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

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 GwirtsmanJoseph 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, Gerard D. Schellenberg, Thomas J. Montine

Research output: Contribution to journalArticle

144 Citations (Scopus)

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.

Original languageEnglish (US)
JournalPLoS Genetics
Volume10
Issue number9
DOIs
StatePublished - Sep 1 2014

Fingerprint

dementia
Genome-Wide Association Study
meta-analysis
Alzheimer disease
Dementia
Meta-Analysis
Alzheimer Disease
genome
brain
loci
Cerebrovascular Trauma
amyloid
blood vessels
Cerebral Amyloid Angiopathy
necropsy
Lewy Body Disease
Genetic Loci
apolipoprotein E
sclerosis
Autopsy

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Beecham, G. W., Hamilton, K., Naj, A. C., Martin, E. R., Huentelman, M., Myers, A. J., ... Montine, T. J. (2014). Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias. PLoS Genetics, 10(9). https://doi.org/10.1371/journal.pgen.1004606

Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias. / Beecham, Gary W.; Hamilton, Kara; Naj, Adam C.; Martin, Eden R.; Huentelman, Matt; Myers, Amanda J.; Corneveaux, Jason J.; Hardy, John; Vonsattel, Jean Paul; Younkin, Steven G; Bennett, David A.; De Jager, Philip L.; Larson, Eric B.; Crane, Paul K.; Kamboh, M. Ilyas; Kofler, Julia K.; Mash, Deborah C.; Duque, Linda; Gilbert, John R.; Gwirtsman, Harry; Buxbaum, Joseph D.; Kramer, Patricia; Dickson, Dennis W; Farrer, Lindsay A.; Frosch, Matthew P.; Ghetti, Bernardino; Haines, Jonathan L.; Hyman, Bradley T.; Kukull, Walter A.; Mayeux, Richard P.; Pericak-Vance, Margaret A.; Schneider, Julie A.; Trojanowski, John Q.; Reiman, Eric M.; Schellenberg, Gerard D.; Montine, Thomas J.

In: PLoS Genetics, Vol. 10, No. 9, 01.09.2014.

Research output: Contribution to journalArticle

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, MI, 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 2014, 'Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias', PLoS Genetics, vol. 10, no. 9. https://doi.org/10.1371/journal.pgen.1004606
Beecham, Gary W. ; Hamilton, Kara ; Naj, Adam C. ; Martin, Eden R. ; Huentelman, Matt ; Myers, Amanda J. ; Corneveaux, Jason J. ; Hardy, John ; Vonsattel, Jean Paul ; Younkin, Steven G ; Bennett, David A. ; De Jager, Philip L. ; Larson, Eric B. ; Crane, Paul K. ; Kamboh, M. Ilyas ; Kofler, Julia K. ; Mash, Deborah C. ; Duque, Linda ; Gilbert, John R. ; Gwirtsman, Harry ; Buxbaum, Joseph D. ; Kramer, Patricia ; Dickson, Dennis W ; Farrer, Lindsay A. ; Frosch, Matthew P. ; Ghetti, Bernardino ; Haines, Jonathan L. ; Hyman, Bradley T. ; Kukull, Walter A. ; Mayeux, Richard P. ; Pericak-Vance, Margaret A. ; Schneider, Julie A. ; Trojanowski, John Q. ; Reiman, Eric M. ; Schellenberg, Gerard D. ; Montine, Thomas J. / Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias. In: PLoS Genetics. 2014 ; Vol. 10, No. 9.
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AU - Beecham, Gary W.

AU - Hamilton, Kara

AU - Naj, Adam C.

AU - Martin, Eden R.

AU - Huentelman, Matt

AU - Myers, Amanda J.

AU - Corneveaux, Jason J.

AU - Hardy, John

AU - Vonsattel, Jean Paul

AU - Younkin, Steven G

AU - Bennett, David A.

AU - De Jager, Philip L.

AU - Larson, Eric B.

AU - Crane, Paul K.

AU - Kamboh, M. Ilyas

AU - Kofler, Julia K.

AU - Mash, Deborah C.

AU - Duque, Linda

AU - Gilbert, John R.

AU - Gwirtsman, Harry

AU - Buxbaum, Joseph D.

AU - Kramer, Patricia

AU - Dickson, Dennis W

AU - Farrer, Lindsay A.

AU - Frosch, Matthew P.

AU - Ghetti, Bernardino

AU - Haines, Jonathan L.

AU - Hyman, Bradley T.

AU - Kukull, Walter A.

AU - Mayeux, Richard P.

AU - Pericak-Vance, Margaret A.

AU - Schneider, Julie A.

AU - Trojanowski, John Q.

AU - Reiman, Eric M.

AU - Schellenberg, Gerard D.

AU - Montine, Thomas J.

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N2 - 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.

AB - 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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