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

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 ne...

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Autores principales:	Gary W Beecham, Kara Hamilton, Adam C Naj, Eden R Martin, Matt Huentelman, Amanda J Myers, Jason J Corneveaux, John Hardy, Jean-Paul Vonsattel, Steven G Younkin, David A Bennett, Philip L De Jager, Eric B Larson, Paul K Crane, M Ilyas Kamboh, Julia K Kofler, Deborah C Mash, Linda Duque, John R Gilbert, Harry Gwirtsman, Joseph D Buxbaum, Patricia Kramer, Dennis W Dickson, Lindsay A Farrer, Matthew P Frosch, Bernardino Ghetti, Jonathan L Haines, Bradley T Hyman, Walter A Kukull, Richard P Mayeux, Margaret A Pericak-Vance, Julie A Schneider, John Q Trojanowski, Eric M Reiman, Alzheimer's Disease Genetics Consortium (ADGC), Gerard D Schellenberg, Thomas J Montine
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/16fab959c9274eda9e554f003340125a
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spelling	oai:doaj.org-article:16fab959c9274eda9e554f003340125a2021-11-25T05:51:36ZGenome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.1553-73901553-740410.1371/journal.pgen.1004606https://doaj.org/article/16fab959c9274eda9e554f003340125a2014-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25188341/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Alzheimer'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.Gary W BeechamKara HamiltonAdam C NajEden R MartinMatt HuentelmanAmanda J MyersJason J CorneveauxJohn HardyJean-Paul VonsattelSteven G YounkinDavid A BennettPhilip L De JagerEric B LarsonPaul K CraneM Ilyas KambohJulia K KoflerDeborah C MashLinda DuqueJohn R GilbertHarry GwirtsmanJoseph D BuxbaumPatricia KramerDennis W DicksonLindsay A FarrerMatthew P FroschBernardino GhettiJonathan L HainesBradley T HymanWalter A KukullRichard P MayeuxMargaret A Pericak-VanceJulie A SchneiderJohn Q TrojanowskiEric M ReimanAlzheimer's Disease Genetics Consortium (ADGC)Gerard D SchellenbergThomas J MontinePublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 10, Iss 9, p e1004606 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Gary W Beecham Kara Hamilton Adam C Naj Eden R Martin Matt Huentelman Amanda J Myers Jason J Corneveaux John Hardy Jean-Paul Vonsattel Steven G Younkin David A Bennett Philip L De Jager Eric B Larson Paul K Crane M Ilyas Kamboh Julia K Kofler Deborah C Mash Linda Duque John R Gilbert Harry Gwirtsman Joseph D Buxbaum Patricia Kramer Dennis W Dickson Lindsay A Farrer Matthew P Frosch Bernardino Ghetti Jonathan L Haines Bradley T Hyman Walter A Kukull Richard P Mayeux Margaret A Pericak-Vance Julie A Schneider John Q Trojanowski Eric M Reiman Alzheimer's Disease Genetics Consortium (ADGC) Gerard D Schellenberg Thomas J Montine Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
description	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.
format	article
author	Gary W Beecham Kara Hamilton Adam C Naj Eden R Martin Matt Huentelman Amanda J Myers Jason J Corneveaux John Hardy Jean-Paul Vonsattel Steven G Younkin David A Bennett Philip L De Jager Eric B Larson Paul K Crane M Ilyas Kamboh Julia K Kofler Deborah C Mash Linda Duque John R Gilbert Harry Gwirtsman Joseph D Buxbaum Patricia Kramer Dennis W Dickson Lindsay A Farrer Matthew P Frosch Bernardino Ghetti Jonathan L Haines Bradley T Hyman Walter A Kukull Richard P Mayeux Margaret A Pericak-Vance Julie A Schneider John Q Trojanowski Eric M Reiman Alzheimer's Disease Genetics Consortium (ADGC) Gerard D Schellenberg Thomas J Montine
author_facet	Gary W Beecham Kara Hamilton Adam C Naj Eden R Martin Matt Huentelman Amanda J Myers Jason J Corneveaux John Hardy Jean-Paul Vonsattel Steven G Younkin David A Bennett Philip L De Jager Eric B Larson Paul K Crane M Ilyas Kamboh Julia K Kofler Deborah C Mash Linda Duque John R Gilbert Harry Gwirtsman Joseph D Buxbaum Patricia Kramer Dennis W Dickson Lindsay A Farrer Matthew P Frosch Bernardino Ghetti Jonathan L Haines Bradley T Hyman Walter A Kukull Richard P Mayeux Margaret A Pericak-Vance Julie A Schneider John Q Trojanowski Eric M Reiman Alzheimer's Disease Genetics Consortium (ADGC) Gerard D Schellenberg Thomas J Montine
author_sort	Gary W Beecham
title	Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
title_short	Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
title_full	Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
title_fullStr	Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
title_full_unstemmed	Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
title_sort	genome-wide association meta-analysis of neuropathologic features of alzheimer's disease and related dementias.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/16fab959c9274eda9e554f003340125a
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Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.

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