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

被引：255

作者：

Beecham, Gary W. ^{[1
]}

Hamilton, Kara ^{[1
]}

Naj, Adam C. ^{[2
]}

Martin, Eden R. ^{[1
]}

Huentelman, Matt ^{[3
]}

Myers, Amanda J. ^{[4
]}

Corneveaux, Jason J. ^{[3
]}

Hardys, John ^{[5
]}

Vonsatte, Jean-Paul, I ^{[6
]}

Younkin, Steven G. ^{[7
]}

Bennett, David A. ^{[8
]}

De Jager, Philip L. ^{[9
]}

Larson, Eric B. ^{[10
]}

Crane, Paul K. ^{[11
]}

Kamboh, M. Ilyas ^{[12
]}

Kofler, Julia K. ^{[13
]}

Mash, Deborah C. ^{[14
]}

Duque, Linda ^{[14
]}

Gilbertl, John R. ^{[1
]}

Gwirtsman, Harry ^{[15
]}

Buxbaum, Joseph D. ^{[16
]}

Kramer, Patricia ^{[17
]}

Dickson, Dennis W. ^{[7
]}

Farrer, Lindsay A. ^{[18
]}

Frosch, Matthew P. ^{[19
]}

Ghetti, Bernardino ^{[20
]}

Haines, Jonathan L. ^{[21
]}

Hyman, Bradley T. ^{[22
]}

Kuku, Walter A. ^{[23
]}

Mayeux, Richard P. ^{[24
]}

Pericak-Vancel, Margaret A. ^{[1
]}

Schneider, Julie A. ^{[8
,25
]}

Trojanowski, John Q. ^{[26
]}

Reiman, Eric M. ^{[27
,28
]}

Schellenberg, Gerard D. ^{[26
]}

Montine, Thomas J. ^{[29
]}

机构：

[1] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA

[2] Univ Penn, Div Epidemiol, Philadelphia, PA 19104 USA

[3] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA

[4] Univ Miami, Dept Psychiat & Behav Sci, Miami, FL USA

[5] UCL, Dept Mol Neurosci, London, England

[6] Columbia Univ, New York Brain Bank, New York, NY USA

[7] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA

[8] Rush Univ, Dept Neurol Sci, Chicago, IL 60612 USA

[9] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol & Psychiat, Boston, MA 02115 USA

[10] Grp Hlth Res Inst, Seattle, WA USA

[11] Univ Washington, Dept Med, Seattle, WA USA

[12] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[13] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA

[14] Univ Miami, Dept Neurol, Miami, FL USA

[15] Vanderbilt Univ, Dept Psychiat, Nashville, TN 37235 USA

[16] Mt Sinai Hosp, Dept Psychiat, New York, NY 10029 USA

[17] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA

[18] Boston Univ, Sch Publ Hlth, Boston, MA USA

[19] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Charlestown, MA USA

[20] Indiana Univ, Dept Pathol & Lab Med, Indianapolis, IN 46204 USA

[21] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[22] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA

[23] Univ Washington, Dept Epidemiol, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA

[24] Columbia Univ, Dept Neurol, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[25] Rush Univ, Med Ctr, Dept Pathol Neuropathol, Chicago, IL 60612 USA

[26] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA

[27] Banner Alzheimers Inst, Arizona Alzheimers Consortium, Phoenix, AZ USA

[28] Univ Arizona, Dept Psychiat, Phoenix, AZ USA

[29] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

来源：

PLOS GENETICS | 2014年 / 10卷 / 09期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

SUSCEPTIBILITY LOCI; COMMON VARIANTS; RISK; DIAGNOSIS; PROTEIN; CD2AP; EPHA1; CD33;

D O I：

10.1371/journal.pgen.1004606

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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). GaINAc 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, BlN1, CLU, MS4A6A, PlCALM, 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.

引用

页数：15

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