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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions</title>
<author><name sortKey="Van Deerlin, Vivianna M" sort="Van Deerlin, Vivianna M" uniqKey="Van Deerlin V" first="Vivianna M." last="Van Deerlin">Vivianna M. Van Deerlin</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 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="A6">The Center for Applied Genomics, Division of Human Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Martinez Lage, Maria" sort="Martinez Lage, Maria" uniqKey="Martinez Lage M" first="Maria" last="Martinez-Lage">Maria Martinez-Lage</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A8">Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chen Plotkin, Alice" sort="Chen Plotkin, Alice" uniqKey="Chen Plotkin A" first="Alice" last="Chen-Plotkin">Alice Chen-Plotkin</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 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="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Graff Radford, Neill R" sort="Graff Radford, Neill R" uniqKey="Graff Radford N" first="Neill R" last="Graff-Radford">Neill R. Graff-Radford</name>
<affiliation><nlm:aff id="A9">Department of Neurology Jacksonville, Mayo College of Medicine, Jacksonville, FL, 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="A10">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 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="A10">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Boeve, Bradley F" sort="Boeve, Bradley F" uniqKey="Boeve B" first="Bradley F." last="Boeve">Bradley F. Boeve</name>
<affiliation><nlm:aff id="A11">Department of Neurology, Mayo Clinic, Rochester, MN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Grossman, Murray" sort="Grossman, Murray" uniqKey="Grossman M" first="Murray" last="Grossman">Murray Grossman</name>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Arnold, Steven E" sort="Arnold, Steven E" uniqKey="Arnold S" first="Steven E." last="Arnold">Steven E. Arnold</name>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A5">Penn Memory Center, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mann, David M A" sort="Mann, David M A" uniqKey="Mann D" first="David M. A." last="Mann">David M. A. Mann</name>
<affiliation><nlm:aff id="A13">University of Manchester, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pickering Brown, Stuart M" sort="Pickering Brown, Stuart M" uniqKey="Pickering Brown S" first="Stuart M." last="Pickering-Brown">Stuart M. Pickering-Brown</name>
<affiliation><nlm:aff id="A12">Clinical Neuroscience Research Group, United Kingdom</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A13">University of Manchester, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Seelaar, Harro" sort="Seelaar, Harro" uniqKey="Seelaar H" first="Harro" last="Seelaar">Harro Seelaar</name>
<affiliation><nlm:aff id="A14">Erasmus Medical Centre 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="A15">Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Center Amsterdam, The Netherlands</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="A14">Erasmus Medical Centre Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Murrell, Jill R" sort="Murrell, Jill R" uniqKey="Murrell J" first="Jill R." last="Murrell">Jill R. Murrell</name>
<affiliation><nlm:aff id="A16">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ghetti, Bernardino" sort="Ghetti, Bernardino" uniqKey="Ghetti B" first="Bernardino" last="Ghetti">Bernardino Ghetti</name>
<affiliation><nlm:aff id="A16">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A17">Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Spina, Salvatore" sort="Spina, Salvatore" uniqKey="Spina S" first="Salvatore" last="Spina">Salvatore Spina</name>
<affiliation><nlm:aff id="A16">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A18">Department of Neurological, Neurosurgical and Behavioral Sciences, University of Siena, Siena, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Grafman, Jordan" sort="Grafman, Jordan" uniqKey="Grafman J" first="Jordan" last="Grafman">Jordan Grafman</name>
<affiliation><nlm:aff id="A19">Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hodges, John" sort="Hodges, John" uniqKey="Hodges J" first="John" last="Hodges">John Hodges</name>
<affiliation><nlm:aff id="A20">Prince of Wales Medical Research Institute, New South Wales, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Spillantini, Maria Grazia" sort="Spillantini, Maria Grazia" uniqKey="Spillantini M" first="Maria Grazia" last="Spillantini">Maria Grazia Spillantini</name>
<affiliation><nlm:aff id="A21">Cambridge Centre for Brain Repair, Dept of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gilman, Sid" sort="Gilman, Sid" uniqKey="Gilman S" first="Sid'" last="Gilman">Sid' Gilman</name>
<affiliation><nlm:aff id="A22">Department of Neurology, University of Michigan, Ann Arbor, MI, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lieberman, Andrew P" sort="Lieberman, Andrew P" uniqKey="Lieberman A" first="Andrew P." last="Lieberman">Andrew P. Lieberman</name>
<affiliation><nlm:aff id="A23">Department of Pathology University of Michigan, Ann Arbor, MI, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kaye, Jeffrey A" sort="Kaye, Jeffrey A" uniqKey="Kaye J" first="Jeffrey A." last="Kaye">Jeffrey A. Kaye</name>
<affiliation><nlm:aff id="A24">Department of Neurology and Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Woltjer, Randall L" sort="Woltjer, Randall L" uniqKey="Woltjer R" first="Randall L." last="Woltjer">Randall L. Woltjer</name>
<affiliation><nlm:aff id="A25">Department of Pathology, Oregon Health and Science University, Portland, OR, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bigio, Eileen H" sort="Bigio, Eileen H" uniqKey="Bigio E" first="Eileen H" last="Bigio">Eileen H. Bigio</name>
<affiliation><nlm:aff id="A26">Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A27">Cognitive Neurology and Alzheimer Disease Center Northwestern University Feinberg School of Medicine, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mesulam, Marsel" sort="Mesulam, Marsel" uniqKey="Mesulam M" first="Marsel" last="Mesulam">Marsel Mesulam</name>
<affiliation><nlm:aff id="A27">Cognitive Neurology and Alzheimer Disease Center Northwestern University Feinberg School of Medicine, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Al Sarraj, Safa" sort="Al Sarraj, Safa" uniqKey="Al Sarraj S" first="Safa" last="Al-Sarraj">Safa Al-Sarraj</name>
<affiliation><nlm:aff id="A28">Department of Clinical Neuropathology, Institute of Psychiatry, Kings College Hospital, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Troakes, Claire" sort="Troakes, Claire" uniqKey="Troakes C" first="Claire" last="Troakes">Claire Troakes</name>
<affiliation><nlm:aff id="A29">MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Kings College Hospital, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rosenberg, Roger N" sort="Rosenberg, Roger N" uniqKey="Rosenberg R" first="Roger N." last="Rosenberg">Roger N. Rosenberg</name>
<affiliation><nlm:aff id="A30">Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Charles L" sort="White, Charles L" uniqKey="White C" first="Charles L." last="White">Charles L. White</name>
<affiliation><nlm:aff id="A31">Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ferrer, Isidro" sort="Ferrer, Isidro" uniqKey="Ferrer I" first="Isidro" last="Ferrer">Isidro Ferrer</name>
<affiliation><nlm:aff id="A32">Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Llad, Albert" sort="Llad, Albert" uniqKey="Llad A" first="Albert" last="Llad">Albert Llad</name>
<affiliation><nlm:aff id="A33">Alzheimer's Disease and Cognitive Disorders Unit, Service of Neurology. ICN. Hospital Clínic Barcelona, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Neumann, Manuela" sort="Neumann, Manuela" uniqKey="Neumann M" first="Manuela" last="Neumann">Manuela Neumann</name>
<affiliation><nlm:aff id="A34">Institute for Neuropathology, University Hospital Zurich, Zurich, Switzerland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kretzschmar, Hans A" sort="Kretzschmar, Hans A" uniqKey="Kretzschmar H" first="Hans A." last="Kretzschmar">Hans A. Kretzschmar</name>
<affiliation><nlm:aff id="A35">Center for Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hulette, Christine Marie" sort="Hulette, Christine Marie" uniqKey="Hulette C" first="Christine Marie" last="Hulette">Christine Marie Hulette</name>
<affiliation><nlm:aff id="A36">Department of Pathology, Duke University Health Sciences Center, Durham, NC, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Welsh Bohmer, Kathleen A" sort="Welsh Bohmer, Kathleen A" uniqKey="Welsh Bohmer K" first="Kathleen A." last="Welsh-Bohmer">Kathleen A. Welsh-Bohmer</name>
<affiliation><nlm:aff id="A37">Dept of Psychiatry, Duke University Health Sciences Center, Durham, NC, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A38">Bryan ADRC, Duke University Health Sciences Center, Durham, NC, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Miller, Bruce L" sort="Miller, Bruce L" uniqKey="Miller B" first="Bruce L" last="Miller">Bruce L. Miller</name>
<affiliation><nlm:aff id="A39">Department of Neurology, University of California at San Francisco, San Francisco, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alzualde, Ainhoa" sort="Alzualde, Ainhoa" uniqKey="Alzualde A" first="Ainhoa" last="Alzualde">Ainhoa Alzualde</name>
<affiliation><nlm:aff id="A40">Neurogenetic Unit, Instituto Biodonostia, San Sebastián, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="De Munain, Adolfo Lopez" sort="De Munain, Adolfo Lopez" uniqKey="De Munain A" first="Adolfo Lopez" last="De Munain">Adolfo Lopez De Munain</name>
<affiliation><nlm:aff id="A41">Servicio de Neurología, Hospital Donostia, San Sebastián, Spain.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mckee, Ann C" sort="Mckee, Ann C" uniqKey="Mckee A" first="Ann C." last="Mckee">Ann C. Mckee</name>
<affiliation><nlm:aff id="A42">Departments Neurology and Pathology, Boston University School of Medicine, Boston MA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A43">Bedford Veterans Administration Medical Center, GRECC, Bedford MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gearing, Marla" sort="Gearing, Marla" uniqKey="Gearing M" first="Marla" last="Gearing">Marla Gearing</name>
<affiliation><nlm:aff id="A44">Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A46">Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A47">Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Levey, Allan I" sort="Levey, Allan I" uniqKey="Levey A" first="Allan I." last="Levey">Allan I. Levey</name>
<affiliation><nlm:aff id="A45">Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A46">Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lah, James J" sort="Lah, James J" uniqKey="Lah J" first="James J." last="Lah">James J. Lah</name>
<affiliation><nlm:aff id="A45">Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA</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="A48">Reta Lila Laboratories, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A49">Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rohrer, Jonathan D" sort="Rohrer, Jonathan D" uniqKey="Rohrer J" first="Jonathan D." last="Rohrer">Jonathan D. Rohrer</name>
<affiliation><nlm:aff id="A50">Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lashley, Tammaryn" sort="Lashley, Tammaryn" uniqKey="Lashley T" first="Tammaryn" last="Lashley">Tammaryn Lashley</name>
<affiliation><nlm:aff id="A49">Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A51">Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mackenzie, Ian R A" sort="Mackenzie, Ian R A" uniqKey="Mackenzie I" first="Ian R. A." last="Mackenzie">Ian R. A. Mackenzie</name>
<affiliation><nlm:aff id="A52">Department of Pathology, University of British Columbia, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Feldman, Howard H" sort="Feldman, Howard H" uniqKey="Feldman H" first="Howard H." last="Feldman">Howard H. Feldman</name>
<affiliation><nlm:aff id="A53">Division of Neurology Vancouver General Hospital and the University of British Columbia, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A54">Neuroscience, Bristol-Myers Squibb, University of Pittsburgh, Pittsburgh PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hamilton, Ronald L" sort="Hamilton, Ronald L" uniqKey="Hamilton R" first="Ronald L." last="Hamilton">Ronald L. Hamilton</name>
<affiliation><nlm:aff id="A55">Department of Pathology, University of Pittsburgh, Pittsburgh PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dekosky, Steven T" sort="Dekosky, Steven T" uniqKey="Dekosky S" first="Steven T." last="Dekosky">Steven T. Dekosky</name>
<affiliation><nlm:aff id="A56">Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Van Der Zee, Julie" sort="Van Der Zee, Julie" uniqKey="Van Der Zee J" first="Julie" last="Van Der Zee">Julie Van Der Zee</name>
<affiliation><nlm:aff id="A57">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A58">Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kumar Singh, Samir" sort="Kumar Singh, Samir" uniqKey="Kumar Singh S" first="Samir" last="Kumar-Singh">Samir Kumar-Singh</name>
<affiliation><nlm:aff id="A57">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A58">Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name>
<affiliation><nlm:aff id="A57">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A58">Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name>
<affiliation><nlm:aff id="A59">Taub Institute for Research on Alzheimer's Disease, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vonsattel, Jean Paul G" sort="Vonsattel, Jean Paul G" uniqKey="Vonsattel J" first="Jean Paul G." last="Vonsattel">Jean Paul G. Vonsattel</name>
<affiliation><nlm:aff id="A59">Taub Institute for Research on Alzheimer's Disease, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A60">New York Brain Bank, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A61">Department of Pathology, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Troncoso, Juan C" sort="Troncoso, Juan C" uniqKey="Troncoso J" first="Juan C." last="Troncoso">Juan C. Troncoso</name>
<affiliation><nlm:aff id="A62">Departments of Pathology and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kril, Jillian J" sort="Kril, Jillian J" uniqKey="Kril J" first="Jillian J" last="Kril">Jillian J. Kril</name>
<affiliation><nlm:aff id="A63">Disciplines of Medicine and Pathology, University of Sydney, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kwok, John B J" sort="Kwok, John B J" uniqKey="Kwok J" first="John B. J." last="Kwok">John B. J. Kwok</name>
<affiliation><nlm:aff id="A64">Prince of Wales Medical Research Institute, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M." last="Halliday">Glenda M. Halliday</name>
<affiliation><nlm:aff id="A64">Prince of Wales Medical Research Institute, Australia</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A65">University of New South Wales, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bird, Thomas D" sort="Bird, Thomas D" uniqKey="Bird T" first="Thomas D." last="Bird">Thomas D. Bird</name>
<affiliation><nlm:aff id="A66">GRECC, VA Puget Sound Health Care System, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A67">Department of Neurology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ince, Paul G" sort="Ince, Paul G" uniqKey="Ince P" first="Paul G." last="Ince">Paul G. Ince</name>
<affiliation><nlm:aff id="A68">Department of Neuroscience, University of Sheffield</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shaw, Pamela J" sort="Shaw, Pamela J" uniqKey="Shaw P" first="Pamela J." last="Shaw">Pamela J. Shaw</name>
<affiliation><nlm:aff id="A68">Department of Neuroscience, University of Sheffield</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cairns, Nigel J" sort="Cairns, Nigel J" uniqKey="Cairns N" first="Nigel J." last="Cairns">Nigel J. Cairns</name>
<affiliation><nlm:aff id="A69">Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A70">Department of Neurology, Washington University School of Medicine, St Louis, MO, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Morris, John C" sort="Morris, John C" uniqKey="Morris J" first="John C." last="Morris">John C. Morris</name>
<affiliation><nlm:aff id="A69">Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A70">Department of Neurology, Washington University School of Medicine, St Louis, MO, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mclean, Catriona Ann" sort="Mclean, Catriona Ann" uniqKey="Mclean C" first="Catriona Ann" last="Mclean">Catriona Ann Mclean</name>
<affiliation><nlm:aff id="A71">Department of Anatomical Pathology, The Alfred Hospital, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Decarli, Charles" sort="Decarli, Charles" uniqKey="Decarli C" first="Charles" last="Decarli">Charles Decarli</name>
<affiliation><nlm:aff id="A72">Alzheimer's Disease Center, Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, Center for Neuroscience, University of California at Davis, Sacramento, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ellis, William G" sort="Ellis, William G" uniqKey="Ellis W" first="William G." last="Ellis">William G. Ellis</name>
<affiliation><nlm:aff id="A73">Department of Pathology, University of California at Davis, Sacramento, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Freeman, Stefanie H" sort="Freeman, Stefanie H" uniqKey="Freeman S" first="Stefanie H." last="Freeman">Stefanie H. Freeman</name>
<affiliation><nlm:aff id="A74">C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Frosch, Matthew P" sort="Frosch, Matthew P" uniqKey="Frosch M" first="Matthew P." last="Frosch">Matthew P. Frosch</name>
<affiliation><nlm:aff id="A74">C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Growdon, John H" sort="Growdon, John H" uniqKey="Growdon J" first="John H." last="Growdon">John H. Growdon</name>
<affiliation><nlm:aff id="A74">C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Perl, Daniel P" sort="Perl, Daniel P" uniqKey="Perl D" first="Daniel P." last="Perl">Daniel P. Perl</name>
<affiliation><nlm:aff id="A75">Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sano, Mary" sort="Sano, Mary" uniqKey="Sano M" first="Mary" last="Sano">Mary Sano</name>
<affiliation><nlm:aff id="A75">Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A76">James J Peters VA Medical Center, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bennett, David A" sort="Bennett, David A" uniqKey="Bennett D" first="David A." last="Bennett">David A. Bennett</name>
<affiliation><nlm:aff id="A77">Rush Alzheimer's Disease Center, Rush University Medical Center, Sun City, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schneider, Julie A" sort="Schneider, Julie A" uniqKey="Schneider J" first="Julie A." last="Schneider">Julie A. Schneider</name>
<affiliation><nlm:aff id="A77">Rush Alzheimer's Disease Center, Rush University Medical Center, Sun City, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Beach, Thomas G" sort="Beach, Thomas G" uniqKey="Beach T" first="Thomas G." last="Beach">Thomas G. Beach</name>
<affiliation><nlm:aff id="A78">Sun Health Research Institute, Sun City, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Reiman, Eric M" sort="Reiman, Eric M" uniqKey="Reiman E" first="Eric M." last="Reiman">Eric M. Reiman</name>
<affiliation><nlm:aff id="A79">Banner Alzheimer's Institute, Translational Genomics Research Institute, University of Arizona, Phoenix, AZ, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A80">Arizona Alzheimer's Consortium, Phoenix, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Woodruff, Bryan K" sort="Woodruff, Bryan K" uniqKey="Woodruff B" first="Bryan K." last="Woodruff">Bryan K. Woodruff</name>
<affiliation><nlm:aff id="A81">Mayo Clinic Arizona, Scottsdale, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cummings, Jeffrey" sort="Cummings, Jeffrey" uniqKey="Cummings J" first="Jeffrey" last="Cummings">Jeffrey Cummings</name>
<affiliation><nlm:aff id="A82">Mary S. Easton Center for Alzheimer's Disease Research, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vinters, Harry V" sort="Vinters, Harry V" uniqKey="Vinters H" first="Harry V." last="Vinters">Harry V. Vinters</name>
<affiliation><nlm:aff id="A83">Department of Pathology and Laboratory Medicine, Los Angeles, CA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A84">Department of Neurology David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Miller, Carol A" sort="Miller, Carol A" uniqKey="Miller C" first="Carol A." last="Miller">Carol A. Miller</name>
<affiliation><nlm:aff id="A85">Keck School of Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chui, Helena C" sort="Chui, Helena C" uniqKey="Chui H" first="Helena C." last="Chui">Helena C. Chui</name>
<affiliation><nlm:aff id="A85">Keck School of Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alafuzoff, Irina" sort="Alafuzoff, Irina" uniqKey="Alafuzoff I" first="Irina" last="Alafuzoff">Irina Alafuzoff</name>
<affiliation><nlm:aff id="A86">Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A87">Department of Clinical Medicine, Kuopio University, Kuopio Finland</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A88">Department of Neurology, Kuopio University, Kuopio Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hartikainen, P Ivi" sort="Hartikainen, P Ivi" uniqKey="Hartikainen P" first="P Ivi" last="Hartikainen">P Ivi Hartikainen</name>
<affiliation><nlm:aff id="A88">Department of Neurology, Kuopio University, Kuopio Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Seilhean, Danielle" sort="Seilhean, Danielle" uniqKey="Seilhean D" first="Danielle" last="Seilhean">Danielle Seilhean</name>
<affiliation><nlm:aff id="A89">UPMC-Univ Paris 06 and APHP, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Galasko, Douglas" sort="Galasko, Douglas" uniqKey="Galasko D" first="Douglas" last="Galasko">Douglas Galasko</name>
<affiliation><nlm:aff id="A90">Department of Neurosciences, University of California, San Diego, San Diego, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Masliah, Eliezer" sort="Masliah, Eliezer" uniqKey="Masliah E" first="Eliezer" last="Masliah">Eliezer Masliah</name>
<affiliation><nlm:aff id="A90">Department of Neurosciences, University of California, San Diego, San Diego, CA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A91">Department of Pathology, University of California, San Diego, San Diego, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cotman, Carl W" sort="Cotman, Carl W" uniqKey="Cotman C" first="Carl W." last="Cotman">Carl W. Cotman</name>
<affiliation><nlm:aff id="A92">Department of Neurology, University of California, Irvine, Irvine, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tu N, M Teresa" sort="Tu N, M Teresa" uniqKey="Tu N M" first="M. Teresa" last="Tu N">M. Teresa Tu N</name>
<affiliation><nlm:aff id="A93">Hospital de Navarra Pathology Department, Spain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A94">Brain Bank of Navarra, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Martinez, M Cristina Caballero" sort="Martinez, M Cristina Caballero" uniqKey="Martinez M" first="M. Cristina Caballero" last="Martínez">M. Cristina Caballero Martínez</name>
<affiliation><nlm:aff id="A94">Brain Bank of Navarra, Spain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A95">Biomedical Research Center, Navarra Health Service-Osasunbidea, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Munoz, David G" sort="Munoz, David G" uniqKey="Munoz D" first="David G." last="Munoz">David G. Munoz</name>
<affiliation><nlm:aff id="A96">Department of Laboratory Medicine and Pathobiology, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Carroll, Steven L" sort="Carroll, Steven L" uniqKey="Carroll S" first="Steven L." last="Carroll">Steven L. Carroll</name>
<affiliation><nlm:aff id="A97">Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marson, Daniel" sort="Marson, Daniel" uniqKey="Marson D" first="Daniel" last="Marson">Daniel Marson</name>
<affiliation><nlm:aff id="A98">Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A99">Alzheimer's Disease Research Center, University of Alabama at Birmingham, Birmingham, AL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Riederer, Peter F" sort="Riederer, Peter F" uniqKey="Riederer P" first="Peter F." last="Riederer">Peter F. Riederer</name>
<affiliation><nlm:aff id="A100">Clinical Neurochemistry Clinic and Policlinic of Psychiatry, Psychosomatic and Psychotherapy of the University of Wuerzburg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bogdanovic, Nenad" sort="Bogdanovic, Nenad" uniqKey="Bogdanovic N" first="Nenad" last="Bogdanovic">Nenad Bogdanovic</name>
<affiliation><nlm:aff id="A101">Geriatric Medicine and Neuropathology at Department of Geriatric Medicine, Karolinska University Hospital, Stockholm Sweden</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="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 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="A6">The Center for Applied Genomics, Division of Human Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A7">Division of Pulmonary Medicine and Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q." last="Trojanowski">John Q. Trojanowski</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Virginia M Y" sort="Lee, Virginia M Y" uniqKey="Lee V" first="Virginia M.-Y." last="Lee">Virginia M.-Y. Lee</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">20154673</idno>
<idno type="pmc">2828525</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828525</idno>
<idno type="RBID">PMC:2828525</idno>
<idno type="doi">10.1038/ng.536</idno>
<date when="2010">2010</date>
<idno type="wicri:Area/Pmc/Corpus">002E00</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002E00</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions</title>
<author><name sortKey="Van Deerlin, Vivianna M" sort="Van Deerlin, Vivianna M" uniqKey="Van Deerlin V" first="Vivianna M." last="Van Deerlin">Vivianna M. Van Deerlin</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 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="A6">The Center for Applied Genomics, Division of Human Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Martinez Lage, Maria" sort="Martinez Lage, Maria" uniqKey="Martinez Lage M" first="Maria" last="Martinez-Lage">Maria Martinez-Lage</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A8">Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chen Plotkin, Alice" sort="Chen Plotkin, Alice" uniqKey="Chen Plotkin A" first="Alice" last="Chen-Plotkin">Alice Chen-Plotkin</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 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="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Graff Radford, Neill R" sort="Graff Radford, Neill R" uniqKey="Graff Radford N" first="Neill R" last="Graff-Radford">Neill R. Graff-Radford</name>
<affiliation><nlm:aff id="A9">Department of Neurology Jacksonville, Mayo College of Medicine, Jacksonville, FL, 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="A10">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 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="A10">Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Boeve, Bradley F" sort="Boeve, Bradley F" uniqKey="Boeve B" first="Bradley F." last="Boeve">Bradley F. Boeve</name>
<affiliation><nlm:aff id="A11">Department of Neurology, Mayo Clinic, Rochester, MN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Grossman, Murray" sort="Grossman, Murray" uniqKey="Grossman M" first="Murray" last="Grossman">Murray Grossman</name>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Arnold, Steven E" sort="Arnold, Steven E" uniqKey="Arnold S" first="Steven E." last="Arnold">Steven E. Arnold</name>
<affiliation><nlm:aff id="A3">Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A5">Penn Memory Center, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mann, David M A" sort="Mann, David M A" uniqKey="Mann D" first="David M. A." last="Mann">David M. A. Mann</name>
<affiliation><nlm:aff id="A13">University of Manchester, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pickering Brown, Stuart M" sort="Pickering Brown, Stuart M" uniqKey="Pickering Brown S" first="Stuart M." last="Pickering-Brown">Stuart M. Pickering-Brown</name>
<affiliation><nlm:aff id="A12">Clinical Neuroscience Research Group, United Kingdom</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A13">University of Manchester, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Seelaar, Harro" sort="Seelaar, Harro" uniqKey="Seelaar H" first="Harro" last="Seelaar">Harro Seelaar</name>
<affiliation><nlm:aff id="A14">Erasmus Medical Centre 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="A15">Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Center Amsterdam, The Netherlands</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="A14">Erasmus Medical Centre Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Murrell, Jill R" sort="Murrell, Jill R" uniqKey="Murrell J" first="Jill R." last="Murrell">Jill R. Murrell</name>
<affiliation><nlm:aff id="A16">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ghetti, Bernardino" sort="Ghetti, Bernardino" uniqKey="Ghetti B" first="Bernardino" last="Ghetti">Bernardino Ghetti</name>
<affiliation><nlm:aff id="A16">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A17">Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Spina, Salvatore" sort="Spina, Salvatore" uniqKey="Spina S" first="Salvatore" last="Spina">Salvatore Spina</name>
<affiliation><nlm:aff id="A16">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A18">Department of Neurological, Neurosurgical and Behavioral Sciences, University of Siena, Siena, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Grafman, Jordan" sort="Grafman, Jordan" uniqKey="Grafman J" first="Jordan" last="Grafman">Jordan Grafman</name>
<affiliation><nlm:aff id="A19">Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hodges, John" sort="Hodges, John" uniqKey="Hodges J" first="John" last="Hodges">John Hodges</name>
<affiliation><nlm:aff id="A20">Prince of Wales Medical Research Institute, New South Wales, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Spillantini, Maria Grazia" sort="Spillantini, Maria Grazia" uniqKey="Spillantini M" first="Maria Grazia" last="Spillantini">Maria Grazia Spillantini</name>
<affiliation><nlm:aff id="A21">Cambridge Centre for Brain Repair, Dept of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gilman, Sid" sort="Gilman, Sid" uniqKey="Gilman S" first="Sid'" last="Gilman">Sid' Gilman</name>
<affiliation><nlm:aff id="A22">Department of Neurology, University of Michigan, Ann Arbor, MI, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lieberman, Andrew P" sort="Lieberman, Andrew P" uniqKey="Lieberman A" first="Andrew P." last="Lieberman">Andrew P. Lieberman</name>
<affiliation><nlm:aff id="A23">Department of Pathology University of Michigan, Ann Arbor, MI, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kaye, Jeffrey A" sort="Kaye, Jeffrey A" uniqKey="Kaye J" first="Jeffrey A." last="Kaye">Jeffrey A. Kaye</name>
<affiliation><nlm:aff id="A24">Department of Neurology and Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Woltjer, Randall L" sort="Woltjer, Randall L" uniqKey="Woltjer R" first="Randall L." last="Woltjer">Randall L. Woltjer</name>
<affiliation><nlm:aff id="A25">Department of Pathology, Oregon Health and Science University, Portland, OR, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bigio, Eileen H" sort="Bigio, Eileen H" uniqKey="Bigio E" first="Eileen H" last="Bigio">Eileen H. Bigio</name>
<affiliation><nlm:aff id="A26">Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A27">Cognitive Neurology and Alzheimer Disease Center Northwestern University Feinberg School of Medicine, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mesulam, Marsel" sort="Mesulam, Marsel" uniqKey="Mesulam M" first="Marsel" last="Mesulam">Marsel Mesulam</name>
<affiliation><nlm:aff id="A27">Cognitive Neurology and Alzheimer Disease Center Northwestern University Feinberg School of Medicine, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Al Sarraj, Safa" sort="Al Sarraj, Safa" uniqKey="Al Sarraj S" first="Safa" last="Al-Sarraj">Safa Al-Sarraj</name>
<affiliation><nlm:aff id="A28">Department of Clinical Neuropathology, Institute of Psychiatry, Kings College Hospital, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Troakes, Claire" sort="Troakes, Claire" uniqKey="Troakes C" first="Claire" last="Troakes">Claire Troakes</name>
<affiliation><nlm:aff id="A29">MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Kings College Hospital, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rosenberg, Roger N" sort="Rosenberg, Roger N" uniqKey="Rosenberg R" first="Roger N." last="Rosenberg">Roger N. Rosenberg</name>
<affiliation><nlm:aff id="A30">Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="White, Charles L" sort="White, Charles L" uniqKey="White C" first="Charles L." last="White">Charles L. White</name>
<affiliation><nlm:aff id="A31">Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ferrer, Isidro" sort="Ferrer, Isidro" uniqKey="Ferrer I" first="Isidro" last="Ferrer">Isidro Ferrer</name>
<affiliation><nlm:aff id="A32">Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Llad, Albert" sort="Llad, Albert" uniqKey="Llad A" first="Albert" last="Llad">Albert Llad</name>
<affiliation><nlm:aff id="A33">Alzheimer's Disease and Cognitive Disorders Unit, Service of Neurology. ICN. Hospital Clínic Barcelona, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Neumann, Manuela" sort="Neumann, Manuela" uniqKey="Neumann M" first="Manuela" last="Neumann">Manuela Neumann</name>
<affiliation><nlm:aff id="A34">Institute for Neuropathology, University Hospital Zurich, Zurich, Switzerland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kretzschmar, Hans A" sort="Kretzschmar, Hans A" uniqKey="Kretzschmar H" first="Hans A." last="Kretzschmar">Hans A. Kretzschmar</name>
<affiliation><nlm:aff id="A35">Center for Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hulette, Christine Marie" sort="Hulette, Christine Marie" uniqKey="Hulette C" first="Christine Marie" last="Hulette">Christine Marie Hulette</name>
<affiliation><nlm:aff id="A36">Department of Pathology, Duke University Health Sciences Center, Durham, NC, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Welsh Bohmer, Kathleen A" sort="Welsh Bohmer, Kathleen A" uniqKey="Welsh Bohmer K" first="Kathleen A." last="Welsh-Bohmer">Kathleen A. Welsh-Bohmer</name>
<affiliation><nlm:aff id="A37">Dept of Psychiatry, Duke University Health Sciences Center, Durham, NC, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A38">Bryan ADRC, Duke University Health Sciences Center, Durham, NC, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Miller, Bruce L" sort="Miller, Bruce L" uniqKey="Miller B" first="Bruce L" last="Miller">Bruce L. Miller</name>
<affiliation><nlm:aff id="A39">Department of Neurology, University of California at San Francisco, San Francisco, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alzualde, Ainhoa" sort="Alzualde, Ainhoa" uniqKey="Alzualde A" first="Ainhoa" last="Alzualde">Ainhoa Alzualde</name>
<affiliation><nlm:aff id="A40">Neurogenetic Unit, Instituto Biodonostia, San Sebastián, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="De Munain, Adolfo Lopez" sort="De Munain, Adolfo Lopez" uniqKey="De Munain A" first="Adolfo Lopez" last="De Munain">Adolfo Lopez De Munain</name>
<affiliation><nlm:aff id="A41">Servicio de Neurología, Hospital Donostia, San Sebastián, Spain.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mckee, Ann C" sort="Mckee, Ann C" uniqKey="Mckee A" first="Ann C." last="Mckee">Ann C. Mckee</name>
<affiliation><nlm:aff id="A42">Departments Neurology and Pathology, Boston University School of Medicine, Boston MA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A43">Bedford Veterans Administration Medical Center, GRECC, Bedford MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gearing, Marla" sort="Gearing, Marla" uniqKey="Gearing M" first="Marla" last="Gearing">Marla Gearing</name>
<affiliation><nlm:aff id="A44">Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A46">Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A47">Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Levey, Allan I" sort="Levey, Allan I" uniqKey="Levey A" first="Allan I." last="Levey">Allan I. Levey</name>
<affiliation><nlm:aff id="A45">Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A46">Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lah, James J" sort="Lah, James J" uniqKey="Lah J" first="James J." last="Lah">James J. Lah</name>
<affiliation><nlm:aff id="A45">Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA</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="A48">Reta Lila Laboratories, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A49">Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rohrer, Jonathan D" sort="Rohrer, Jonathan D" uniqKey="Rohrer J" first="Jonathan D." last="Rohrer">Jonathan D. Rohrer</name>
<affiliation><nlm:aff id="A50">Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lashley, Tammaryn" sort="Lashley, Tammaryn" uniqKey="Lashley T" first="Tammaryn" last="Lashley">Tammaryn Lashley</name>
<affiliation><nlm:aff id="A49">Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A51">Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, London, United Kingdom</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mackenzie, Ian R A" sort="Mackenzie, Ian R A" uniqKey="Mackenzie I" first="Ian R. A." last="Mackenzie">Ian R. A. Mackenzie</name>
<affiliation><nlm:aff id="A52">Department of Pathology, University of British Columbia, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Feldman, Howard H" sort="Feldman, Howard H" uniqKey="Feldman H" first="Howard H." last="Feldman">Howard H. Feldman</name>
<affiliation><nlm:aff id="A53">Division of Neurology Vancouver General Hospital and the University of British Columbia, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A54">Neuroscience, Bristol-Myers Squibb, University of Pittsburgh, Pittsburgh PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hamilton, Ronald L" sort="Hamilton, Ronald L" uniqKey="Hamilton R" first="Ronald L." last="Hamilton">Ronald L. Hamilton</name>
<affiliation><nlm:aff id="A55">Department of Pathology, University of Pittsburgh, Pittsburgh PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dekosky, Steven T" sort="Dekosky, Steven T" uniqKey="Dekosky S" first="Steven T." last="Dekosky">Steven T. Dekosky</name>
<affiliation><nlm:aff id="A56">Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Van Der Zee, Julie" sort="Van Der Zee, Julie" uniqKey="Van Der Zee J" first="Julie" last="Van Der Zee">Julie Van Der Zee</name>
<affiliation><nlm:aff id="A57">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A58">Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kumar Singh, Samir" sort="Kumar Singh, Samir" uniqKey="Kumar Singh S" first="Samir" last="Kumar-Singh">Samir Kumar-Singh</name>
<affiliation><nlm:aff id="A57">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A58">Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name>
<affiliation><nlm:aff id="A57">Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A58">Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name>
<affiliation><nlm:aff id="A59">Taub Institute for Research on Alzheimer's Disease, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vonsattel, Jean Paul G" sort="Vonsattel, Jean Paul G" uniqKey="Vonsattel J" first="Jean Paul G." last="Vonsattel">Jean Paul G. Vonsattel</name>
<affiliation><nlm:aff id="A59">Taub Institute for Research on Alzheimer's Disease, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A60">New York Brain Bank, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A61">Department of Pathology, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Troncoso, Juan C" sort="Troncoso, Juan C" uniqKey="Troncoso J" first="Juan C." last="Troncoso">Juan C. Troncoso</name>
<affiliation><nlm:aff id="A62">Departments of Pathology and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kril, Jillian J" sort="Kril, Jillian J" uniqKey="Kril J" first="Jillian J" last="Kril">Jillian J. Kril</name>
<affiliation><nlm:aff id="A63">Disciplines of Medicine and Pathology, University of Sydney, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kwok, John B J" sort="Kwok, John B J" uniqKey="Kwok J" first="John B. J." last="Kwok">John B. J. Kwok</name>
<affiliation><nlm:aff id="A64">Prince of Wales Medical Research Institute, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M." last="Halliday">Glenda M. Halliday</name>
<affiliation><nlm:aff id="A64">Prince of Wales Medical Research Institute, Australia</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A65">University of New South Wales, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bird, Thomas D" sort="Bird, Thomas D" uniqKey="Bird T" first="Thomas D." last="Bird">Thomas D. Bird</name>
<affiliation><nlm:aff id="A66">GRECC, VA Puget Sound Health Care System, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A67">Department of Neurology, University of Washington, Seattle, WA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ince, Paul G" sort="Ince, Paul G" uniqKey="Ince P" first="Paul G." last="Ince">Paul G. Ince</name>
<affiliation><nlm:aff id="A68">Department of Neuroscience, University of Sheffield</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shaw, Pamela J" sort="Shaw, Pamela J" uniqKey="Shaw P" first="Pamela J." last="Shaw">Pamela J. Shaw</name>
<affiliation><nlm:aff id="A68">Department of Neuroscience, University of Sheffield</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cairns, Nigel J" sort="Cairns, Nigel J" uniqKey="Cairns N" first="Nigel J." last="Cairns">Nigel J. Cairns</name>
<affiliation><nlm:aff id="A69">Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A70">Department of Neurology, Washington University School of Medicine, St Louis, MO, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Morris, John C" sort="Morris, John C" uniqKey="Morris J" first="John C." last="Morris">John C. Morris</name>
<affiliation><nlm:aff id="A69">Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A70">Department of Neurology, Washington University School of Medicine, St Louis, MO, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mclean, Catriona Ann" sort="Mclean, Catriona Ann" uniqKey="Mclean C" first="Catriona Ann" last="Mclean">Catriona Ann Mclean</name>
<affiliation><nlm:aff id="A71">Department of Anatomical Pathology, The Alfred Hospital, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Decarli, Charles" sort="Decarli, Charles" uniqKey="Decarli C" first="Charles" last="Decarli">Charles Decarli</name>
<affiliation><nlm:aff id="A72">Alzheimer's Disease Center, Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, Center for Neuroscience, University of California at Davis, Sacramento, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ellis, William G" sort="Ellis, William G" uniqKey="Ellis W" first="William G." last="Ellis">William G. Ellis</name>
<affiliation><nlm:aff id="A73">Department of Pathology, University of California at Davis, Sacramento, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Freeman, Stefanie H" sort="Freeman, Stefanie H" uniqKey="Freeman S" first="Stefanie H." last="Freeman">Stefanie H. Freeman</name>
<affiliation><nlm:aff id="A74">C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Frosch, Matthew P" sort="Frosch, Matthew P" uniqKey="Frosch M" first="Matthew P." last="Frosch">Matthew P. Frosch</name>
<affiliation><nlm:aff id="A74">C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Growdon, John H" sort="Growdon, John H" uniqKey="Growdon J" first="John H." last="Growdon">John H. Growdon</name>
<affiliation><nlm:aff id="A74">C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Perl, Daniel P" sort="Perl, Daniel P" uniqKey="Perl D" first="Daniel P." last="Perl">Daniel P. Perl</name>
<affiliation><nlm:aff id="A75">Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sano, Mary" sort="Sano, Mary" uniqKey="Sano M" first="Mary" last="Sano">Mary Sano</name>
<affiliation><nlm:aff id="A75">Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A76">James J Peters VA Medical Center, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bennett, David A" sort="Bennett, David A" uniqKey="Bennett D" first="David A." last="Bennett">David A. Bennett</name>
<affiliation><nlm:aff id="A77">Rush Alzheimer's Disease Center, Rush University Medical Center, Sun City, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schneider, Julie A" sort="Schneider, Julie A" uniqKey="Schneider J" first="Julie A." last="Schneider">Julie A. Schneider</name>
<affiliation><nlm:aff id="A77">Rush Alzheimer's Disease Center, Rush University Medical Center, Sun City, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Beach, Thomas G" sort="Beach, Thomas G" uniqKey="Beach T" first="Thomas G." last="Beach">Thomas G. Beach</name>
<affiliation><nlm:aff id="A78">Sun Health Research Institute, Sun City, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Reiman, Eric M" sort="Reiman, Eric M" uniqKey="Reiman E" first="Eric M." last="Reiman">Eric M. Reiman</name>
<affiliation><nlm:aff id="A79">Banner Alzheimer's Institute, Translational Genomics Research Institute, University of Arizona, Phoenix, AZ, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A80">Arizona Alzheimer's Consortium, Phoenix, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Woodruff, Bryan K" sort="Woodruff, Bryan K" uniqKey="Woodruff B" first="Bryan K." last="Woodruff">Bryan K. Woodruff</name>
<affiliation><nlm:aff id="A81">Mayo Clinic Arizona, Scottsdale, AZ, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cummings, Jeffrey" sort="Cummings, Jeffrey" uniqKey="Cummings J" first="Jeffrey" last="Cummings">Jeffrey Cummings</name>
<affiliation><nlm:aff id="A82">Mary S. Easton Center for Alzheimer's Disease Research, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vinters, Harry V" sort="Vinters, Harry V" uniqKey="Vinters H" first="Harry V." last="Vinters">Harry V. Vinters</name>
<affiliation><nlm:aff id="A83">Department of Pathology and Laboratory Medicine, Los Angeles, CA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A84">Department of Neurology David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Miller, Carol A" sort="Miller, Carol A" uniqKey="Miller C" first="Carol A." last="Miller">Carol A. Miller</name>
<affiliation><nlm:aff id="A85">Keck School of Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chui, Helena C" sort="Chui, Helena C" uniqKey="Chui H" first="Helena C." last="Chui">Helena C. Chui</name>
<affiliation><nlm:aff id="A85">Keck School of Medicine, University of Southern California, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Alafuzoff, Irina" sort="Alafuzoff, Irina" uniqKey="Alafuzoff I" first="Irina" last="Alafuzoff">Irina Alafuzoff</name>
<affiliation><nlm:aff id="A86">Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A87">Department of Clinical Medicine, Kuopio University, Kuopio Finland</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A88">Department of Neurology, Kuopio University, Kuopio Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hartikainen, P Ivi" sort="Hartikainen, P Ivi" uniqKey="Hartikainen P" first="P Ivi" last="Hartikainen">P Ivi Hartikainen</name>
<affiliation><nlm:aff id="A88">Department of Neurology, Kuopio University, Kuopio Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Seilhean, Danielle" sort="Seilhean, Danielle" uniqKey="Seilhean D" first="Danielle" last="Seilhean">Danielle Seilhean</name>
<affiliation><nlm:aff id="A89">UPMC-Univ Paris 06 and APHP, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Galasko, Douglas" sort="Galasko, Douglas" uniqKey="Galasko D" first="Douglas" last="Galasko">Douglas Galasko</name>
<affiliation><nlm:aff id="A90">Department of Neurosciences, University of California, San Diego, San Diego, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Masliah, Eliezer" sort="Masliah, Eliezer" uniqKey="Masliah E" first="Eliezer" last="Masliah">Eliezer Masliah</name>
<affiliation><nlm:aff id="A90">Department of Neurosciences, University of California, San Diego, San Diego, CA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A91">Department of Pathology, University of California, San Diego, San Diego, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cotman, Carl W" sort="Cotman, Carl W" uniqKey="Cotman C" first="Carl W." last="Cotman">Carl W. Cotman</name>
<affiliation><nlm:aff id="A92">Department of Neurology, University of California, Irvine, Irvine, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tu N, M Teresa" sort="Tu N, M Teresa" uniqKey="Tu N M" first="M. Teresa" last="Tu N">M. Teresa Tu N</name>
<affiliation><nlm:aff id="A93">Hospital de Navarra Pathology Department, Spain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A94">Brain Bank of Navarra, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Martinez, M Cristina Caballero" sort="Martinez, M Cristina Caballero" uniqKey="Martinez M" first="M. Cristina Caballero" last="Martínez">M. Cristina Caballero Martínez</name>
<affiliation><nlm:aff id="A94">Brain Bank of Navarra, Spain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A95">Biomedical Research Center, Navarra Health Service-Osasunbidea, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Munoz, David G" sort="Munoz, David G" uniqKey="Munoz D" first="David G." last="Munoz">David G. Munoz</name>
<affiliation><nlm:aff id="A96">Department of Laboratory Medicine and Pathobiology, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Carroll, Steven L" sort="Carroll, Steven L" uniqKey="Carroll S" first="Steven L." last="Carroll">Steven L. Carroll</name>
<affiliation><nlm:aff id="A97">Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marson, Daniel" sort="Marson, Daniel" uniqKey="Marson D" first="Daniel" last="Marson">Daniel Marson</name>
<affiliation><nlm:aff id="A98">Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A99">Alzheimer's Disease Research Center, University of Alabama at Birmingham, Birmingham, AL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Riederer, Peter F" sort="Riederer, Peter F" uniqKey="Riederer P" first="Peter F." last="Riederer">Peter F. Riederer</name>
<affiliation><nlm:aff id="A100">Clinical Neurochemistry Clinic and Policlinic of Psychiatry, Psychosomatic and Psychotherapy of the University of Wuerzburg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bogdanovic, Nenad" sort="Bogdanovic, Nenad" uniqKey="Bogdanovic N" first="Nenad" last="Bogdanovic">Nenad Bogdanovic</name>
<affiliation><nlm:aff id="A101">Geriatric Medicine and Neuropathology at Department of Geriatric Medicine, Karolinska University Hospital, Stockholm Sweden</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="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 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="A6">The Center for Applied Genomics, Division of Human Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A7">Division of Pulmonary Medicine and Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q." last="Trojanowski">John Q. Trojanowski</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Virginia M Y" sort="Lee, Virginia M Y" uniqKey="Lee V" first="Virginia M.-Y." last="Lee">Virginia M.-Y. Lee</name>
<affiliation><nlm:aff id="A1">Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 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="2010">2010</date>
</imprint>
</series>
</biblStruct>
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<front><div type="abstract" xml:lang="en"><p id="P4">Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)<xref rid="R1" ref-type="bibr">1</xref>
. FTLD-TDP is frequently familial resulting from progranulin (<italic>GRN</italic>
) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains <italic>TMEM106B</italic>
in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (<italic>P=</italic>
1.08×10<sup>−11</sup>
; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; <italic>P=</italic>
2×10<sup>−4</sup>
). <italic>TMEM106B</italic>
variants may confer risk by increasing <italic>TMEM106B</italic>
expression. <italic>TMEM106B</italic>
variants also contribute to genetic risk for FTLD-TDP in patients with <italic>GRN</italic>
mutations. Our data implicate <italic>TMEM106B</italic>
as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Cairns, Nj" uniqKey="Cairns N">NJ Cairns</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Neary, D" uniqKey="Neary D">D Neary</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mckhann, Gm" uniqKey="Mckhann G">GM McKhann</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mercy, L" uniqKey="Mercy L">L Mercy</name>
</author>
<author><name sortKey="Hodges, Jr" uniqKey="Hodges J">JR Hodges</name>
</author>
<author><name sortKey="Dawson, K" uniqKey="Dawson K">K Dawson</name>
</author>
<author><name sortKey="Barker, Ra" uniqKey="Barker R">RA Barker</name>
</author>
<author><name sortKey="Brayne, C" uniqKey="Brayne C">C Brayne</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ratnavalli, E" uniqKey="Ratnavalli E">E Ratnavalli</name>
</author>
<author><name sortKey="Brayne, C" uniqKey="Brayne C">C Brayne</name>
</author>
<author><name sortKey="Dawson, K" uniqKey="Dawson K">K Dawson</name>
</author>
<author><name sortKey="Hodges, Jr" uniqKey="Hodges J">JR Hodges</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Forman, Ms" uniqKey="Forman M">MS Forman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Goldman, Js" uniqKey="Goldman J">JS Goldman</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="Cruts, M" uniqKey="Cruts M">M Cruts</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gass, J" uniqKey="Gass J">J Gass</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gijselinck, I" uniqKey="Gijselinck I">I Gijselinck</name>
</author>
<author><name sortKey="Van Broeckhoven, C" uniqKey="Van Broeckhoven C">C Van Broeckhoven</name>
</author>
<author><name sortKey="Cruts, M" uniqKey="Cruts M">M Cruts</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cruts, M" uniqKey="Cruts M">M Cruts</name>
</author>
<author><name sortKey="Van Broeckhoven, C" uniqKey="Van Broeckhoven C">C Van Broeckhoven</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Van Deerlin, Vm" uniqKey="Van Deerlin V">VM Van Deerlin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hakonarson, H" uniqKey="Hakonarson H">H Hakonarson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mccarthy, Mi" uniqKey="Mccarthy M">MI McCarthy</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Neumann, M" uniqKey="Neumann M">M Neumann</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cairns, Nj" uniqKey="Cairns N">NJ Cairns</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mackenzie, Ir" uniqKey="Mackenzie I">IR Mackenzie</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Falush, D" uniqKey="Falush D">D Falush</name>
</author>
<author><name sortKey="Stephens, M" uniqKey="Stephens M">M Stephens</name>
</author>
<author><name sortKey="Pritchard, Jk" uniqKey="Pritchard J">JK Pritchard</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Patterson, N" uniqKey="Patterson N">N Patterson</name>
</author>
<author><name sortKey="Price, Al" uniqKey="Price A">AL Price</name>
</author>
<author><name sortKey="Reich, D" uniqKey="Reich D">D Reich</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="Dixon, Al" uniqKey="Dixon A">AL Dixon</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Chen Plotkin, As" uniqKey="Chen Plotkin A">AS Chen-Plotkin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Pastor, P" uniqKey="Pastor P">P Pastor</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wijsman, Em" uniqKey="Wijsman E">EM Wijsman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Le Ber, I" uniqKey="Le Ber I">I Le Ber</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Scheet, P" uniqKey="Scheet P">P Scheet</name>
</author>
<author><name sortKey="Stephens, M" uniqKey="Stephens M">M Stephens</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">20154673</article-id>
<article-id pub-id-type="pmc">2828525</article-id>
<article-id pub-id-type="doi">10.1038/ng.536</article-id>
<article-id pub-id-type="manuscript">NIHMS172758</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Van Deerlin</surname>
<given-names>Vivianna M.</given-names>
</name>
<xref ref-type="author-notes" rid="FN1">*</xref>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sleiman</surname>
<given-names>Patrick M. A.</given-names>
</name>
<xref ref-type="author-notes" rid="FN1">*</xref>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martinez-Lage</surname>
<given-names>Maria</given-names>
</name>
<xref ref-type="author-notes" rid="FN1">*</xref>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen-Plotkin</surname>
<given-names>Alice</given-names>
</name>
<xref ref-type="author-notes" rid="FN1">*</xref>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Li-San</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Graff-Radford</surname>
<given-names>Neill R</given-names>
</name>
<xref ref-type="aff" rid="A9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dickson</surname>
<given-names>Dennis W.</given-names>
</name>
<xref ref-type="aff" rid="A10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rademakers</surname>
<given-names>Rosa</given-names>
</name>
<xref ref-type="aff" rid="A10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boeve</surname>
<given-names>Bradley F.</given-names>
</name>
<xref ref-type="aff" rid="A11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Grossman</surname>
<given-names>Murray</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Arnold</surname>
<given-names>Steven E.</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A4">4</xref>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mann</surname>
<given-names>David M.A.</given-names>
</name>
<xref ref-type="aff" rid="A13">13</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pickering-Brown</surname>
<given-names>Stuart M.</given-names>
</name>
<xref ref-type="aff" rid="A12">12</xref>
<xref ref-type="aff" rid="A13">13</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Seelaar</surname>
<given-names>Harro</given-names>
</name>
<xref ref-type="aff" rid="A14">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Heutink</surname>
<given-names>Peter</given-names>
</name>
<xref ref-type="aff" rid="A15">15</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van Swieten</surname>
<given-names>John C.</given-names>
</name>
<xref ref-type="aff" rid="A14">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Murrell</surname>
<given-names>Jill R.</given-names>
</name>
<xref ref-type="aff" rid="A16">16</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ghetti</surname>
<given-names>Bernardino</given-names>
</name>
<xref ref-type="aff" rid="A16">16</xref>
<xref ref-type="aff" rid="A17">17</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Spina</surname>
<given-names>Salvatore</given-names>
</name>
<xref ref-type="aff" rid="A16">16</xref>
<xref ref-type="aff" rid="A18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Grafman</surname>
<given-names>Jordan</given-names>
</name>
<xref ref-type="aff" rid="A19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hodges</surname>
<given-names>John</given-names>
</name>
<xref ref-type="aff" rid="A20">20</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Spillantini</surname>
<given-names>Maria Grazia</given-names>
</name>
<xref ref-type="aff" rid="A21">21</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gilman</surname>
<given-names>Sid'</given-names>
</name>
<xref ref-type="aff" rid="A22">22</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lieberman</surname>
<given-names>Andrew P.</given-names>
</name>
<xref ref-type="aff" rid="A23">23</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kaye</surname>
<given-names>Jeffrey A.</given-names>
</name>
<xref ref-type="aff" rid="A24">24</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Woltjer</surname>
<given-names>Randall L.</given-names>
</name>
<xref ref-type="aff" rid="A25">25</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bigio</surname>
<given-names>Eileen H</given-names>
</name>
<xref ref-type="aff" rid="A26">26</xref>
<xref ref-type="aff" rid="A27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mesulam</surname>
<given-names>Marsel</given-names>
</name>
<xref ref-type="aff" rid="A27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>al-Sarraj</surname>
<given-names>Safa</given-names>
</name>
<xref ref-type="aff" rid="A28">28</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Troakes</surname>
<given-names>Claire</given-names>
</name>
<xref ref-type="aff" rid="A29">29</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rosenberg</surname>
<given-names>Roger N.</given-names>
</name>
<xref ref-type="aff" rid="A30">30</xref>
</contrib>
<contrib contrib-type="author"><name><surname>White</surname>
<given-names>Charles L.</given-names>
<suffix>III</suffix>
</name>
<xref ref-type="aff" rid="A31">31</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ferrer</surname>
<given-names>Isidro</given-names>
</name>
<xref ref-type="aff" rid="A32">32</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lladó</surname>
<given-names>Albert</given-names>
</name>
<xref ref-type="aff" rid="A33">33</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Neumann</surname>
<given-names>Manuela</given-names>
</name>
<xref ref-type="aff" rid="A34">34</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kretzschmar</surname>
<given-names>Hans A.</given-names>
</name>
<xref ref-type="aff" rid="A35">35</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hulette</surname>
<given-names>Christine Marie</given-names>
</name>
<xref ref-type="aff" rid="A36">36</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Welsh-Bohmer</surname>
<given-names>Kathleen A.</given-names>
</name>
<xref ref-type="aff" rid="A37">37</xref>
<xref ref-type="aff" rid="A38">38</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Miller</surname>
<given-names>Bruce L</given-names>
</name>
<xref ref-type="aff" rid="A39">39</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alzualde</surname>
<given-names>Ainhoa</given-names>
</name>
<xref ref-type="aff" rid="A40">40</xref>
</contrib>
<contrib contrib-type="author"><name><surname>de Munain</surname>
<given-names>Adolfo Lopez</given-names>
</name>
<xref ref-type="aff" rid="A41">41</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McKee</surname>
<given-names>Ann C.</given-names>
</name>
<xref ref-type="aff" rid="A42">42</xref>
<xref ref-type="aff" rid="A43">43</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gearing</surname>
<given-names>Marla</given-names>
</name>
<xref ref-type="aff" rid="A44">44</xref>
<xref ref-type="aff" rid="A46">46</xref>
<xref ref-type="aff" rid="A47">47</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Levey</surname>
<given-names>Allan I.</given-names>
</name>
<xref ref-type="aff" rid="A45">45</xref>
<xref ref-type="aff" rid="A46">46</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lah</surname>
<given-names>James J.</given-names>
</name>
<xref ref-type="aff" rid="A45">45</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hardy</surname>
<given-names>John</given-names>
</name>
<xref ref-type="aff" rid="A48">48</xref>
<xref ref-type="aff" rid="A49">49</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rohrer</surname>
<given-names>Jonathan D.</given-names>
</name>
<xref ref-type="aff" rid="A50">50</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lashley</surname>
<given-names>Tammaryn</given-names>
</name>
<xref ref-type="aff" rid="A49">49</xref>
<xref ref-type="aff" rid="A51">51</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mackenzie</surname>
<given-names>Ian R.A.</given-names>
</name>
<xref ref-type="aff" rid="A52">52</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Feldman</surname>
<given-names>Howard H.</given-names>
</name>
<xref ref-type="aff" rid="A53">53</xref>
<xref ref-type="aff" rid="A54">54</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hamilton</surname>
<given-names>Ronald L.</given-names>
</name>
<xref ref-type="aff" rid="A55">55</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dekosky</surname>
<given-names>Steven T.</given-names>
</name>
<xref ref-type="aff" rid="A56">56</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van der Zee</surname>
<given-names>Julie</given-names>
</name>
<xref ref-type="aff" rid="A57">57</xref>
<xref ref-type="aff" rid="A58">58</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kumar-Singh</surname>
<given-names>Samir</given-names>
</name>
<xref ref-type="aff" rid="A57">57</xref>
<xref ref-type="aff" rid="A58">58</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Van Broeckhoven</surname>
<given-names>Christine</given-names>
</name>
<xref ref-type="aff" rid="A57">57</xref>
<xref ref-type="aff" rid="A58">58</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mayeux</surname>
<given-names>Richard</given-names>
</name>
<xref ref-type="aff" rid="A59">59</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vonsattel</surname>
<given-names>Jean Paul G.</given-names>
</name>
<xref ref-type="aff" rid="A59">59</xref>
<xref ref-type="aff" rid="A60">60</xref>
<xref ref-type="aff" rid="A61">61</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Troncoso</surname>
<given-names>Juan C.</given-names>
</name>
<xref ref-type="aff" rid="A62">62</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kril</surname>
<given-names>Jillian J</given-names>
</name>
<xref ref-type="aff" rid="A63">63</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kwok</surname>
<given-names>John B.J.</given-names>
</name>
<xref ref-type="aff" rid="A64">64</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Halliday</surname>
<given-names>Glenda M.</given-names>
</name>
<xref ref-type="aff" rid="A64">64</xref>
<xref ref-type="aff" rid="A65">65</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bird</surname>
<given-names>Thomas D.</given-names>
</name>
<xref ref-type="aff" rid="A66">66</xref>
<xref ref-type="aff" rid="A67">67</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ince</surname>
<given-names>Paul G.</given-names>
</name>
<xref ref-type="aff" rid="A68">68</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shaw</surname>
<given-names>Pamela J.</given-names>
</name>
<xref ref-type="aff" rid="A68">68</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cairns</surname>
<given-names>Nigel J.</given-names>
</name>
<xref ref-type="aff" rid="A69">69</xref>
<xref ref-type="aff" rid="A70">70</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Morris</surname>
<given-names>John C.</given-names>
</name>
<xref ref-type="aff" rid="A69">69</xref>
<xref ref-type="aff" rid="A70">70</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McLean</surname>
<given-names>Catriona Ann</given-names>
</name>
<xref ref-type="aff" rid="A71">71</xref>
</contrib>
<contrib contrib-type="author"><name><surname>DeCarli</surname>
<given-names>Charles</given-names>
</name>
<xref ref-type="aff" rid="A72">72</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ellis</surname>
<given-names>William G.</given-names>
</name>
<xref ref-type="aff" rid="A73">73</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Freeman</surname>
<given-names>Stefanie H.</given-names>
</name>
<xref ref-type="aff" rid="A74">74</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Frosch</surname>
<given-names>Matthew P.</given-names>
</name>
<xref ref-type="aff" rid="A74">74</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Growdon</surname>
<given-names>John H.</given-names>
</name>
<xref ref-type="aff" rid="A74">74</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Perl</surname>
<given-names>Daniel P.</given-names>
</name>
<xref ref-type="aff" rid="A75">75</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sano</surname>
<given-names>Mary</given-names>
</name>
<xref ref-type="aff" rid="A75">75</xref>
<xref ref-type="aff" rid="A76">76</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bennett</surname>
<given-names>David A.</given-names>
</name>
<xref ref-type="aff" rid="A77">77</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schneider</surname>
<given-names>Julie A.</given-names>
</name>
<xref ref-type="aff" rid="A77">77</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Beach</surname>
<given-names>Thomas G.</given-names>
</name>
<xref ref-type="aff" rid="A78">78</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Reiman</surname>
<given-names>Eric M.</given-names>
</name>
<xref ref-type="aff" rid="A79">79</xref>
<xref ref-type="aff" rid="A80">80</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Woodruff</surname>
<given-names>Bryan K.</given-names>
</name>
<xref ref-type="aff" rid="A81">81</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cummings</surname>
<given-names>Jeffrey</given-names>
</name>
<xref ref-type="aff" rid="A82">82</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vinters</surname>
<given-names>Harry V.</given-names>
</name>
<xref ref-type="aff" rid="A83">83</xref>
<xref ref-type="aff" rid="A84">84</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Miller</surname>
<given-names>Carol A.</given-names>
</name>
<xref ref-type="aff" rid="A85">85</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chui</surname>
<given-names>Helena C.</given-names>
</name>
<xref ref-type="aff" rid="A85">85</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alafuzoff</surname>
<given-names>Irina</given-names>
</name>
<xref ref-type="aff" rid="A86">86</xref>
<xref ref-type="aff" rid="A87">87</xref>
<xref ref-type="aff" rid="A88">88</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hartikainen</surname>
<given-names>Päivi</given-names>
</name>
<xref ref-type="aff" rid="A88">88</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Seilhean</surname>
<given-names>Danielle</given-names>
</name>
<xref ref-type="aff" rid="A89">89</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Galasko</surname>
<given-names>Douglas</given-names>
</name>
<xref ref-type="aff" rid="A90">90</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Masliah</surname>
<given-names>Eliezer</given-names>
</name>
<xref ref-type="aff" rid="A90">90</xref>
<xref ref-type="aff" rid="A91">91</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cotman</surname>
<given-names>Carl W.</given-names>
</name>
<xref ref-type="aff" rid="A92">92</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tuñón</surname>
<given-names>M. Teresa</given-names>
</name>
<xref ref-type="aff" rid="A93">93</xref>
<xref ref-type="aff" rid="A94">94</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martínez</surname>
<given-names>M. Cristina Caballero</given-names>
</name>
<xref ref-type="aff" rid="A94">94</xref>
<xref ref-type="aff" rid="A95">95</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Munoz</surname>
<given-names>David G.</given-names>
</name>
<xref ref-type="aff" rid="A96">96</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Carroll</surname>
<given-names>Steven L.</given-names>
</name>
<xref ref-type="aff" rid="A97">97</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marson</surname>
<given-names>Daniel</given-names>
</name>
<xref ref-type="aff" rid="A98">98</xref>
<xref ref-type="aff" rid="A99">99</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Riederer</surname>
<given-names>Peter F.</given-names>
</name>
<xref ref-type="aff" rid="A100">100</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bogdanovic</surname>
<given-names>Nenad</given-names>
</name>
<xref ref-type="aff" rid="A101">101</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schellenberg</surname>
<given-names>Gerard D.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<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="A6">6</xref>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Trojanowski</surname>
<given-names>John Q.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Virginia M.-Y.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA USA</aff>
<aff id="A2"><label>2</label>
Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA USA</aff>
<aff id="A3"><label>3</label>
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA USA</aff>
<aff id="A4"><label>4</label>
Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA USA</aff>
<aff id="A5"><label>5</label>
Penn Memory Center, University of Pennsylvania School of Medicine, Philadelphia, PA USA</aff>
<aff id="A6"><label>6</label>
The Center for Applied Genomics, Division of Human Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA USA</aff>
<aff id="A7"><label>7</label>
Division of Pulmonary Medicine and Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA USA</aff>
<aff id="A8"><label>8</label>
Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain</aff>
<aff id="A9"><label>9</label>
Department of Neurology Jacksonville, Mayo College of Medicine, Jacksonville, FL, USA</aff>
<aff id="A10"><label>10</label>
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</aff>
<aff id="A11"><label>11</label>
Department of Neurology, Mayo Clinic, Rochester, MN, USA</aff>
<aff id="A12"><label>12</label>
Clinical Neuroscience Research Group, United Kingdom</aff>
<aff id="A13"><label>13</label>
University of Manchester, United Kingdom</aff>
<aff id="A14"><label>14</label>
Erasmus Medical Centre Rotterdam, The Netherlands</aff>
<aff id="A15"><label>15</label>
Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Center Amsterdam, The Netherlands</aff>
<aff id="A16"><label>16</label>
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</aff>
<aff id="A17"><label>17</label>
Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA</aff>
<aff id="A18"><label>18</label>
Department of Neurological, Neurosurgical and Behavioral Sciences, University of Siena, Siena, Italy</aff>
<aff id="A19"><label>19</label>
Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA</aff>
<aff id="A20"><label>20</label>
Prince of Wales Medical Research Institute, New South Wales, Australia</aff>
<aff id="A21"><label>21</label>
Cambridge Centre for Brain Repair, Dept of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom</aff>
<aff id="A22"><label>22</label>
Department of Neurology, University of Michigan, Ann Arbor, MI, USA</aff>
<aff id="A23"><label>23</label>
Department of Pathology University of Michigan, Ann Arbor, MI, USA</aff>
<aff id="A24"><label>24</label>
Department of Neurology and Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA</aff>
<aff id="A25"><label>25</label>
Department of Pathology, Oregon Health and Science University, Portland, OR, USA</aff>
<aff id="A26"><label>26</label>
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA</aff>
<aff id="A27"><label>27</label>
Cognitive Neurology and Alzheimer Disease Center Northwestern University Feinberg School of Medicine, Chicago, IL, USA</aff>
<aff id="A28"><label>28</label>
Department of Clinical Neuropathology, Institute of Psychiatry, Kings College Hospital, London, United Kingdom</aff>
<aff id="A29"><label>29</label>
MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Kings College Hospital, London, United Kingdom</aff>
<aff id="A30"><label>30</label>
Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA</aff>
<aff id="A31"><label>31</label>
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA</aff>
<aff id="A32"><label>32</label>
Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain</aff>
<aff id="A33"><label>33</label>
Alzheimer's Disease and Cognitive Disorders Unit, Service of Neurology. ICN. Hospital Clínic Barcelona, Barcelona, Spain</aff>
<aff id="A34"><label>34</label>
Institute for Neuropathology, University Hospital Zurich, Zurich, Switzerland</aff>
<aff id="A35"><label>35</label>
Center for Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany</aff>
<aff id="A36"><label>36</label>
Department of Pathology, Duke University Health Sciences Center, Durham, NC, USA</aff>
<aff id="A37"><label>37</label>
Dept of Psychiatry, Duke University Health Sciences Center, Durham, NC, USA</aff>
<aff id="A38"><label>38</label>
Bryan ADRC, Duke University Health Sciences Center, Durham, NC, USA</aff>
<aff id="A39"><label>39</label>
Department of Neurology, University of California at San Francisco, San Francisco, CA, USA</aff>
<aff id="A40"><label>40</label>
Neurogenetic Unit, Instituto Biodonostia, San Sebastián, Spain</aff>
<aff id="A41"><label>41</label>
Servicio de Neurología, Hospital Donostia, San Sebastián, Spain.</aff>
<aff id="A42"><label>42</label>
Departments Neurology and Pathology, Boston University School of Medicine, Boston MA</aff>
<aff id="A43"><label>43</label>
Bedford Veterans Administration Medical Center, GRECC, Bedford MA, USA</aff>
<aff id="A44"><label>44</label>
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA</aff>
<aff id="A45"><label>45</label>
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA</aff>
<aff id="A46"><label>46</label>
Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA</aff>
<aff id="A47"><label>47</label>
Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA</aff>
<aff id="A48"><label>48</label>
Reta Lila Laboratories, UCL Institute of Neurology, London, United Kingdom</aff>
<aff id="A49"><label>49</label>
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom</aff>
<aff id="A50"><label>50</label>
Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom</aff>
<aff id="A51"><label>51</label>
Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, London, United Kingdom</aff>
<aff id="A52"><label>52</label>
Department of Pathology, University of British Columbia, Canada</aff>
<aff id="A53"><label>53</label>
Division of Neurology Vancouver General Hospital and the University of British Columbia, Canada</aff>
<aff id="A54"><label>54</label>
Neuroscience, Bristol-Myers Squibb, University of Pittsburgh, Pittsburgh PA, USA</aff>
<aff id="A55"><label>55</label>
Department of Pathology, University of Pittsburgh, Pittsburgh PA, USA</aff>
<aff id="A56"><label>56</label>
Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA, USA</aff>
<aff id="A57"><label>57</label>
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium</aff>
<aff id="A58"><label>58</label>
Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium</aff>
<aff id="A59"><label>59</label>
Taub Institute for Research on Alzheimer's Disease, Columbia University, New York, NY, USA</aff>
<aff id="A60"><label>60</label>
New York Brain Bank, Columbia University, New York, NY, USA</aff>
<aff id="A61"><label>61</label>
Department of Pathology, Columbia University, New York, NY, USA</aff>
<aff id="A62"><label>62</label>
Departments of Pathology and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA</aff>
<aff id="A63"><label>63</label>
Disciplines of Medicine and Pathology, University of Sydney, Australia</aff>
<aff id="A64"><label>64</label>
Prince of Wales Medical Research Institute, Australia</aff>
<aff id="A65"><label>65</label>
University of New South Wales, Australia</aff>
<aff id="A66"><label>66</label>
GRECC, VA Puget Sound Health Care System, University of Washington, Seattle, WA, USA</aff>
<aff id="A67"><label>67</label>
Department of Neurology, University of Washington, Seattle, WA, USA</aff>
<aff id="A68"><label>68</label>
Department of Neuroscience, University of Sheffield</aff>
<aff id="A69"><label>69</label>
Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA</aff>
<aff id="A70"><label>70</label>
Department of Neurology, Washington University School of Medicine, St Louis, MO, USA</aff>
<aff id="A71"><label>71</label>
Department of Anatomical Pathology, The Alfred Hospital, Australia</aff>
<aff id="A72"><label>72</label>
Alzheimer's Disease Center, Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, Center for Neuroscience, University of California at Davis, Sacramento, CA, USA</aff>
<aff id="A73"><label>73</label>
Department of Pathology, University of California at Davis, Sacramento, CA, USA</aff>
<aff id="A74"><label>74</label>
C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA</aff>
<aff id="A75"><label>75</label>
Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA</aff>
<aff id="A76"><label>76</label>
James J Peters VA Medical Center, New York, NY, USA</aff>
<aff id="A77"><label>77</label>
Rush Alzheimer's Disease Center, Rush University Medical Center, Sun City, AZ, USA</aff>
<aff id="A78"><label>78</label>
Sun Health Research Institute, Sun City, AZ, USA</aff>
<aff id="A79"><label>79</label>
Banner Alzheimer's Institute, Translational Genomics Research Institute, University of Arizona, Phoenix, AZ, USA</aff>
<aff id="A80"><label>80</label>
Arizona Alzheimer's Consortium, Phoenix, AZ, USA</aff>
<aff id="A81"><label>81</label>
Mayo Clinic Arizona, Scottsdale, AZ, USA</aff>
<aff id="A82"><label>82</label>
Mary S. Easton Center for Alzheimer's Disease Research, Los Angeles, CA, USA</aff>
<aff id="A83"><label>83</label>
Department of Pathology and Laboratory Medicine, Los Angeles, CA, USA</aff>
<aff id="A84"><label>84</label>
Department of Neurology David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</aff>
<aff id="A85"><label>85</label>
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA</aff>
<aff id="A86"><label>86</label>
Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden</aff>
<aff id="A87"><label>87</label>
Department of Clinical Medicine, Kuopio University, Kuopio Finland</aff>
<aff id="A88"><label>88</label>
Department of Neurology, Kuopio University, Kuopio Finland</aff>
<aff id="A89"><label>89</label>
UPMC-Univ Paris 06 and APHP, France</aff>
<aff id="A90"><label>90</label>
Department of Neurosciences, University of California, San Diego, San Diego, CA, USA</aff>
<aff id="A91"><label>91</label>
Department of Pathology, University of California, San Diego, San Diego, CA, USA</aff>
<aff id="A92"><label>92</label>
Department of Neurology, University of California, Irvine, Irvine, CA, USA</aff>
<aff id="A93"><label>93</label>
Hospital de Navarra Pathology Department, Spain</aff>
<aff id="A94"><label>94</label>
Brain Bank of Navarra, Spain</aff>
<aff id="A95"><label>95</label>
Biomedical Research Center, Navarra Health Service-Osasunbidea, Spain</aff>
<aff id="A96"><label>96</label>
Department of Laboratory Medicine and Pathobiology, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Canada</aff>
<aff id="A97"><label>97</label>
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA</aff>
<aff id="A98"><label>98</label>
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA</aff>
<aff id="A99"><label>99</label>
Alzheimer's Disease Research Center, University of Alabama at Birmingham, Birmingham, AL, USA</aff>
<aff id="A100"><label>100</label>
Clinical Neurochemistry Clinic and Policlinic of Psychiatry, Psychosomatic and Psychotherapy of the University of Wuerzburg, Germany</aff>
<aff id="A101"><label>101</label>
Geriatric Medicine and Neuropathology at Department of Geriatric Medicine, Karolinska University Hospital, Stockholm Sweden</aff>
<author-notes><corresp id="CR1">Correspondence and requests for materials should be addressed to VVD (<email>vivianna@mail.med.upenn.edu</email>
) or JQT (<email>trojanow@mail.med.upenn.edu</email>
).</corresp>
<fn fn-type="equal" id="FN1"><label>*</label>
<p id="P1">Co-first authors with equal contributions</p>
</fn>
<fn id="FN4"><p id="P2">Author Contributions</p>
<p id="P3">VVD, PS, MML, and ACP contributed equally to this manuscript. The overall study was designed and implemented by VMYL, JQT, VVD, HH and MML and discussed with GDS, LSW, and ACP. Coordination, sample handling, DNA extraction, genetic analysis and data management were done primarily by VVD and MML. Genotyping and additional testing, including immunohistochemical analysis, was done by PS, HH, VVD, or MML. Data analysis and quality control were performed by PS, LSW, and ACP and discussed and reviewed by VVD, HH, GS, VMYL, JQT, and MML. Expression analysis was designed and implemented by ACP. The manuscript was prepared by ACP, VVD, and PS and reviewed by MML, GDS, HH, JQT, VMYL, and LSW. The members of the International FTLD Collaboration, which includes all other authors, contributed cases, evaluated pathology, performed genetic studies and reviewed the manuscript.</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>29</day>
<month>1</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="epub"><day>14</day>
<month>2</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="ppub"><month>3</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>9</month>
<year>2010</year>
</pub-date>
<volume>42</volume>
<issue>3</issue>
<fpage>234</fpage>
<lpage>239</lpage>
<pmc-comment>elocation-id from pubmed: 10.1038/ng.536</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="P4">Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)<xref rid="R1" ref-type="bibr">1</xref>
. FTLD-TDP is frequently familial resulting from progranulin (<italic>GRN</italic>
) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains <italic>TMEM106B</italic>
in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (<italic>P=</italic>
1.08×10<sup>−11</sup>
; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; <italic>P=</italic>
2×10<sup>−4</sup>
). <italic>TMEM106B</italic>
variants may confer risk by increasing <italic>TMEM106B</italic>
expression. <italic>TMEM106B</italic>
variants also contribute to genetic risk for FTLD-TDP in patients with <italic>GRN</italic>
mutations. Our data implicate <italic>TMEM106B</italic>
as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.</p>
</abstract>
</article-meta>
</front>
<body><p id="P5">FTLD manifests clinically with progressive behavioral and/or language deficits with a prevalence of 3.5-15/100,000 in 45 to 64 year olds<xref rid="R2" ref-type="bibr">2</xref>
-<xref rid="R5" ref-type="bibr">5</xref>
. The clinical presentation of cases with FTLD pathology varies depending on the referral base<xref rid="R6" ref-type="bibr">6</xref>
and among these cases, ~50% are diagnosed as FTLD-TDP<xref rid="R1" ref-type="bibr">1</xref>
. A family history of a similar neurodegenerative disease may be present in up to 50% of FTLD cases, supporting the existence of a genetic predisposition<xref rid="R7" ref-type="bibr">7</xref>
. Autosomal dominant <italic>GRN</italic>
mutations occur in ~20% of FTLD-TDP cases<xref rid="R8" ref-type="bibr">8</xref>
-<xref rid="R11" ref-type="bibr">11</xref>
. <italic>GRN</italic>
mutations are loss-of-function mutations with most resulting in premature termination of the mutant transcript invoking nonsense-mediated RNA decay and with the ensuing haploinsufficiency causing disease<xref rid="R11" ref-type="bibr">11</xref>
,<xref rid="R12" ref-type="bibr">12</xref>
. However, a substantial number of familial FTLD-TDP cases are not explained by <italic>GRN</italic>
mutations. Further, patients with the same <italic>GRN</italic>
mutation show variable clinical phenotypes or ages of disease onset which likely reflect additional genetic and environmental factors<xref rid="R13" ref-type="bibr">13</xref>
.</p>
<p id="P6">The GWA phase of the study included 515 cases of FTLD-TDP and 2509 disease-free population controls genotyped on the Illumina HH550 or 610-Quad BeadChips as described<xref rid="R14" ref-type="bibr">14</xref>
(<xref ref-type="table" rid="T1">Table 1</xref>
). A large population control cohort was acceptable since the general population incidence of FTLD is low<xref rid="R4" ref-type="bibr">4</xref>
,<xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R15" ref-type="bibr">15</xref>
. Cases were obtained under institutional review board approval by members of the International FTLD Collaboration consisting of investigators from 45 clinical centers and brain banks representing 11 countries (United States, Canada, United Kingdom, The Netherlands, Belgium, Spain, Germany, Australia, Finland, France, and Sweden). All cases met either pathological (n=499) or genetic (n=16) criteria for FTLD-TDP which was confirmed by detecting TDP-43 inclusions using immunohistochemistry (IHC)<xref rid="R1" ref-type="bibr">1</xref>
,<xref rid="R16" ref-type="bibr">16</xref>
. A genetic criterion for inclusion (<italic>i.e.</italic>
presence of a known pathogenic <italic>GRN</italic>
mutation) was used since <italic>GRN</italic>
mutation cases are always diagnosed as FTLD-TDP <xref rid="R8" ref-type="bibr">8</xref>
,<xref rid="R9" ref-type="bibr">9</xref>
,<xref rid="R17" ref-type="bibr">17</xref>
,<xref rid="R18" ref-type="bibr">18</xref>
. All cases were checked for relatedness using identity by state (IBS). The results confirmed that although some <italic>GRN</italic>
-associated FTLD-TDP cases share the same mutation on chromosome 17 with similarity in the immediate vicinity of <italic>GRN</italic>
, they are no more related in the remainder of the genome than individuals without <italic>GRN</italic>
mutations. Detailed inclusion criteria are provided in Methods; cohort features are in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>
.</p>
<p id="P7">Cochran-Armitage trend test statistics were calculated at all markers following quality control filtering. In addition to self-reported ancestry, all cases and controls were initially screened at ancestry informative markers (AIM) using the STRUCTURE software package<xref rid="R19" ref-type="bibr">19</xref>
to reduce the risk of population stratification from self-reported ancestry alone. Each case was subsequently matched to four controls by ‘genetic matching’ by smartPCA<xref rid="R20" ref-type="bibr">20</xref>
as previously described<xref rid="R21" ref-type="bibr">21</xref>
. The genomic inflation factor (λ) for this study was 1.05 indicating that background stratification was minimal as demonstrated in the quantile-quantile (Q-Q) plots (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 1</xref>
).</p>
<p id="P8">Three SNPs reached genome-wide significance following Bonferroni correction (<xref ref-type="fig" rid="F1">Figures 1a and b</xref>
). All three SNPs (rs6966915, rs1020004, and rs1990622) mapped to a 68 kb interval (<xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 2</xref>
) on 7p21.3 (top marker, rs1990622, minor allele frequency (MAF) 32.1% in cases and 43.6% in controls, OR = 0.61, [95% CI 0.53 – 0.71], <italic>P=</italic>
1.08×10<sup>−11</sup>
). For rs1990622, the more common (T) allele confers risk with an OR of 1.64 [95% CI 1.34-2.00]. The interval contained nine additional markers in strong LD (r<sup>2</sup>
>0.45) that were also associated with FTLD-TDP (<italic>P-</italic>
value range = 8.9×10<sup>−3</sup>
- 7.5×10<sup>−7</sup>
; OR range 0.63-0.77) (<xref ref-type="table" rid="T2">Table 2</xref>
). All 12 associated SNPs map to a single LD block spanning <italic>TMEM106B</italic>
, which encodes an uncharacterized transmembrane protein of 274 amino acids (<xref ref-type="fig" rid="F1">Figures 1b and c</xref>
). SNPs rs1020004 and rs6966915 lie within introns 3 and 5, respectively, of <italic>TMEM106B</italic>
, while rs1990622 is 6.9 kb downstream of the gene. These findings argue strongly for the association of the 7p21 locus, and the gene <italic>TMEM106B</italic>
, with FTLD-TDP.</p>
<p id="P9">The association with FTLD-TDP in the GWA was replicated by TaqMan SNP genotyping in 89 independent FTLD-TDP cases and 553 Caucasian control samples at two of the genome-wide significant SNPs (rs1020004 and rs1990622) (<xref ref-type="table" rid="T1">Table 1</xref>
and <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>
). A polymorphic variation adjacent to rs6966915 interfered with interpretation of TaqMan genotyping therefore precluding its use in the replication. The replication set was selected based on the same pathological criteria and had similar characteristics as the GWA phase cohort (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>
). In this replication cohort, the top SNPs again showed significant association (<italic>P=</italic>
0.004 for rs1020004 and <italic>P=</italic>
0.0002 for rs1990622) with the same directions of association as those found in the GWA phase (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>
). These results suggest that in the 7p21 locus, encompassing the gene <italic>TMEM106B</italic>
, we have identified a common genetic susceptibility factor for FTLD-TDP. Of interest, this association was not confirmed in a cohort of 192 living patients with unselected FTLD (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 2</xref>
). This likely reflects heterogeneity in neuropathological substrates underlying FTLD, with only ~50% of unselected clinical FTLD cases expected to have FTLD-TDP. Assuming that <italic>TMEM106B</italic>
genetic variants confer risk of FTLD-TDP specifically, the power to detect this association in 192 clinical FTLD cases and 553 controls is ~30% for an alpha-value of 0.05. To have >90% power to detect this association, a clinical FTLD cohort would require more than 1400 clinical FTLD cases and an equal number of controls.</p>
<p id="P10">We next evaluated <italic>TMEM106B</italic>
gene expression in different human tissues to identify phenotype-associated differential expression and also any potential genetic regulators of expression. We queried the mRNA-by-SNP browser (<ext-link ext-link-type="uri" xlink:href="http://www.sph.umich.edu/csg/liang/asthma/">http://www.sph.umich.edu/csg/liang/asthma/</ext-link>
, last accessed June 6, 2009), for genetic regulators of <italic>TMEM106B</italic>
expression (eSNPs) in lymphoblastoid cell lines<xref rid="R22" ref-type="bibr">22</xref>
. The top SNP, rs1990622, was significantly correlated with <italic>TMEM106B</italic>
average expression levels (LOD 6.32; <italic>P=</italic>
6.9×10<sup>−8</sup>
), as was SNP rs1020004 (LOD 5.16, <italic>P=</italic>
1.10×10<sup>−6</sup>
). The risk allele (T) of rs1990622 was associated with a higher level of mRNA expression, indicating that <italic>TMEM106B</italic>
may be under <italic>cis</italic>
-acting regulation by either the FTLD-TDP associated SNPs or another SNP(s) in LD with the associated variants. As the expression data in the publicly available database is derived from lymphoblastoid cell lines from normal individuals<xref rid="R22" ref-type="bibr">22</xref>
, and the diseased organ in FTLD-TDP is brain, we asked if a similar correlation between genotype and expression phenotype for <italic>TMEM106B</italic>
is also present in tissue types affected by disease, and in diseased individuals themselves. Accordingly, we used total RNA isolated from FTLD-TDP postmortem brains (n=18) and neurologically normal control brains (n=7) to evaluate <italic>TMEM106B</italic>
expression in frontal cortex, which is severely affected in FTLD-TDP, by quantitative reverse-transcription PCR (QRT-PCR). All RNA samples used were confirmed to be of equivalent high quality as described<xref rid="R23" ref-type="bibr">23</xref>
(<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 3</xref>
). For the same individuals for which we obtained expression data, we genotyped SNPs rs1020004 and rs1990622 using allelic discrimination assays.</p>
<p id="P11">Corroborating results from the cell lines, expression of <italic>TMEM106B</italic>
was significantly correlated with <italic>TMEM106B</italic>
genotype, with risk allele carriers showing higher expression (overall <italic>P=</italic>
0.027, TT vs. TC <italic>P=</italic>
0.017, TT vs. CC <italic>P=</italic>
0.03, for rs1990622, <xref ref-type="fig" rid="F2">Fig. 2a</xref>
and <xref ref-type="supplementary-material" rid="SD1">Supplementary Fig. 3a</xref>
). Strikingly, however, expression of <italic>TMEM106B</italic>
was >2.5 times higher in FTLD-TDP cases compared to normal controls (<italic>P=</italic>
0.045, <xref ref-type="fig" rid="F2">Fig. 2b</xref>
). In addition, the effects of genotype and <italic>TMEM106B</italic>
expression on risk of developing disease are at least partly independent, as are the effects of genotype and disease status on <italic>TMEM106B</italic>
expression (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 4a and b</xref>
). Thus, these data suggest that increased <italic>TMEM106B</italic>
brain expression might be linked to mechanisms of disease in FTLD-TDP, and that risk alleles at <italic>TMEM106B</italic>
confer genetic susceptibility by increasing gene expression.</p>
<p id="P12">The primary criterion for inclusion in the GWAS was a neuropathological diagnosis of FTLD-TDP; therefore we studied all cases together regardless of <italic>GRN</italic>
mutation status. Nevertheless, <italic>a priori</italic>
it was difficult to predict whether additional genetic susceptibility loci would be identified in a group with Mendelian inheritance of highly penetrant mutations. We therefore separately evaluated FTLD-TDP cases with (n=89) and without (n=426) <italic>GRN</italic>
mutations. Association to the 7p21 locus persisted in both the <italic>GRN</italic>
negative and positive clusters and there was no significant heterogeneity in the ORs for the disease/SNP association between the clusters (<xref ref-type="fig" rid="F3">Fig. 3</xref>
and <xref ref-type="supplementary-material" rid="SD1">Supplementary Tables 2 and 5</xref>
). Using family history status as a covariate in a logistic regression showed that the 7p21 association is independent of family history (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 6</xref>
). Thus, <italic>TMEM106B</italic>
variants may act as a modifier locus in the presence of <italic>GRN</italic>
mutations, as the <italic>APOE</italic>
locus has been shown to modify age of onset in patients with <italic>PSEN1</italic>
<xref rid="R24" ref-type="bibr">24</xref>
or <italic>PSEN2</italic>
<xref rid="R25" ref-type="bibr">25</xref>
mutations.</p>
<p id="P13">Additionally, in the whole GWA cohort, we observed a correlation between rs1020004 genotype and disease duration (<italic>P</italic>
=0.03) with homozygotes for the risk allele (AA, wild-type) having shorter duration of disease (i.e. more severe disease) than individuals homozygous for the minor allele (GG, <xref ref-type="supplementary-material" rid="SD1">Supplementary Figure 4</xref>
). These results provide strong confirmatory evidence for association of the 7p21 locus with increased risk for FTLD-TDP in both <italic>GRN</italic>
positive and negative cases.</p>
<p id="P14">In addition to the 7p21 locus, analysis of the <italic>GRN</italic>
cases alone showed highly significant association with SNPs near the <italic>GRN</italic>
locus on 17q21 (<xref ref-type="fig" rid="F3">Fig. 3</xref>
and <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 7</xref>
). Not unexpectedly, haplotype analysis of the cases indicated that the chromosome 17 association was driven by a shared haplotype among the p.R493X (NM_002087.2:c.1477C>T) mutation carriers which represented 20.2% (18/89) of the <italic>GRN</italic>
mutation cases. To determine if the observed association at the <italic>GRN</italic>
locus was dependent on the association at the <italic>TMEM106B</italic>
locus we carried out a logistic regression analysis conditioning on the most significantly associated SNP at the 7p21 locus, rs1990622, in the patients with <italic>GRN</italic>
mutations. The conditional analysis had no effect on the association at the <italic>GRN</italic>
locus suggesting that the associations with 17q21 and 7p21 are independent. IBS analysis confirms that these individuals are unrelated and therefore the identified association on chromosome 7 cannot be discounted in <italic>GRN</italic>
mutation carriers. Indeed, conditioning on the top SNP at the <italic>GRN</italic>
locus, rs8079488, also had no effect on the <italic>TMEM106B</italic>
association (results not shown). In addition to the 7p21 locus, the GWAS of <italic>GRN</italic>
negative cases showed a trend for association at five other loci (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 8</xref>
) including a locus on chromosome 9p21.2 that falls within a 7.7 Mb critical interval defined from five previous linkage studies, representing a potential refinement of that region<xref rid="R26" ref-type="bibr">26</xref>
. We observed no association at the <italic>GRN</italic>
locus in the cases without <italic>GRN</italic>
mutations.</p>
<p id="P15">We then evaluated mRNA expression of <italic>TMEM106B</italic>
in FTLD-TDP with and without <italic>GRN</italic>
mutations separately, and the <italic>GRN</italic>
mutants showed increased expression (overall <italic>P=</italic>
0.0009), compared to controls (<italic>P=</italic>
0.0005) and FTLD-TDP without <italic>GRN</italic>
mutations (<italic>P=</italic>
0.002) (<xref ref-type="fig" rid="F2">Figure 2c</xref>
). Furthermore, controlling for rs1990622 genotype and focusing on heterozygotes (n=14), the presence of a <italic>GRN</italic>
mutation remained significantly associated with increased <italic>TMEM106B</italic>
expression (<italic>P=</italic>
0.039, <xref ref-type="fig" rid="F2">Fig. 2d</xref>
) compared to normal controls. These results are compatible with a model in which mutations in <italic>GRN</italic>
are upstream of increased <italic>TMEM106B</italic>
expression in increasing risk for FTLD-TDP.</p>
<p id="P16">A mechanistic understanding of the pathogenesis of FTLD has been hampered the heterogeneity in clinical and pathological features. With the discovery of TDP-43 as a major FTLD disease protein, the pathologically-defined entity of FTLD-TDP emerged<xref rid="R16" ref-type="bibr">16</xref>
. Identification of <italic>GRN</italic>
mutations as a major genetic cause of FTLD-TDP, led to definition of a genetic subgroup of FTLD-TDP. This study identifies <italic>TMEM106B</italic>
as a genetic risk factor for FTLD-TDP. We speculate that the homogeneous pathologically-defined study population used here enabled us to detect a robust signal with relatively small case numbers.</p>
<p id="P17">Our data suggest a potential disease mechanism in which risk-associated polymorphisms at 7p21 increase <italic>TMEM106B</italic>
expression, and elevated <italic>TMEM106B</italic>
expression increases risk for FTLD-TDP. Additionally, we show that <italic>TMEM106B</italic>
genotypes are a significant risk factor for FTLD-TDP even in <italic>GRN</italic>
mutation carriers implying that <italic>GRN</italic>
mutations may act upstream of <italic>TMEM106B</italic>
in a pathogenic cascade. Future directions of research on this novel genetic risk factor will include a detailed evaluation of the <italic>TMEM106B</italic>
locus by sequencing, collection of more pathologically-defined FTLD-TDP cases for a genome-wide replication, and studies of expression profiles in additional tissues and brain regions. A better understanding of this gene may in turn provide an opportunity to intervene in an otherwise fatal and devastating neurodegenerative disease.</p>
<sec sec-type="methods" id="S1"><title>METHODS</title>
<sec id="S2"><title>Inclusion criteria</title>
<p id="P18">Individuals of European descent with dementia clinically +/− motor neuron disease (MND) and an autopsy diagnosis of FTLD-TDP confirmed by TDP-43 IHC were included. Mixed pathologies were not excluded. Living individuals with a pathogenic <italic>GRN</italic>
mutation were also included<xref rid="R18" ref-type="bibr">18</xref>
. Only a single proband per family was permitted. Appropriate informed consent was obtained. 598 unique FTLD-TDP cases met inclusion criteria; 515 were used for the GWAS after PCA matching to controls. Characteristics described in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>
. Whole genome amplification (WGA), performed in duplicate and pooled, was used for 15 (Repli-g Mini, Qiagen), but only 6 cases ultimately passed quality control parameters for the GWAS. The replication, using SNP genotyping, included cases of insufficient quality or quantity for the GWA phase (n=27), cases available only as formalin-fixed paraffin-embedded tissue (n=6), and cases randomly not used for GWA phase (n=56). Three FTLD-TDP cases with mutations in valosin-containing protein (VCP) gene were included (two in GWA and one in replication)<xref rid="R18" ref-type="bibr">18</xref>
.</p>
</sec>
<sec id="S3"><title>Controls</title>
<p id="P19">GWAS controls consisted of 2509 samples, including 1297 self-reported Caucasian children of European ancestry recruited from CHOP Health Care Network and 1212 samples from the 1958 birth cohort genotyped by the WTCCC<xref rid="R27" ref-type="bibr">27</xref>
. Although the controls were not selected for absence of neurodegenerative disease, the large size of the cohort relative to the low population frequency of FTLD overrides this potential concern. Furthermore, the minor allele frequencies at the 7p21 loci are very similar (<1-2% variation) between CHOP and WTCCC cohorts suggesting they accurately reflect the control allelic frequencies in the general population (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 9</xref>
). To reduce the risk of population stratification all internal controls were screened using the STRUCTURE package<xref rid="R19" ref-type="bibr">19</xref>
at 220 AIMs. To improve clustering the samples were spiked with 90 CEPH, Yoruban and Chinese/Japanese individuals genotyped as part of the HapMap project. Cases were excluded if their inferred proportion of ancestry was less than 90% that of the CEU cluster.</p>
<p id="P20">For the replication 553 controls were as follows: 275 from Coriell Institute (Neurologically Normal Caucasian control panels, Camden, NJ), 155 clinical controls from neurology clinics at University of Pennsylvania (UPenn), 28 brain samples of neurologically normal individuals > 60 years from the UPenn Center for Neurodegenerative Disease Research (CNDR), and 95 population controls from CHOP.</p>
</sec>
<sec id="S4"><title>DNA extraction and quality assessment</title>
<p id="P21">Samples sent as DNA from external sites were extracted using different methods. Remaining samples (376) were extracted at UPenn from frozen brain tissue or blood. Genomic DNA was extracted from frozen brain tissue (50 mg) by the Qiagen MagAttract DNA Mini M48 Kit on the M48 BioRobot. Genomic DNA was purified from whole blood using FlexiGene kit (Qiagen). High quality DNA was required for the Illumina genotyping. All DNA samples were evaluated for purity by spectrophotometric analysis (Nanodrop) and for degradation by 1% agarose gel electrophoresis (Invitrogen).</p>
</sec>
<sec id="S5"><title>TDP-43 IHC</title>
<p id="P22">Autopsy cases were confirmed to have TDP-43 pathology by IHC performed by the sending institution or at UPenn CNDR as previously described<xref rid="R16" ref-type="bibr">16</xref>
. TDP-43 negative cases were excluded.</p>
</sec>
<sec id="S6"><title><italic>GRN</italic>
sequencing</title>
<p id="P23">To stratify the analysis according to <italic>GRN</italic>
mutation status, exons 1-13 (with exon 1 representing exon 0 in Gass <italic>et al.</italic>
<xref rid="R10" ref-type="bibr">10</xref>
) and adjacent intronic regions were sequenced as described<xref rid="R13" ref-type="bibr">13</xref>
in cases not previously evaluated. <italic>GRN</italic>
sequencing was not possible due to limited sample quantity in a few cases (n=13 in GWA, n=15 in replication). Novel variants identified in this study not predicted to cause a frameshift or premature termination and previously described variants of uncertain significance were grouped with <italic>GRN</italic>
mutation negative cases. The most common mutations identified are given in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>
.</p>
</sec>
<sec id="S7"><title>Illumina genotyping and quality control</title>
<p id="P24">The FTLD-TDP cases and CHOP control samples were genotyped on either the Illumina HH550 BeadChip or the Illumina human610-quad BeadChip at the Center for Applied Genomics at CHOP as previously described<xref rid="R14" ref-type="bibr">14</xref>
. The 1958 birth cohort samples were genotyped on the HH550 BeadChip by the WTCCC<xref rid="R27" ref-type="bibr">27</xref>
. Sixteen individuals, 13 cases and 3 controls, were excluded from GWA phase for low genotyping (<98% chip-wide genotyping success). We further rejected 13,316 SNPs with call rates <95%, 23,552 SNPs with MAF < 1% and 1,940 SNPs with Hardy Weinberg equilibrium <italic>P</italic>
<10<sup>−5</sup>
in the controls samples; the λ was 1.05. Cases and controls were screened for relatedness using the IBS estimations in <italic>plink</italic>
(<ext-link ext-link-type="uri" xlink:href="http://pngu.mgh.harvard.edu/purcell/plink/index.shtml">http://pngu.mgh.harvard.edu/~purcell/plink/index.shtml</ext-link>
) on 100,000 randomly distributed markers throughout the genome. Pairwise Pi-hat values in excess of 0.01 were indicative of relatedness.</p>
<p id="P25">Following the quality control measures cases were matched to controls by ‘genetic matching’ as previously described<xref rid="R21" ref-type="bibr">21</xref>
. We computed principal components for our dataset by running smartpca, a part of the EIGENSTRAT package, on 100,000 random autosomal SNPs and applied a matching algorithm implemented in MATLAB to the output. The matching algorithm assigns each sample a coordinate based on k eigenvalue-scaled principal components. It then matches each case to m unique controls within a distance d, keeping only cases that match exactly m controls. The distance thresholds were manually optimized to minimize λ and maximize power (i.e. number of cases). We matched each case to four controls, using the first three principal components and a distance threshold of 0.025.</p>
</sec>
<sec id="S8"><title>Statistical Analysis for Association</title>
<p id="P26">Statistical tests for association were performed using <italic>plink</italic>
. Single marker analyses for the genome-wide data were done using the Cochran-Armitage trend test. The genomic inflation factors were 1.05 for the complete case set and 1.03 for the <italic>GRN</italic>
mutation carriers, indicating only minor background stratification. The Breslow-Day test within <italic>plink</italic>
was used to test for heterogeneity of odds ratio for the disease/SNP association between <italic>GRN</italic>
mutation carriers and non-carriers. Conditional SNP regression analyses were completed in <italic>plink,</italic>
the allele dosages of the conditioning SNP were included as covariates in the logistic regression models. To determine if the association at the <italic>TMEM106B</italic>
locus was dependent on family history we included family history status as a covariate in a logistic regression model using <italic>plink</italic>
. Haplotypes were reconstructed and population frequencies estimated using the EM algorithm implemented in the program fastPHASE<xref rid="R28" ref-type="bibr">28</xref>
. For the age of onset and disease duration analyses we performed an analysis of variance (ANOVA) with the general linear models procedure in R (<ext-link ext-link-type="uri" xlink:href="http://www.r-project.org">www.r-project.org</ext-link>
). Independent variables for each ANOVA were the log transformed age of onset or disease duration in years and the individual SNP genotype with additive encoding (ie three categories where 0 is homozygous for the ancestral allele, 1 is heterozygous and 2 is homozygous for the minor allele). Power calculations were based on the rs1990622 allele frequencies observed for cases and controls in the GWAS, using a two-tailed test. We assumed that clinical FTLD cases without TDP-43 pathology as the neuropathological substrate would have allele frequencies similar to controls.</p>
</sec>
<sec id="S9"><title>SNP Genotyping for Replication</title>
<p id="P27">For the replication, genotyping was performed using TaqMan chemistry-based allelic discrimination assays (Applied Biosystems (ABI), Foster City, CA) on the ABI 7500 Fast Real-Time System followed by analysis with SDS 7500 software v2.0.1. The ABI assays used were: rs1020004, C_7604953_10 and rs1990622, C_11171598_10. A nearby novel genetic variation (possible deletion) was found to interfere with correct genotyping of the T allele of SNP rs6966915 using ABI reagents C_31573289_10 (as well as by DNA sequencing), thus this SNP was not used further.</p>
</sec>
<sec id="S10"><title>Human samples for expression analysis</title>
<p id="P28">Frontal cortex human brain samples from the CNDR Brain Bank characterized following consensus criteria<xref rid="R1" ref-type="bibr">1</xref>
,<xref rid="R3" ref-type="bibr">3</xref>
were dissected as previously described<xref rid="R23" ref-type="bibr">23</xref>
. Neurologically normal controls (n=7), FTLD-TDP cases with (n=8), and without (n=10) <italic>GRN</italic>
mutations were sampled (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 10</xref>
). <italic>GRN</italic>
mutations were confirmed to be absent from control cases. RNA quality was verified using an Agilent 2100 Bioanalyzer (RIN>6 for inclusion) as previously described<xref rid="R23" ref-type="bibr">23</xref>
. mRNA expression was quantified by QRT-PCR on the ABI7500 using the delta-delta C<sub>T</sub>
method, and the geometric mean of two housekeeping genes (β-actin and Cyclophilin A), shown to have stable expression in frontal cortex samples from FTLD-TDP and normal individuals<xref rid="R23" ref-type="bibr">23</xref>
. Detailed information on primers is available on request.</p>
</sec>
<sec id="S11"><title>Statistical analyses of expression data and replication cohort</title>
<p id="P29">For all brain expression and replication cohort analyses, statistical tests were performed using open source R software packages. R-scripts are available upon request. For evaluations of the effect of disease status, SNP genotype, and gender on <italic>TMEM106B</italic>
expression, linear regressions were used to compute p-values in univariate models. We evaluated assumptions of linearity by checking QQ plots (observed vs. predicted under normal distribution). For pairwise comparisons within the linear models, risk allele homozygotes and <italic>GRN</italic>
mutants, respectively, were designated the reference group for marginal t-tests evaluating genotype effects and the effects of <italic>GRN</italic>
mutations on expression. Normalized gene expression sample genotype and gender data are provided in <xref ref-type="supplementary-material" rid="SD1">Supplementary Data 1 and 2</xref>
. For evaluations of the independent contributory effects of SNP genotype and <italic>TMEM106B</italic>
expression on disease state, logistic regressions were used to compute AIC values in multivariate vs. univariate models (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 4a</xref>
). For evaluations of the independent contributory effects of SNP genotype and disease state on <italic>TMEM106B</italic>
expression, linear regressions were used in multivariate vs. univariate models (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 4b</xref>
). For analyses of association of SNP genotypes with disease in our TaqMan replication cohort, Cochran-Armitage trend tests were used to compute <italic>P</italic>
-values under a codominant model.</p>
</sec>
</sec>
<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="NIHMS172758-supplement-1.pdf" mimetype="application" mime-subtype="pdf" xlink:type="simple" id="d37e2142" position="anchor"></media>
</supplementary-material>
</sec>
</body>
<back><ack id="S12"><title>Acknowledgements</title>
<p>This project was enabled by the contributions and efforts of many individuals in several supportive capacities. Most importantly, we extend our appreciation to the patients and families who made this research possible. Extensive technical assistance was provided by R. Greene, T. Unger, and C. Kim and study coordination by E. McCarty Wood. The following individuals contributed through sample ascertainment, epidemiology, coordination, and/or clinical evaluation of cases: R.C. Petersen, D.S. Knopman, K.A. Josephs, D. Neary, J. Snowden, J. Heidebrink, N. Barbas, R. Reñe, J.R. Burke, K. Hayden, J. Browndyke, P. Gaskell, M. Szymanski, J.D. Glass, M. Rossor, F. Moreno, B. Indakoetxea, M. Barandiaran, S. Engelborghs, P.P. De Deyn, W.S Brooks, T. Chow, V. Meininger, L. Lacomblez, E. Gruenblatt. The following individuals contributed through pathological characterization and evaluation of cases: L. Kwong, J.E. Parisi, W. Kamphorst, I. Ruiz, T. Revesz, J.-J.Martin, R. Highley, C. Duyckaerts. The following individuals contributed through general technical assistance and/or genetic studies: E. Moore, M. Baker, R. Crook, S. Rollinson, N. Halliwell, S. Usher, R.M. Richardson, M. Mishra, C. Foong, J. Ervin, K. Price Bryan, J. Ervin, C. Kubilus, A. Gorostidi, M. Cruts, I. Gijselinck, H. McCann, P.R. Schofield, G. Forster, K. Firch, J. Pomaician, I. Leber, V. Sazdovitch, I. Volkmann. The following individuals also contributed: D. Clark, S. Weintraub, N. Johnson, A. King, I. Bodi, C. Shaw, J. Kirby, V. Haroutunian, D. Purohit. We also thank the Brain Bank of University of Barcelona/Hospital Clinic, Clinic for Alzheimer's Disease and Related Disorders University of British Columbia, Australian Brain Donor Programs supported by the National Health and Medical Research Council of Australia, Biobank at the Institute Born-Bunge, and the French clinical and genetic research network on FTD/FTD-MND. Many grant funding agencies provided financial support for this study, including the National Institutes of Health (AG10124, AG17586, AG16574, AG03949, AG17586, NS44266, AG15116, NS53488, AG10124, AG 010133, AG08671, NS044233, NS15655, AG008017, AG13854, P3AG12300, AG028377, AG 019724, AG13846, AG025688, AG05133, AG08702, AG05146, AG005136, AG005681, AG03991, AG010129, AG05134, NS038372, AG02219, AG05138, AG10161, AG19610, AG19610, AG16570, AG 16570, AG05142, AG005131, AG5131, AG18440, AG16582, AG 16573, and NIH Intramural Program). Additional funds were provided by: Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program, the Pacific Alzheimer's disease Research Foundation (PARF) grant #C06-01, the Alzheimer's Research Trust, Alzheimer's Society, Medical Research Council (Programme Grant and Returning Scientist Award), Stichting Dioraphte(07010500), Hersenstichting (15F07.2.34), Prinses Beatrix Fonds (006-0204), Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, the McCune Foundation, Instituto Carlos III, Federal Ministry of Education and Research (01GI0505), SAIOTEK Program (Basque Government), Department of Innovation, Diputación Foral de Gipúzkoa (DFG 0876/08), ILUNDAIN Fundazioa, CIBERNED, Wellcome Trust, Canadian Institutes of Health Research (75480), Fund for Scientific Research Flanders (FWO-V), IAP P6/43 network of the Belgian Science Policy Office (BELSPO), the Joseph Iseman Fund, the Louis and Rachel Rudin Foundation, National Health and Medical Research Council of Australia, Veteran's Affairs Research Funds, Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05-901 to the Arizona Parkinson's Disease Consortium), the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson's Research, the Daljits and Elaine Sarkara Chair in Diagnostic Medicine, BrainNet Europe II, and MMCYT Ref SAF 2001-4888.</p>
</ack>
<fn-group><fn id="FN2"><p id="P30"><bold>Supplementary Information</bold>
is available online</p>
</fn>
<fn id="FN3"><p id="P31">Accession Numbers</p>
<p id="P32"><italic>GRN</italic>
: NM_002087.2</p>
<p id="P33"><italic>TMEM106B</italic>
: NM_018374.3</p>
</fn>
<fn id="FN5"><p id="P34">Competing Financial Interest</p>
<p id="P35">A patent application on TMEM106B has been submitted. Dr. James Lah is currently involved in clinical trials involving: Elan, Janssen, Medivation, and Ceregene. Dr. Howard Feldman has been a full time employee in Neuroscience Global Clinical Research and Development at Briston-Myers Squibb.</p>
</fn>
</fn-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>Cairns</surname>
<given-names>NJ</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration</article-title>
<source>Acta Neuropathol</source>
<year>2007</year>
<volume>114</volume>
<fpage>5</fpage>
<lpage>22</lpage>
<pub-id pub-id-type="pmid">17579875</pub-id>
</element-citation>
</ref>
<ref id="R2"><label>2</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Neary</surname>
<given-names>D</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria</article-title>
<source>Neurology</source>
<year>1998</year>
<volume>51</volume>
<fpage>1546</fpage>
<lpage>54</lpage>
<pub-id pub-id-type="pmid">9855500</pub-id>
</element-citation>
</ref>
<ref id="R3"><label>3</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McKhann</surname>
<given-names>GM</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease</article-title>
<source>Arch Neurol</source>
<year>2001</year>
<volume>58</volume>
<fpage>1803</fpage>
<lpage>9</lpage>
<pub-id pub-id-type="pmid">11708987</pub-id>
</element-citation>
</ref>
<ref id="R4"><label>4</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mercy</surname>
<given-names>L</given-names>
</name>
<name><surname>Hodges</surname>
<given-names>JR</given-names>
</name>
<name><surname>Dawson</surname>
<given-names>K</given-names>
</name>
<name><surname>Barker</surname>
<given-names>RA</given-names>
</name>
<name><surname>Brayne</surname>
<given-names>C</given-names>
</name>
</person-group>
<article-title>Incidence of early-onset dementias in Cambridgeshire, United Kingdom</article-title>
<source>Neurology</source>
<year>2008</year>
<volume>71</volume>
<fpage>1496</fpage>
<lpage>9</lpage>
<pub-id pub-id-type="pmid">18981371</pub-id>
</element-citation>
</ref>
<ref id="R5"><label>5</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ratnavalli</surname>
<given-names>E</given-names>
</name>
<name><surname>Brayne</surname>
<given-names>C</given-names>
</name>
<name><surname>Dawson</surname>
<given-names>K</given-names>
</name>
<name><surname>Hodges</surname>
<given-names>JR</given-names>
</name>
</person-group>
<article-title>The prevalence of frontotemporal dementia</article-title>
<source>Neurology</source>
<year>2002</year>
<volume>58</volume>
<fpage>1615</fpage>
<lpage>21</lpage>
<pub-id pub-id-type="pmid">12058088</pub-id>
</element-citation>
</ref>
<ref id="R6"><label>6</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Forman</surname>
<given-names>MS</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Frontotemporal dementia: clinicopathological correlations</article-title>
<source>Ann Neurol</source>
<year>2006</year>
<volume>59</volume>
<fpage>952</fpage>
<lpage>62</lpage>
<pub-id pub-id-type="pmid">16718704</pub-id>
</element-citation>
</ref>
<ref id="R7"><label>7</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goldman</surname>
<given-names>JS</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Frontotemporal Dementia: Genetics and Genetic Counseling Dilemmas</article-title>
<source>Neurologist</source>
<year>2004</year>
<volume>10</volume>
<fpage>227</fpage>
<lpage>234</lpage>
<pub-id pub-id-type="pmid">15335440</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>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17</article-title>
<source>Nature</source>
<year>2006</year>
<volume>442</volume>
<fpage>916</fpage>
<lpage>9</lpage>
<pub-id pub-id-type="pmid">16862116</pub-id>
</element-citation>
</ref>
<ref id="R9"><label>9</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cruts</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21</article-title>
<source>Nature</source>
<year>2006</year>
<volume>442</volume>
<fpage>920</fpage>
<lpage>4</lpage>
<pub-id pub-id-type="pmid">16862115</pub-id>
</element-citation>
</ref>
<ref id="R10"><label>10</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gass</surname>
<given-names>J</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration</article-title>
<source>Hum Mol Genet</source>
<year>2006</year>
<volume>15</volume>
<fpage>2988</fpage>
<lpage>3001</lpage>
<pub-id pub-id-type="pmid">16950801</pub-id>
</element-citation>
</ref>
<ref id="R11"><label>11</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gijselinck</surname>
<given-names>I</given-names>
</name>
<name><surname>Van Broeckhoven</surname>
<given-names>C</given-names>
</name>
<name><surname>Cruts</surname>
<given-names>M</given-names>
</name>
</person-group>
<article-title>Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update</article-title>
<source>Hum Mutat</source>
<year>2008</year>
<volume>29</volume>
<fpage>1373</fpage>
<lpage>86</lpage>
<pub-id pub-id-type="pmid">18543312</pub-id>
</element-citation>
</ref>
<ref id="R12"><label>12</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cruts</surname>
<given-names>M</given-names>
</name>
<name><surname>Van Broeckhoven</surname>
<given-names>C</given-names>
</name>
</person-group>
<article-title>Loss of progranulin function in frontotemporal lobar degeneration</article-title>
<source>Trends Genet</source>
<year>2008</year>
<volume>24</volume>
<fpage>186</fpage>
<lpage>94</lpage>
<pub-id pub-id-type="pmid">18328591</pub-id>
</element-citation>
</ref>
<ref id="R13"><label>13</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Van Deerlin</surname>
<given-names>VM</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations</article-title>
<source>Arch Neurol</source>
<year>2007</year>
<volume>64</volume>
<fpage>1148</fpage>
<lpage>53</lpage>
<pub-id pub-id-type="pmid">17698705</pub-id>
</element-citation>
</ref>
<ref id="R14"><label>14</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hakonarson</surname>
<given-names>H</given-names>
</name>
<etal></etal>
</person-group>
<article-title>A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene</article-title>
<source>Nature</source>
<year>2007</year>
<volume>448</volume>
<fpage>591</fpage>
<lpage>4</lpage>
<pub-id pub-id-type="pmid">17632545</pub-id>
</element-citation>
</ref>
<ref id="R15"><label>15</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McCarthy</surname>
<given-names>MI</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Genome-wide association studies for complex traits: consensus, uncertainty and challenges</article-title>
<source>Nat Rev Genet</source>
<year>2008</year>
<volume>9</volume>
<fpage>356</fpage>
<lpage>69</lpage>
<pub-id pub-id-type="pmid">18398418</pub-id>
</element-citation>
</ref>
<ref id="R16"><label>16</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Neumann</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis</article-title>
<source>Science</source>
<year>2006</year>
<volume>314</volume>
<fpage>130</fpage>
<lpage>3</lpage>
<pub-id pub-id-type="pmid">17023659</pub-id>
</element-citation>
</ref>
<ref id="R17"><label>17</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cairns</surname>
<given-names>NJ</given-names>
</name>
<etal></etal>
</person-group>
<article-title>TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions</article-title>
<source>Am J Pathol</source>
<year>2007</year>
<volume>171</volume>
<fpage>227</fpage>
<lpage>40</lpage>
<pub-id pub-id-type="pmid">17591968</pub-id>
</element-citation>
</ref>
<ref id="R18"><label>18</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mackenzie</surname>
<given-names>IR</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations</article-title>
<source>Acta Neuropathol</source>
<year>2009</year>
<volume>117</volume>
<fpage>15</fpage>
<lpage>8</lpage>
<pub-id pub-id-type="pmid">19015862</pub-id>
</element-citation>
</ref>
<ref id="R19"><label>19</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falush</surname>
<given-names>D</given-names>
</name>
<name><surname>Stephens</surname>
<given-names>M</given-names>
</name>
<name><surname>Pritchard</surname>
<given-names>JK</given-names>
</name>
</person-group>
<article-title>Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies</article-title>
<source>Genetics</source>
<year>2003</year>
<volume>164</volume>
<fpage>1567</fpage>
<lpage>87</lpage>
<pub-id pub-id-type="pmid">12930761</pub-id>
</element-citation>
</ref>
<ref id="R20"><label>20</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Patterson</surname>
<given-names>N</given-names>
</name>
<name><surname>Price</surname>
<given-names>AL</given-names>
</name>
<name><surname>Reich</surname>
<given-names>D</given-names>
</name>
</person-group>
<article-title>Population structure and eigenanalysis</article-title>
<source>PLoS Genet</source>
<year>2006</year>
<volume>2</volume>
<fpage>e190</fpage>
<pub-id pub-id-type="pmid">17194218</pub-id>
</element-citation>
</ref>
<ref id="R21"><label>21</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>
<volume>82</volume>
<fpage>453</fpage>
<lpage>63</lpage>
<pub-id pub-id-type="pmid">18252225</pub-id>
</element-citation>
</ref>
<ref id="R22"><label>22</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dixon</surname>
<given-names>AL</given-names>
</name>
<etal></etal>
</person-group>
<article-title>A genome-wide association study of global gene expression</article-title>
<source>Nat Genet</source>
<year>2007</year>
<volume>39</volume>
<fpage>1202</fpage>
<lpage>7</lpage>
<pub-id pub-id-type="pmid">17873877</pub-id>
</element-citation>
</ref>
<ref id="R23"><label>23</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen-Plotkin</surname>
<given-names>AS</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration</article-title>
<source>Hum Mol Genet</source>
<year>2008</year>
<volume>17</volume>
<fpage>1349</fpage>
<lpage>62</lpage>
<pub-id pub-id-type="pmid">18223198</pub-id>
</element-citation>
</ref>
<ref id="R24"><label>24</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pastor</surname>
<given-names>P</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred</article-title>
<source>Ann Neurol</source>
<year>2003</year>
<volume>54</volume>
<fpage>163</fpage>
<lpage>9</lpage>
<pub-id pub-id-type="pmid">12891668</pub-id>
</element-citation>
</ref>
<ref id="R25"><label>25</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wijsman</surname>
<given-names>EM</given-names>
</name>
<etal></etal>
</person-group>
<article-title>APOE and other loci affect age-at-onset in Alzheimer's disease families with PS2 mutation</article-title>
<source>Am J Med Genet B Neuropsychiatr Genet</source>
<year>2005</year>
<volume>132B</volume>
<fpage>14</fpage>
<lpage>20</lpage>
<pub-id pub-id-type="pmid">15389756</pub-id>
</element-citation>
</ref>
<ref id="R26"><label>26</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Le Ber</surname>
<given-names>I</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease</article-title>
<source>Neurology</source>
<year>2009</year>
<volume>72</volume>
<fpage>1669</fpage>
<lpage>76</lpage>
<pub-id pub-id-type="pmid">19433740</pub-id>
</element-citation>
</ref>
<ref id="R27"><label>27</label>
<element-citation publication-type="journal"><article-title>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls</article-title>
<source>Nature</source>
<year>2007</year>
<volume>447</volume>
<fpage>661</fpage>
<lpage>78</lpage>
<pub-id pub-id-type="pmid">17554300</pub-id>
</element-citation>
</ref>
<ref id="R28"><label>28</label>
<element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Scheet</surname>
<given-names>P</given-names>
</name>
<name><surname>Stephens</surname>
<given-names>M</given-names>
</name>
</person-group>
<article-title>A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase</article-title>
<source>Am J Hum Genet</source>
<year>2006</year>
<volume>78</volume>
<fpage>629</fpage>
<lpage>44</lpage>
<pub-id pub-id-type="pmid">16532393</pub-id>
</element-citation>
</ref>
</ref-list>
</back>
<floats-group><fig id="F1" position="float"><label>Figure 1</label>
<caption><title>Region of genome-wide association at 7p21</title>
<p><bold>a.</bold>
Manhattan plot of −log10(observed <italic>P</italic>
-value) across genome demonstrating region of genome-wide significant association on chromosome 7; <bold>b.</bold>
Regional plot of the <italic>TMEM106B</italic>
associated interval. <bold>Foreground plot:</bold>
Scatter plot of the −log<sub>10 </sub>
<italic>P</italic>
-values plotted against physical position (NCBI build 36). <bold>Background Plot:</bold>
Estimated recombination rates (from phase 2 of the HapMap) plotted to reflect the local LD structure. The color of the dots represents the strength of LD between the top SNP rs1990622, and its proxies (red: r2 ≥ 0.8; orange 0.8 < r2 ≥ 0.4; blue < 0.4). Gene annotations were obtained from assembly 18 of the UCSC genome browser; <bold>c.</bold>
Location of 3 highest associated SNPs (green arrows) relative to the gene structure of <italic>TMEM106B</italic>
(blue bars, 3′ and 5′-untranslated regions; larger red bars, coding exons; thick gray line, intronic regions; gray dashed line, downstream chromosome sequence) and chromosome 7 location.</p>
</caption>
<graphic xlink:href="nihms-172758-f0001"></graphic>
</fig>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><title><italic>TMEM106B</italic>
expression variation by genotype and disease state</title>
<p><bold>a. </bold>
<italic>TMEM106B</italic>
mRNA expression by QRT-PCR in frontal cortex differed significantly by genotype at rs1990622 (overall <italic>P=</italic>
0.027, genotype TT vs. TC <italic>P=</italic>
0.017, TT vs. CC <italic>P=</italic>
0.03). Black circles, FTLD-TDP (n=18); open squares, normal (n=7); horizontal lines, group mean.<bold></bold>
Significance of <italic>P</italic>
-values are denoted by the numbers of asterisks. <bold> b. </bold>
<italic>TMEM106B</italic>
mRNA expression in frontal cortex was significantly higher in samples from FTLD-TDP patients compared to normal controls (<italic>P</italic>
=0.045). <bold>c. </bold>
<italic>TMEM106B</italic>
expression in frontal cortex samples in FTLD-TDP with (<italic>GRN</italic>
pos, n=8) or without (<italic>GRN</italic>
neg, n=10) <italic>GRN</italic>
mutations compared to normals (n=7). <italic>GRN</italic>
mutation carriers had significantly higher levels of <italic>TMEM106B</italic>
expression (overall <italic>P</italic>
=0.0009, <italic>GRN</italic>
pos vs. controls <italic>P</italic>
=0.0005, <italic>GRN</italic>
pos vs. <italic>GRN</italic>
neg <italic>P</italic>
=0.002). <bold>d.</bold>
When only cases heterozygous at rs1990622 (n=14) were evaluated, <italic>GRN</italic>
mutations remained significantly associated with a higher level of <italic>TMEM106B</italic>
expression (<italic>P</italic>
=0.039) in frontal cortex. QRT-PCR was performed in triplicate for all expression studies. Expression values were normalized to the geometric mean of two housekeeping genes and are shown relative to a single reference normal control sample<xref rid="R23" ref-type="bibr">23</xref>
. Error bars represent the standard error of the mean. Normalized gene expression data and sample genotype and gender data used for these analyses are provided online in <xref ref-type="supplementary-material" rid="SD1">Supplementary Material</xref>
.</p>
</caption>
<graphic xlink:href="nihms-172758-f0002"></graphic>
</fig>
<fig id="F3" position="float"><label>Figure 3</label>
<caption><title>Manhattan plot in cases with and without <italic>GRN</italic>
mutations</title>
<p>Manhattan plot of −log10(observed <italic>P</italic>
-value) across genome in cases with (a) and without (b) GRN mutations. The subset of cases with <italic>GRN</italic>
mutations demonstrates regions of genome-wide significant association on chromosomes 7 and 17. The chr 17 association is confirmed to be driven by a shared haplotype in c.1477C>T (p.R493X) <italic>GRN</italic>
mutation carriers representing ~20% of mutation positive cases, however the chromosome 7 association is not related to any single <italic>GRN</italic>
mutation and remains when the cases with c.1477C>T are removed (<italic>P</italic>
=1.446×10<sup>−10</sup>
). The same locus on chr 7 identified in the <italic>GRN</italic>
mutation cases is also the strongest signal in the <italic>GRN</italic>
negative cases, although it does not reach genome-wide significance. A list of the SNPs with the highest signals in b is given in <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 8</xref>
.</p>
</caption>
<graphic xlink:href="nihms-172758-f0003"></graphic>
</fig>
<table-wrap id="T1" position="float" orientation="landscape"><label>Table 1</label>
<caption><p>Summary of samples and controls used for GWA and replication phases</p>
</caption>
<table frame="box" rules="all"><thead><tr><th align="center" valign="middle" rowspan="1" colspan="1">Phase</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Case<break></break>
Numbers</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Case Study<break></break>
Source</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Control<break></break>
Numbers</th>
<th align="left" valign="middle" rowspan="1" colspan="1">Control Study Source</th>
<th align="left" valign="middle" rowspan="1" colspan="1">Method of<break></break>
Testing</th>
<th align="center" valign="middle" rowspan="1" colspan="1">λ
</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">GWA</td>
<td align="center" valign="middle" rowspan="1" colspan="1">515</td>
<td align="center" valign="middle" rowspan="1" colspan="1">International<break></break>
FTLD<break></break>
Consortium</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2509</td>
<td align="left" valign="middle" rowspan="1" colspan="1">1297 CHOP European-<break></break>
Caucasian,<break></break>
1212 WTCCC</td>
<td align="left" valign="middle" rowspan="1" colspan="1">Illumina<break></break>
HH550 or<break></break>
610-Quad<break></break>
BeadChips</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.05</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Replication</td>
<td align="center" valign="middle" rowspan="1" colspan="1">89</td>
<td align="center" valign="middle" rowspan="1" colspan="1">International<break></break>
FTLD<break></break>
Consortium</td>
<td align="center" valign="middle" rowspan="1" colspan="1">553</td>
<td align="left" valign="middle" rowspan="1" colspan="1">Penn Autopsy, Penn ADC,<break></break>
Coriell Neurologically<break></break>
Normal panel, CHOP<break></break>
European-Caucasian</td>
<td align="left" valign="middle" rowspan="1" colspan="1">TaqMan<break></break>
genotyping of<break></break>
2 SNPs</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>CHOP, Children's Hospital of Philadelphia; Penn ADC, University of Pennsylvania
Alzheimer's Disease Center; WTCCC, Wellcome Trust Case Control Consortium; λ,
genomic control inflation factor.</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T2" position="float" orientation="landscape"><label>Table 2</label>
<caption><p>SNPs on chromosome 7 in region with highest association in the GWAS</p>
</caption>
<table frame="box" rules="all"><thead><tr><th align="center" valign="middle" rowspan="1" colspan="1">SNP rs ID</th>
<th align="center" valign="middle" rowspan="1" colspan="1">BP</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Minor<break></break>
Allele</th>
<th align="center" valign="middle" rowspan="1" colspan="1">MAF<break></break>
case</th>
<th align="center" valign="middle" rowspan="1" colspan="1">MAF<break></break>
cont</th>
<th align="center" valign="middle" rowspan="1" colspan="1">CA <italic>P</italic>
-val</th>
<th align="center" valign="middle" rowspan="1" colspan="1">OR</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Lower<break></break>
95% CI</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Upper<break></break>
95% CI</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">rs1006869</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12071795</td>
<td align="center" valign="middle" rowspan="1" colspan="1">G</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.148</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.184</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.82×10<sup>−3</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.77</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.64</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.92</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">rs1990602</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12088321</td>
<td align="center" valign="middle" rowspan="1" colspan="1">G</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.133</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.166</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.97×10<sup>−3</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.77</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.64</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.94</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">rs10226395</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12101859</td>
<td align="center" valign="middle" rowspan="1" colspan="1">C</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.154</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.191</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.90×10<sup>−3</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.77</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.64</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.93</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">rs1003433</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12130625</td>
<td align="center" valign="middle" rowspan="1" colspan="1">G</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.287</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.351</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.45×10<sup>−5</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.75</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.64</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.86</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">rs6952272</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12166585</td>
<td align="center" valign="middle" rowspan="1" colspan="1">T</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.154</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.207</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.88×10<sup>−5</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.70</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.58</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.84</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">rs12671332</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12182087</td>
<td align="center" valign="middle" rowspan="1" colspan="1">C</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.173</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.245</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.50×10<sup>−7</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.64</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.54</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.77</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">rs1468915</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12194417</td>
<td align="center" valign="middle" rowspan="1" colspan="1">C</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.171</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.242</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.49×10<sup>−7</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.65</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.54</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.77</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>rs1020004</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>12222303</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>G</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.233</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.338</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>5.00×10<sup>−11</sup>
</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.60</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.51</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.70</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>rs6966915</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>12232513</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>T</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.321</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.435</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>1.63×10<sup>−11</sup>
</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.61</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.53</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.71</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">rs10488192</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12243606</td>
<td align="center" valign="middle" rowspan="1" colspan="1">T</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.139</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.204</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.46×10<sup>−6</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.63</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.52</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.76</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>rs1990622</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>12250312</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>C</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.321</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.436</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>1.08×10<sup>−11</sup>
</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.61</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.53</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><bold>0.71</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">rs6945902</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12252934</td>
<td align="center" valign="middle" rowspan="1" colspan="1">A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.183</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.230</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.17×10<sup>−4</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.75</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.63</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.89</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>SNPs are listed in genomic order based on location on chromosome 7. SNPs in bold text have the lowest <italic>P</italic>
-values.</p>
<p>Chr, chromosome; BP, base pairs (NCBI build 36); MAF, minor allele frequency; cont, controls; CA <italic>P</italic>
-val, Cochrane-Armitage <italic>P</italic>
-value; OR, odds ratio; CI, confidence interval.</p>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>
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