspan="1" colspan="1">0.85<break></break>0.77 – 0.94</td><td align="center" rowspan="1" colspan="1">1.5 × 10<sup>−3</sup></td><td align="center" rowspan="1" colspan="1">0.79<break></break>0.74 – 0.85</td><td align="center" valign="top" rowspan="1" colspan="1">2.3 × 10<sup>−10</sup></td></tr><tr><td align="center" rowspan="1" colspan="1">2p11.2</td><td align="center" rowspan="1" colspan="1">rs7571971<break></break>88,676,716</td><td align="center" rowspan="1" colspan="1"><italic>EIF2AK3</italic></td><td align="center" rowspan="1" colspan="1">0.31</td><td align="center" rowspan="1" colspan="1">0.26</td><td align="center" rowspan="1" colspan="1">0.75<break></break>0.66 – 0.84</td><td align="center" rowspan="1" colspan="1">7.4 × 10<sup>−7</sup></td><td align="center" rowspan="1" colspan="1">0.31</td><td align="center" rowspan="1" colspan="1">0.25</td><td align="center" rowspan="1" colspan="1">0.75<break></break>0.67 – 0.83</td><td align="center" rowspan="1" colspan="1">8.7 × 10<sup>−8</sup></td><td align="center" rowspan="1" colspan="1">0.75<break></break>0.69 – 0.81</td><td align="center" rowspan="1" colspan="1">3.2 × 10<sup>−13</sup></td></tr><tr><td align="center" rowspan="1" colspan="1">3p22.1</td><td align="center" rowspan="1" colspan="1">rs1768208<break></break>39,498,257</td><td align="center" rowspan="1" colspan="1"><italic>MOBP</italic></td><td align="center" rowspan="1" colspan="1">0.36</td><td align="center" rowspan="1" colspan="1">0.29</td><td align="center" rowspan="1" colspan="1">0.70<break></break>0.63 – 0.79</td><td align="center" valign="top" rowspan="1" colspan="1">10 × 10<sup>−10</sup></td><td align="center" rowspan="1" colspan="1">0.35</td><td align="center" rowspan="1" colspan="1">0.29</td><td align="center" rowspan="1" colspan="1">0.74<break></break>0.67 – 0.82</td><td align="center" valign="top" rowspan="1" colspan="1">1.3 × 10<sup>−8</sup></td><td align="center" rowspan="1" colspan="1">0.72<break></break>0.67 – 0.78</td><td align="center" valign="top" rowspan="1" colspan="1">1.0 × 10<sup>−16</sup></td></tr><tr><td align="center" rowspan="3" valign="middle" colspan="1">17q21.31</td><td align="center" valign="top" rowspan="1" colspan="1">rs8070723<break></break>41,436,651</td><td align="center" valign="top" rowspan="1" colspan="1"><italic>MAPT</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.05</td><td align="center" valign="top" rowspan="1" colspan="1">0.23</td><td align="center" valign="top" rowspan="1" colspan="1">5.50<break></break>4.40 – 6.86</td><td align="center" valign="top" rowspan="1" colspan="1">2.1 × 10<sup>−51</sup></td><td align="center" valign="top" rowspan="1" colspan="1">0.06</td><td align="center" valign="top" rowspan="1" colspan="1">0.23</td><td align="center" valign="top" rowspan="1" colspan="1">4.74<break></break>3.92 – 5.74</td><td align="center" valign="top" rowspan="1" colspan="1">4.8 × 10<sup>−67</sup></td><td align="center" valign="top" rowspan="1" colspan="1">5.46<break></break>4.72 – 6.31</td><td align="center" valign="top" rowspan="1" colspan="1">1.5 × 10<sup>−116</sup></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1">rs242557<break></break>41,375,823</td><td align="center" valign="top" rowspan="1" colspan="1"><italic>MAPT</italic></td><td align="center" valign="top" rowspan="1" colspan="1">0.53</td><td align="center" valign="top" rowspan="1" colspan="1">0.35</td><td align="center" valign="top" rowspan="1" colspan="1">0.48<break></break>0.43 – 0.53</td><td align="center" valign="top" rowspan="1" colspan="1">2.2 × 10<sup>−37</sup></td><td align="center" valign="top" rowspan="1" colspan="1">0.50</td><td align="center" valign="top" rowspan="1" colspan="1">0.36</td><td align="center" valign="top" rowspan="1" colspan="1">0.54<break></break>0.48 – 0.59</td><td align="center" valign="top" rowspan="1" colspan="1">5.0 × 10<sup>−35</sup></td><td align="center" valign="top" rowspan="1" colspan="1">0.51<break></break>0.47 – 0.55</td><td align="center" valign="top" rowspan="1" colspan="1">4.2 × 10<sup>−70</sup></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"><sup>c</sup>rs242557/<break></break>rs8070723</td><td align="center" valign="top" rowspan="1" colspan="1"><italic>MAPT</italic></td><td align="center" valign="top" rowspan="1" colspan="1">---</td><td align="center" valign="top" rowspan="1" colspan="1">---</td><td align="center" valign="top" rowspan="1" colspan="1">0.66<break></break>0.58 – 0.74</td><td align="center" valign="top" rowspan="1" colspan="1">1.3 × 10<sup>−11</sup></td><td align="center" valign="top" rowspan="1" colspan="1">---</td><td align="center" valign="top" rowspan="1" colspan="1">---</td><td align="center" valign="top" rowspan="1" colspan="1">0.74<break></break>0.67 – 0.83</td><td align="center" valign="top" rowspan="1" colspan="1">6.3 × 10<sup>−8</sup></td><td align="center" valign="top" rowspan="1" colspan="1">0.70<break></break>0.65 – 0.76</td><td align="center" valign="top" rowspan="1" colspan="1">9.5 × 10<sup>−18</sup></td></tr></tbody></table><table-wrap-foot><fn id="TFN5"><label>a</label><p id="P34">MAF, minor allele frequency;</p></fn><fn id="TFN6"><label>b</label><p id="P35">OR based on major allele,</p></fn><fn id="TFN7"><label>c</label><p id="P36">rs242557 controlling for rs8070723;</p></fn><fn id="TFN8" fn-type="abbr"><p id="P37"><bold>Abbreviations and gene symbols:</bold> P<sub>1</sub>, stage 1 P value; P<sub>2</sub>, stage 2 P value; P<sub>J</sub>, joint P value;<italic> STX6</italic>, syntaxin 6; <italic>EIF2AK3</italic>, eukaryotic translation initiation factor 2-α kinase 3; <italic>MOBP</italic>, myelin-associated oligodendrocyte basic protein; <italic>MAPT</italic>, microtubule associated protein tau; a summary of the function of each gene listed is in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 9</xref>. Associations were determined using an additive genetic model. Exploratory analyses (results not shown) of PSP using dominant and recessive models did not produce new loci although some of the associations in 17q21.31 were also consistent with these non-additive models. These less parsimonious models did not fit the data significantly better than the additive model. By evaluating 5000 SNPs with the smallest P-values in more complicated models involving main effects and interactions<sup><xref rid="R38" ref-type="bibr">38</xref></sup>, no noteworthy gene-gene interactions were uncovered. There were additional SNPs in the regions for the above loci that were significant or strongly suggestive for association; however, they were no longer significant after controlling the most significant SNP in the region (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 5</xref>). All loci significant in the joint analyses remained so after controlling for the <italic>MAPT</italic> inversion (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 10</xref>).</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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