Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes

被引：334

作者：

Jun, Gyungah ^{[1
,2
,3
]}

Naj, Adam C. ^{[7
]}

Beecham, Gary W. ^{[7
,8
]}

Wang, Li-San

Buros, Jacqueline ^{[1
]}

Gallins, Paul J. ^{[7
]}

Buxbaum, Joseph D. ^{[13
,14
,15
]}

Ertekin-Taner, Nilufer ^{[9
,10
]}

Fallin, Daniele ^{[18
]}

Friedland, Robert ^{[19
]}

Inzelberg, Rivka ^{[20
,21
]}

Kramer, Patricia ^{[22
,23
]}

Rogaeva, Ekaterina ^{[24
]}

George-Hyslop, Peter St. ^{[24
,25
]}

Cantwell, Laura B.

Dombroski, Beth A.

Saykin, Andrew J. ^{[26
,27
]}

Reiman, Eric M. ^{[28
,29
,30
]}

Bennett, David A. ^{[31
,32
]}

Morris, John C. ^{[33
,34
]}

Lunetta, Kathryn L. ^{[3
]}

Martin, Eden R. ^{[8
]}

Montine, Thomas J. ^{[36
]}

Goate, Alison M. ^{[35
]}

Blacker, Deborah ^{[6
]}

Tsuang, Debby W. ^{[37
]}

Beekly, Duane ^{[38
]}

Cupples, L. Adrienne ^{[3
]}

Hakonarson, Hakon ^{[12
]}

Kukull, Walter ^{[38
,39
]}

Foroud, Tatiana M. ^{[27
]}

Haines, Jonathan ^{[40
]}

Mayeux, Richard ^{[16
,17
]}

Farrer, Lindsay A. ^{[1
,4
,5
]}

Pericak-Vance, Margaret A. ^{[7
,8
]}

Schellenberg, Gerard D. ^{[11
]}

机构：

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

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

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

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

[5] Boston Univ, Dept Genet & Genom & Epidemiol, Boston, MA 02215 USA

[6] Massachusetts Gen Hosp, Dept Psychiat & Epidemiol, Charlestown, MA USA

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

[8] Univ Miami, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL USA

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

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

[11] Univ Penn, Sch Med, Dept Pathol & Lab Med, Stellar Chance Labs, Philadelphia, PA 19104 USA

[12] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

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

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

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

[16] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA

[17] Columbia Univ, Taub Inst, New York, NY USA

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

[19] Univ Louisville, Dept Neurol, Louisville, KY 40292 USA

[20] Tel Aviv Univ, Chaim Sheba Med Ctr, Dept Neurol, Tel Aviv, Israel

[21] Tel Aviv Univ, Chaim Sheba Med Ctr, Dept Med, Tel Aviv, Israel

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

[23] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA

[24] Univ Toronto, Dept Med, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada

[25] Univ Cambridge, Cambridge Inst Med Res, Dept Clin Neurosci, Cambridge, England

[26] Indiana Univ, Dept Radiol & Imaging Sci, Indianapolis, IN 46204 USA

[27] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN 46204 USA

[28] Univ Arizona, Arizona Alzheimers Consortium, Phoenix, AZ USA

[29] Univ Arizona, Neurogenom Div, Translat Genom Res Inst, Phoenix, AZ USA

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

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

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

[33] Washington Univ, Dept Neurol, St Louis, MO USA

[34] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA

[35] Washington Univ, Dept Psychiat, St Louis, MO USA

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

[37] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

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

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

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

来源：

ARCHIVES OF NEUROLOGY | 2010年 / 67卷 / 12期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; MILD COGNITIVE IMPAIRMENT; AGE-AT-ONSET; IDENTIFIES VARIANTS; MISSENSE MUTATIONS; LINKAGE ANALYSIS; GENE; DEMENTIA; SUSCEPTIBILITY; NEUROPATHOLOGY;

D O I：

10.1001/archneurol.2010.201

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objectives: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. Design: Association study of AD and CLU, PICALM, CR1, and APOE genotypes. Setting: Academic research institutions in the United States, Canada, and Israel. Participants: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. Results: Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CRI (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE 64 was significantly associated with AD (ORs, 1.809.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE 64 allele greatly reduced evidence for association with PICALM but not CRI or CLU. Models with the main SNP effect, presence or absence of APOE 64, and an interaction term showed significant interaction between presence or absence of APOE epsilon 4 and PICALM. Conclusions: We confirm in a completely independent data set that CRI, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE epsilon 4-positive subjects. Thus, APOE and PICALM synergistically interact.

引用

页码：1473 / 1484

页数：12

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