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Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

Identifieur interne : 002C10 ( Main/Exploration ); précédent : 002C09; suivant : 002C11

Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

Auteurs : Gary W. Beecham [États-Unis] ; Kara Hamilton [États-Unis] ; Adam C. Naj [États-Unis] ; Eden R. Martin [États-Unis] ; Matt Huentelman [États-Unis] ; Amanda J. Myers [États-Unis] ; Jason J. Corneveaux [États-Unis] ; John Hardy [Royaume-Uni] ; Jean-Paul Vonsattel [États-Unis] ; Steven G. Younkin [États-Unis] ; David A. Bennett [États-Unis] ; Philip L. De Jager [États-Unis] ; Eric B. Larson [États-Unis] ; Paul K. Crane [États-Unis] ; M. Ilyas Kamboh [États-Unis] ; Julia K. Kofler [États-Unis] ; Deborah C. Mash [États-Unis] ; Linda Duque [États-Unis] ; John R. Gilbert [États-Unis] ; Harry Gwirtsman [États-Unis] ; Joseph D. Buxbaum [États-Unis] ; Patricia Kramer [États-Unis] ; Dennis W. Dickson [États-Unis] ; Lindsay A. Farrer [États-Unis] ; Matthew P. Frosch [États-Unis] ; Bernardino Ghetti [États-Unis] ; Jonathan L. Haines [États-Unis] ; Bradley T. Hyman [États-Unis] ; Walter A. Kukull [États-Unis] ; Richard P. Mayeux [États-Unis] ; Margaret A. Pericak-Vance [États-Unis] ; Julie A. Schneider [États-Unis] ; John Q. Trojanowski [États-Unis] ; Eric M. Reiman [États-Unis] ; Gerard D. Schellenberg [États-Unis] ; Thomas J. Montine [États-Unis]

Source :

RBID : PMC:4154667

Descripteurs français

English descriptors

Abstract

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.


Url:
DOI: 10.1371/journal.pgen.1004606
PubMed: 25188341
PubMed Central: 4154667


Affiliations:

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Le document en format XML

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<name sortKey="Gilbert, John R" sort="Gilbert, John R" uniqKey="Gilbert J" first="John R." last="Gilbert">John R. Gilbert</name>
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<wicri:regionArea>Department of Psychiatry, Mount Sinai Hospital, New York, New York</wicri:regionArea>
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<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, Oregon</wicri:regionArea>
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<addr-line>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America</addr-line>
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<wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea>
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<name sortKey="Farrer, Lindsay A" sort="Farrer, Lindsay A" uniqKey="Farrer L" first="Lindsay A." last="Farrer">Lindsay A. Farrer</name>
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<name sortKey="Frosch, Matthew P" sort="Frosch, Matthew P" uniqKey="Frosch M" first="Matthew P." last="Frosch">Matthew P. Frosch</name>
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<addr-line>C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America</addr-line>
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<wicri:regionArea>C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts</wicri:regionArea>
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<name sortKey="Ghetti, Bernardino" sort="Ghetti, Bernardino" uniqKey="Ghetti B" first="Bernardino" last="Ghetti">Bernardino Ghetti</name>
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<addr-line>Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, United States of America</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana</wicri:regionArea>
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<region type="state">Indiana</region>
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<name sortKey="Haines, Jonathan L" sort="Haines, Jonathan L" uniqKey="Haines J" first="Jonathan L." last="Haines">Jonathan L. Haines</name>
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<nlm:aff id="aff21">
<addr-line>Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio</wicri:regionArea>
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<region type="state">Ohio</region>
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<name sortKey="Hyman, Bradley T" sort="Hyman, Bradley T" uniqKey="Hyman B" first="Bradley T." last="Hyman">Bradley T. Hyman</name>
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<addr-line>Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
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<name sortKey="Kukull, Walter A" sort="Kukull, Walter A" uniqKey="Kukull W" first="Walter A." last="Kukull">Walter A. Kukull</name>
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<addr-line>Department of Epidemiology, National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, United States of America</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington</wicri:regionArea>
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<settlement type="city">Seattle</settlement>
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<name sortKey="Mayeux, Richard P" sort="Mayeux, Richard P" uniqKey="Mayeux R" first="Richard P." last="Mayeux">Richard P. Mayeux</name>
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<addr-line>Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York</wicri:regionArea>
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<region type="state">État de New York</region>
<settlement type="city">New York</settlement>
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<orgName type="university">Université Columbia</orgName>
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<name sortKey="Pericak Vance, Margaret A" sort="Pericak Vance, Margaret A" uniqKey="Pericak Vance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name>
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<nlm:aff id="aff1">
<addr-line>John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida</wicri:regionArea>
<placeName>
<region type="state">Floride</region>
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<name sortKey="Schneider, Julie A" sort="Schneider, Julie A" uniqKey="Schneider J" first="Julie A." last="Schneider">Julie A. Schneider</name>
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<nlm:aff id="aff8">
<addr-line>Department of Neurological Sciences, Rush University, Chicago, Illinois, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurological Sciences, Rush University, Chicago, Illinois</wicri:regionArea>
<placeName>
<region type="state">Illinois</region>
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</nlm:aff>
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</nlm:aff>
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<wicri:regionArea>Department of Pathology, University of Washington, Seattle, Washington</wicri:regionArea>
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</nlm:aff>
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<region type="state">Floride</region>
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</affiliation>
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</nlm:aff>
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</placeName>
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<addr-line>Department of Molecular Neuroscience, University College London, London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Molecular Neuroscience, University College London, London</wicri:regionArea>
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<settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
<settlement type="city">Londres</settlement>
</placeName>
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<region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
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<addr-line>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea>
<placeName>
<region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Bennett, David A" sort="Bennett, David A" uniqKey="Bennett D" first="David A." last="Bennett">David A. Bennett</name>
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<addr-line>Department of Neurological Sciences, Rush University, Chicago, Illinois, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurological Sciences, Rush University, Chicago, Illinois</wicri:regionArea>
<placeName>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="De Jager, Philip L" sort="De Jager, Philip L" uniqKey="De Jager P" first="Philip L." last="De Jager">Philip L. De Jager</name>
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<addr-line>Department of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
<placeName>
<region type="state">Massachusetts</region>
</placeName>
</affiliation>
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<addr-line>Group Health Research Institute, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Group Health Research Institute, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
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<nlm:aff id="aff11">
<addr-line>Department of Medicine, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, University of Washington, Seattle, Washington</wicri:regionArea>
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<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
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<affiliation wicri:level="2">
<nlm:aff id="aff12">
<addr-line>Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName>
<region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
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<author>
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<nlm:aff id="aff13">
<addr-line>Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName>
<region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
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<author>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Miami, Miami, Florida</wicri:regionArea>
<placeName>
<region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Duque, Linda" sort="Duque, Linda" uniqKey="Duque L" first="Linda" last="Duque">Linda Duque</name>
<affiliation wicri:level="2">
<nlm:aff id="aff14">
<addr-line>Department of Neurology, University of Miami, Miami, Florida, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, University of Miami, Miami, Florida</wicri:regionArea>
<placeName>
<region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Gilbert, John R" sort="Gilbert, John R" uniqKey="Gilbert J" first="John R." last="Gilbert">John R. Gilbert</name>
<affiliation wicri:level="2">
<nlm:aff id="aff1">
<addr-line>John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida</wicri:regionArea>
<placeName>
<region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Gwirtsman, Harry" sort="Gwirtsman, Harry" uniqKey="Gwirtsman H" first="Harry" last="Gwirtsman">Harry Gwirtsman</name>
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<nlm:aff id="aff15">
<addr-line>Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, Vanderbilt University, Nashville, Tennessee</wicri:regionArea>
<placeName>
<region type="state">Tennessee</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Buxbaum, Joseph D" sort="Buxbaum, Joseph D" uniqKey="Buxbaum J" first="Joseph D." last="Buxbaum">Joseph D. Buxbaum</name>
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<nlm:aff id="aff16">
<addr-line>Department of Psychiatry, Mount Sinai Hospital, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, Mount Sinai Hospital, New York, New York</wicri:regionArea>
<placeName>
<region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Kramer, Patricia" sort="Kramer, Patricia" uniqKey="Kramer P" first="Patricia" last="Kramer">Patricia Kramer</name>
<affiliation wicri:level="4">
<nlm:aff id="aff17">
<addr-line>Department of Neurology, Oregon Health & Science University, Portland, Oregon, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Oregon Health & Science University, Portland, Oregon</wicri:regionArea>
<placeName>
<region type="state">Oregon</region>
<settlement type="city">Portland</settlement>
</placeName>
<orgName type="university">Université des sciences et de la médecine de l'Oregon</orgName>
</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 wicri:level="2">
<nlm:aff id="aff7">
<addr-line>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea>
<placeName>
<region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Farrer, Lindsay A" sort="Farrer, Lindsay A" uniqKey="Farrer L" first="Lindsay A." last="Farrer">Lindsay A. Farrer</name>
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<nlm:aff id="aff18">
<addr-line>Biomedical Genetics, Boston University School of Public Health, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Biomedical Genetics, Boston University School of Public Health, Boston, Massachusetts</wicri:regionArea>
<placeName>
<region type="state">Massachusetts</region>
</placeName>
</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 wicri:level="2">
<nlm:aff id="aff19">
<addr-line>C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts</wicri:regionArea>
<placeName>
<region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Ghetti, Bernardino" sort="Ghetti, Bernardino" uniqKey="Ghetti B" first="Bernardino" last="Ghetti">Bernardino Ghetti</name>
<affiliation wicri:level="2">
<nlm:aff id="aff20">
<addr-line>Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana</wicri:regionArea>
<placeName>
<region type="state">Indiana</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Haines, Jonathan L" sort="Haines, Jonathan L" uniqKey="Haines J" first="Jonathan L." last="Haines">Jonathan L. Haines</name>
<affiliation wicri:level="2">
<nlm:aff id="aff21">
<addr-line>Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio</wicri:regionArea>
<placeName>
<region type="state">Ohio</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Hyman, Bradley T" sort="Hyman, Bradley T" uniqKey="Hyman B" first="Bradley T." last="Hyman">Bradley T. Hyman</name>
<affiliation wicri:level="2">
<nlm:aff id="aff22">
<addr-line>Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
<placeName>
<region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Kukull, Walter A" sort="Kukull, Walter A" uniqKey="Kukull W" first="Walter A." last="Kukull">Walter A. Kukull</name>
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<nlm:aff id="aff23">
<addr-line>Department of Epidemiology, National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
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</author>
<author>
<name sortKey="Mayeux, Richard P" sort="Mayeux, Richard P" uniqKey="Mayeux R" first="Richard P." last="Mayeux">Richard P. Mayeux</name>
<affiliation wicri:level="4">
<nlm:aff id="aff24">
<addr-line>Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York</wicri:regionArea>
<placeName>
<region type="state">État de New York</region>
<settlement type="city">New York</settlement>
</placeName>
<orgName type="university">Université Columbia</orgName>
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</author>
<author>
<name sortKey="Pericak Vance, Margaret A" sort="Pericak Vance, Margaret A" uniqKey="Pericak Vance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name>
<affiliation wicri:level="2">
<nlm:aff id="aff1">
<addr-line>John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida</wicri:regionArea>
<placeName>
<region type="state">Floride</region>
</placeName>
</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 wicri:level="2">
<nlm:aff id="aff8">
<addr-line>Department of Neurological Sciences, Rush University, Chicago, Illinois, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurological Sciences, Rush University, Chicago, Illinois</wicri:regionArea>
<placeName>
<region type="state">Illinois</region>
</placeName>
</affiliation>
<affiliation wicri:level="2">
<nlm:aff id="aff25">
<addr-line>Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois</wicri:regionArea>
<placeName>
<region type="state">Illinois</region>
</placeName>
</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 wicri:level="2">
<nlm:aff id="aff26">
<addr-line>Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea>
<placeName>
<region type="state">Pennsylvanie</region>
</placeName>
</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 wicri:level="2">
<nlm:aff id="aff27">
<addr-line>Arizona Alzheimer's Consortium, Banner Alzheimer's Institute, Phoenix, Arizona, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Arizona Alzheimer's Consortium, Banner Alzheimer's Institute, Phoenix, Arizona</wicri:regionArea>
<placeName>
<region type="state">Arizona</region>
</placeName>
</affiliation>
<affiliation wicri:level="2">
<nlm:aff id="aff28">
<addr-line>Department of Psychiatry, University of Arizona, Phoenix, Arizona, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry, University of Arizona, Phoenix, Arizona</wicri:regionArea>
<placeName>
<region type="state">Arizona</region>
</placeName>
</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 wicri:level="2">
<nlm:aff id="aff26">
<addr-line>Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea>
<placeName>
<region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Montine, Thomas J" sort="Montine, Thomas J" uniqKey="Montine T" first="Thomas J." last="Montine">Thomas J. Montine</name>
<affiliation wicri:level="4">
<nlm:aff id="aff29">
<addr-line>Department of Pathology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology, University of Washington, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
</analytic>
<series>
<title level="j">PLoS Genetics</title>
<idno type="ISSN">1553-7390</idno>
<idno type="eISSN">1553-7404</idno>
<imprint>
<date when="2014">2014</date>
</imprint>
</series>
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<profileDesc>
<textClass>
<keywords scheme="KwdEn" xml:lang="en">
<term>ATP Binding Cassette Transporter, Sub-Family G, Member 1</term>
<term>ATP-Binding Cassette Transporters (genetics)</term>
<term>Alzheimer Disease (diagnosis)</term>
<term>Alzheimer Disease (genetics)</term>
<term>Brain (pathology)</term>
<term>Case-Control Studies</term>
<term>Chromosome Mapping</term>
<term>Chromosomes, Human, Pair 18</term>
<term>Chromosomes, Human, Pair 9</term>
<term>Dementia (diagnosis)</term>
<term>Dementia (etiology)</term>
<term>Genetic Predisposition to Disease</term>
<term>Genome-Wide Association Study</term>
<term>Hippocampus (metabolism)</term>
<term>Hippocampus (pathology)</term>
<term>Humans</term>
<term>N-Acetylgalactosaminyltransferases (genetics)</term>
<term>Odds Ratio</term>
<term>Phenotype</term>
<term>Plaque, Amyloid</term>
<term>Quantitative Trait Loci</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Cartographie chromosomique</term>
<term>Chromosomes humains de la paire 18</term>
<term>Chromosomes humains de la paire 9</term>
<term>Démence (diagnostic)</term>
<term>Démence (étiologie)</term>
<term>Encéphale (anatomopathologie)</term>
<term>Hippocampe (anatomopathologie)</term>
<term>Hippocampe (métabolisme)</term>
<term>Humains</term>
<term>Locus de caractère quantitatif</term>
<term>Maladie d'Alzheimer (diagnostic)</term>
<term>Maladie d'Alzheimer (génétique)</term>
<term>Membre-1 de la sous-famille G des transporteurs à cassette liant l'ATP</term>
<term>N-acetylgalactosaminyltransferase (génétique)</term>
<term>Odds ratio</term>
<term>Phénotype</term>
<term>Plaque amyloïde</term>
<term>Prédisposition génétique à une maladie</term>
<term>Transporteurs ABC (génétique)</term>
<term>Étude d'association pangénomique</term>
<term>Études cas-témoins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>N-Acetylgalactosaminyltransferases</term>
</keywords>
<keywords scheme="MESH" type="chemical" xml:lang="en">
<term>ATP Binding Cassette Transporter, Sub-Family G, Member 1</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Encéphale</term>
<term>Hippocampe</term>
</keywords>
<keywords scheme="MESH" qualifier="diagnosis" xml:lang="en">
<term>Alzheimer Disease</term>
<term>Dementia</term>
</keywords>
<keywords scheme="MESH" qualifier="diagnostic" xml:lang="fr">
<term>Démence</term>
<term>Maladie d'Alzheimer</term>
</keywords>
<keywords scheme="MESH" qualifier="etiology" xml:lang="en">
<term>Dementia</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>ATP-Binding Cassette Transporters</term>
<term>Alzheimer Disease</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Maladie d'Alzheimer</term>
<term>N-acetylgalactosaminyltransferase</term>
<term>Transporteurs ABC</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>Hippocampus</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Hippocampe</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Brain</term>
<term>Hippocampus</term>
</keywords>
<keywords scheme="MESH" qualifier="étiologie" xml:lang="fr">
<term>Démence</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Case-Control Studies</term>
<term>Chromosome Mapping</term>
<term>Chromosomes, Human, Pair 18</term>
<term>Chromosomes, Human, Pair 9</term>
<term>Genetic Predisposition to Disease</term>
<term>Genome-Wide Association Study</term>
<term>Humans</term>
<term>Odds Ratio</term>
<term>Phenotype</term>
<term>Plaque, Amyloid</term>
<term>Quantitative Trait Loci</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Cartographie chromosomique</term>
<term>Chromosomes humains de la paire 18</term>
<term>Chromosomes humains de la paire 9</term>
<term>Humains</term>
<term>Locus de caractère quantitatif</term>
<term>Membre-1 de la sous-famille G des transporteurs à cassette liant l'ATP</term>
<term>Odds ratio</term>
<term>Phénotype</term>
<term>Plaque amyloïde</term>
<term>Prédisposition génétique à une maladie</term>
<term>Étude d'association pangénomique</term>
<term>Études cas-témoins</term>
</keywords>
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<front>
<div type="abstract" xml:lang="en">
<p>Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (
<italic>APOE</italic>
). GalNAc transferase 7 (
<italic>GALNT7</italic>
), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (
<italic>ABCG1</italic>
), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (
<italic>KCNMB2</italic>
) was strongly associated with HS. Twelve of the 21 non-
<italic>APOE</italic>
genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample:
<italic>CR1</italic>
,
<italic>BIN1</italic>
,
<italic>CLU</italic>
,
<italic>MS4A6A</italic>
,
<italic>PICALM</italic>
,
<italic>ABCA7</italic>
,
<italic>CD33</italic>
,
<italic>PTK2B</italic>
,
<italic>SORL1</italic>
,
<italic>MEF2C</italic>
,
<italic>ZCWPW1</italic>
, and
<italic>CASS4</italic>
with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.</p>
</div>
</front>
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