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

Beecham, GW and Hamilton, K and Naj, AC and Martin, ER and Huentelman, M and Myers, AJ and Corneveaux, JJ and Hardy, J and Vonsattel, JP and Younkin, SG and Bennett, DA and De Jager, PL and Larson, EB and Crane, PK and Kamboh, MI and Kofler, JK and Mash, DC and Duque, L and Gilbert, JR and Gwirtsman, H and Buxbaum, JD and Kramer, P and Dickson, DW and Farrer, LA and Frosch, MP and Ghetti, B and Haines, JL and Hyman, BT and Kukull, WA and Mayeux, RP and Pericak-Vance, MA and Schneider, JA and Trojanowski, JQ and Reiman, EM and Schellenberg, GD and Montine, TJ (2014) Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias. PLoS Genetics, 10 (9). ISSN 1553-7390

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Beecham, GW
Hamilton, K
Naj, AC
Martin, ER
Huentelman, M
Myers, AJ
Corneveaux, JJ
Hardy, J
Vonsattel, JP
Younkin, SG
Bennett, DA
De Jager, PL
Larson, EB
Crane, PK
Kamboh, MIkamboh@pitt.eduKAMBOH
Kofler, JKjkofler@pitt.eduJKOFLER
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
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 September 2014
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 10
Number: 9
DOI or Unique Handle: 10.1371/journal.pgen.1004606
Schools and Programs: School of Public Health > Human Genetics
School of Medicine > Pathology
Refereed: Yes
ISSN: 1553-7390
Date Deposited: 23 Sep 2014 16:16
Last Modified: 12 Oct 2021 11:56


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