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
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AG041232 / AG / NIA NIH HHS / United States
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/ / Medical Research Council / United Kingdom
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AG05128 / AG / NIA NIH HHS / United States
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