title: Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
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.
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Beecham
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
authors.forename: Kara
authors.initials: K
authors.lastname: Hamilton
authors.affiliation: Division of Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Naj
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Matt
authors.initials: M
authors.lastname: Huentelman
authors.affiliation: Department of Psychiatry & Behavioral Sciences, University of Miami, Miami, Florida, United States of America.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Myers
authors.affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.affiliation: Department of Molecular Neuroscience, University College London, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: New York Brain Bank, Columbia University, New York, New York, United States of America.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.affiliation: Department of Neurological Sciences, Rush University, Chicago, Illinois, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Department of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Group Health Research Institute, Seattle, Washington, United States of America.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Kofler
authors.affiliation: Department of Neurology, University of Miami, Miami, Florida, United States of America.
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.affiliation: Department of Neurology, University of Miami, Miami, Florida, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Duque
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Harry
authors.initials: H
authors.lastname: Gwirtsman
authors.affiliation: Department of Psychiatry, Mount Sinai Hospital, New York, New York, United States of America.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kramer
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Biomedical Genetics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, United States of America.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Department of Epidemiology, National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, United States of America.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kukull
authors.affiliation: 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.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Mayeux
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Department of Neurological Sciences, Rush University, Chicago, Illinois, United States of America; Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Arizona Alzheimer's Consortium, Banner Alzheimer's Institute, Phoenix, Arizona, United States of America; Department of Psychiatry, University of Arizona, Phoenix, Arizona, United States of America.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics*; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18; D002899:Chromosomes, Human, Pair 9; D003704:Dementia / Q000175:diagnosis* / Q000209:etiology*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D058225:Plaque, Amyloid; D040641:Quantitative Trait Loci
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D017350:N-Acetylgalactosaminyltransferases