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Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.

TitleGenome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
Publication TypeJournal Article
Year of Publication2014
AuthorsBeecham, GW, Hamilton, K, Naj, AC, Martin, ER, Huentelman, M, Myers, AJ, Corneveaux, JJ, Hardy, J, Vonsattel, J-P, Younkin, SG, Bennett, DA, De Jager, PL, Larson, EB, Crane, PK, M Kamboh, I, Kofler, JK, Mash, DC, Duque, L, Gilbert, JR, Gwirtsman, H, Buxbaum, JD, Kramer, P, Dickson, DW, Farrer, LA, Frosch, MP, Ghetti, B, Haines, JL, Hyman, BT, Kukull, WA, Mayeux, RP, Pericak-Vance, MA, Schneider, JA, Trojanowski, JQ, Reiman, EM, Schellenberg, GD, Montine, TJ
Corporate AuthorsAlzheimer's Disease Genetics Consortium (ADGC)
JournalPLoS Genet
Volume10
Issue9
Paginatione1004606
Date Published2014 Sep
ISSN1553-7404
KeywordsAlzheimer Disease, ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters, Brain, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 9, Dementia, Genetic Predisposition to Disease, Genome-Wide Association Study, Hippocampus, Humans, N-Acetylgalactosaminyltransferases, Odds Ratio, Phenotype, Plaque, Amyloid, Quantitative Trait Loci
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.

DOI10.1371/journal.pgen.1004606
Alternate JournalPLoS Genet.
PubMed ID25188341
PubMed Central IDPMC4154667
Grant ListMH60451 / MH / NIMH NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
AG041232 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
U01 AG10483 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
P50 AG016577 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
R01 AG020688 / AG / NIA NIH HHS / United States
R01 AG017173 / AG / NIA NIH HHS / United States
P50 AG016575 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom
P30 AG028377 / AG / NIA NIH HHS / United States
AG05128 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
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R01 AG017917 / AG / NIA NIH HHS / United States
UO1 HG004610 / HG / NHGRI NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
1R01AG035137 / AG / NIA NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
RC2 AG036535 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
AG010491 / AG / NIA NIH HHS / United States
P30 AG08051 / AG / NIA NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
NS39764 / NS / NINDS NIH HHS / United States
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5R01AG022374 / AG / NIA NIH HHS / United States
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P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
U24 AG026390 / AG / NIA NIH HHS / United States
1RC2AG036502 / AG / NIA NIH HHS / United States
UO1 AG06781 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
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AG027944 / AG / NIA NIH HHS / United States
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MO1RR00096 / RR / NCRR NIH HHS / United States
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