Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans

被引：326

作者：

Reitz, Christiane ^{[1
,2
,3
]}

Jun, Gyungah ^{[6
,7
,8
]}

Naj, Adam ^{[11
]}

Rajbhandary, Ruchita ^{[11
]}

Vardarajan, Badri Narayan ^{[6
,7
]}

Wang, Li-San ^{[12
]}

Valladares, Otto ^{[12
]}

Lin, Chiao-Feng ^{[12
]}

Larson, Eric B. ^{[16
]}

Graff-Radford, Neill R. ^{[17
,18
]}

Evans, Denis ^{[19
]}

De Jager, Philip L. ^{[23
,24
,25
]}

Crane, Paul K. ^{[13
]}

Buxbaum, Joseph D. ^{[30
,31
,32
,33
]}

Murrell, Jill R. ^{[26
]}

Raj, Towfique

Ertekin-Taner, Nilufer ^{[17
,18
]}

Logue, Mark ^{[6
]}

Baldwin, Clinton T. ^{[6
]}

Green, Robert C. ^{[29
]}

Barnes, Lisa L. ^{[20
,21
]}

Cantwell, Laura B. ^{[12
]}

Fallin, M. Daniele ^{[34
]}

Go, Rodney C. P. ^{[35
]}

Griffith, Patrick ^{[36
]}

Obisesan, Thomas O. ^{[37
]}

Manly, Jennifer J. ^{[12
]}

Lunetta, Kathryn L. ^{[7
]}

Kamboh, M. Ilyas ^{[38
,39
]}

Lopez, Oscar L. ^{[39
]}

Bennett, David A. ^{[22
]}

Hendrie, Hugh ^{[27
,28
]}

Hall, Kathleen S. ^{[28
]}

Goate, Alison M.

Byrd, Goldie S.

Kukull, Walter A. ^{[14
,15
]}

Foroud, Tatiana M. ^{[26
]}

Haines, Jonathan L. ^{[40
,41
]}

Farrer, Lindsay A. ^{[6
,7
,8
,9
,10
]}

Pericak-Vance, Margaret A. ^{[11
]}

Schellenberg, Gerard D. ^{[12
]}

Mayeux, Richard ^{[1
,2
,3
,4
,5
]}

机构：

[1] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, Coll Phys & Surg, New York, NY 10032 USA

[2] Columbia Univ, Gertrude H Sergievsky Ctr, Coll Phys & Surg, New York, NY 10032 USA

[3] Columbia Univ, Dept Neurol, Coll Phys & Surg, New York, NY 10032 USA

[4] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10032 USA

[5] Columbia Univ, Dept Epidemiol, Coll Phys & Surg, New York, NY 10032 USA

[6] Boston Univ, Dept Med, Genet Program, Boston, MA 02215 USA

[7] Boston Univ, Dept Biostat, Boston, MA 02215 USA

[8] Boston Univ, Dept Ophthalmol, Boston, MA 02215 USA

[9] Boston Univ, Dept Epidemiol, Boston, MA 02215 USA

[10] Boston Univ, Dept Neurol, Boston, MA 02215 USA

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

[12] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA

[13] Univ Washington, Dept Med, Seattle, WA 98195 USA

[14] Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA

[15] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

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

[17] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[18] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[19] Rush Univ, Rush Inst Hlth Aging, Dept Internal Med, Med Ctr, Chicago, IL 60612 USA

[20] Rush Univ, Dept Neurol Sci, Med Ctr, Chicago, IL 60612 USA

[21] Rush Univ, Dept Behav Sci, Med Ctr, Chicago, IL 60612 USA

[22] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL 60612 USA

[23] Brigham & Womens Hosp, Program Translat Neuropsychiat Genom, Dept Neurol, Boston, MA 02115 USA

[24] Harvard Univ, Sch Med, Boston, MA USA

[25] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[26] Indiana Univ, Dept Med & Mol Genet, Bloomington, IN 47405 USA

[27] Indiana Univ, Ctr Aging Res, Bloomington, IN 47405 USA

[28] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA

[29] Brigham & Womens Hosp, Partners Ctr Personalized Genet Med, Boston, MA 02115 USA

[30] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA

[31] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA

[32] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA

[33] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY USA

[34] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA

[35] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL USA

[36] Meharry Med Coll, Dept Neurol, Nashville, TN 37208 USA

[37] Howard Univ Hosp, Div Geriatr, Washington, DC USA

[38] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA

[39] Univ Pittsburgh, Alzheimers Dis Res Ctr, Pittsburgh, PA USA

[40] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[41] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Nashville, TN USA

来源：

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION | 2013年 / 309卷 / 14期

关键词：

GENOME-WIDE ASSOCIATION; MILD COGNITIVE IMPAIRMENT; IDENTIFIES VARIANTS; COMMON VARIANTS; AGING PROJECT; DEMENTIA; CLU; METAANALYSIS; IMPUTATION; GENOTYPE;

D O I：

10.1001/jama.2013.2973

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Importance Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. Objective To identify genetic loci associated with late-onset Alzheimer disease in African Americans. Design, Setting, and Participants The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. Main Outcomes and Measures Presence of Alzheimer disease according to standardized criteria. Results Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele=G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P=2.2 x 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8<D'<0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE epsilon 4-determining SNP rs429358 (allele=C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P=5.5 x 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005<empirical P<.001). Conclusions and Relevance In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings. JAMA. 2013;309(14):1483-1492 www.jama.com

引用

页码：1483 / 1492

页数：10

共 53 条

[1] Single-nucleotide polymorphism analysis by pyrosequencing [J].

Ahmadian, A ;

Gharizadeh, B ;

Gustafsson, AC ;

Sterky, F ;

Nyrén, P ;

Uhlén, M ;

Lundeberg, J .

ANALYTICAL BIOCHEMISTRY, 2000, 280 (01) :103-110

[2]

[Anonymous], 1990 CENS POP HOUS S

[3] The Minority Aging Research Study: Ongoing Efforts to Obtain Brain Donation in African Americans without Dementia [J].

Barnes, Lisa L. ;

Shah, Raj C. ;

Aggarwal, Neelum T. ;

Bennett, David A. ;

Schneider, Julie A. .

CURRENT ALZHEIMER RESEARCH, 2012, 9 (06) :734-745

[4] Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease [J].

Beecham, Gary W. ;

Martin, Eden R. ;

Li, Yi-Ju ;

Slifer, Michael A. ;

Gilbert, John R. ;

Haines, Jonathan L. ;

Pericak-Vance, Margaret A. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2009, 84 (01) :35-43

[5] The Rush Memory and Aging Project: Study design and baseline characteristics of the study cohort [J].

Bennett, DA ;

Schneider, JA ;

Buchman, AS ;

de Leon, CM ;

Bienias, JL ;

Wilson, RS .

NEUROEPIDEMIOLOGY, 2005, 25 (04) :163-175

[6] Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions [J].

Bennett, DA ;

Schneider, JA ;

Bienias, JL ;

Evans, DA ;

Wilson, RS .

NEUROLOGY, 2005, 64 (05) :834-841

[7] Natural history of mild cognitive impairment in older persons [J].

Bennett, DA ;

Wilson, RS ;

Schneider, JA ;

Evans, DA ;

Beckett, LA ;

Aggarwal, NT ;

Barnes, LL ;

Fox, JH ;

Bach, J .

NEUROLOGY, 2002, 59 (02) :198-205

[8] Clinicopathologic studies in cognitively healthy aging and Alzheimer disease - Relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype [J].

Berg, L ;

McKeel, DW ;

Miller, JP ;

Storandt, M ;

Rubin, EH ;

Morris, JC ;

Baty, J ;

Coats, M ;

Norton, J ;

Goate, AM ;

Price, JL ;

Gearing, M ;

Mirra, SS ;

Saunders, AM .

ARCHIVES OF NEUROLOGY, 1998, 55 (03) :326-335

[9] Design of the Chicago Health and Aging Project (CHAP) [J].

Bienias, Julia L. ;

Beckett, Laurel A. ;

Bennett, David A. ;

Wilson, Robert S. ;

Evans, Denis A. .

JOURNAL OF ALZHEIMERS DISEASE, 2003, 5 (05) :349-355

[10] Vascular risk factors for Alzheimer's disease: An epidemiologic perspective [J].

Breteler, MMB .

NEUROBIOLOGY OF AGING, 2000, 21 (02) :153-160

← 1 2 3 4 5 6 →