Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease

被引：408

作者：

Li, Hao ^{[2
]}

Wetten, Sally ^{[1
]}

Li, Li ^{[2
]}

Jean, Pamela L. St. ^{[2
]}

Upmanyu, Ruchi ^{[1
]}

Surh, Linda ^{[1
]}

Hosford, David ^{[2
]}

Barnes, Michael R. ^{[1
]}

Briley, James David ^{[2
]}

Borrie, Michael ^{[3
]}

Coletta, Natalie ^{[5
]}

Delisle, Richard ^{[6
]}

Dhalla, Daniella ^{[5
]}

Ehm, Margaret G. ^{[2
]}

Feldman, Howard H. ^{[7
]}

Fornazzari, Luis ^{[8
]}

Gauthier, Serge ^{[10
]}

Goodgame, Neil ^{[1
]}

Guzman, Danilo ^{[11
]}

Hammond, Sandra ^{[1
]}

Hollingworth, Paul ^{[12
]}

Hsiung, Ging-Yuek ^{[7
]}

Johnson, Joan ^{[2
]}

Kelly, Devon D. ^{[2
]}

Keren, Ron ^{[9
]}

Kertesz, Andrew ^{[4
]}

King, Karen S. ^{[2
]}

Lovestone, Simon ^{[13
]}

Loy-English, Inge ^{[11
]}

Matthews, Paul M. ^{[14
,15
]}

Owen, Michael J. ^{[12
]}

Plumpton, Mary ^{[1
]}

Pryse-Phillips, William ^{[5
]}

Prinjha, Rab K. ^{[1
]}

Richardson, Jill C. ^{[1
]}

Saunders, Ann ^{[2
]}

Slater, Andrew J. ^{[2
]}

George-Hyslop, Peter H. St. ^{[9
]}

Stinnett, Sandra W. ^{[2
]}

Swartz, Jina E. ^{[1
]}

Taylor, Rachel L. ^{[1
]}

Wherrett, John ^{[9
]}

Williams, Julie ^{[12
]}

Yarnall, David P. ^{[2
]}

Gibson, Rachel A. ^{[1
]}

Irizarry, Michael C. ^{[2
]}

Middleton, Lefkos T. ^{[1
]}

Roses, Allen D. ^{[2
]}

机构：

[1] GlaxoSmithKline, New Frontiers Sci Pk, Harlow CM19 5AW, Essex, England

[2] GlaxoSmithKline, Res Triangle Pk, NC USA

[3] Parkwood Hosp, Div Geriatr Med, London, ON, Canada

[4] St Josephs Hosp, Dept Cognit Neurol, London, ON N6A 4V2, Canada

[5] GlaxoSmithKline Inc, Mississauga, ON, Canada

[6] Neurol Clin, Trois Rivieres, PQ, Canada

[7] Univ British Columbia, Vancouver Hosp & Hlth Sci Ctr, Div Neurol, Vancouver, BC V5Z 1M9, Canada

[8] Univ Toronto, Memory Clin, Toronto, ON, Canada

[9] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada

[10] McGill Ctr Studies Aging, Verdun, PQ, Canada

[11] Univ Ottawa, Clin Trials Unit, SCO Hlth Serv, Ottawa, ON, Canada

[12] Cardiff Univ, Sch Med, MRC, Neuropsychiat Genet Grp, Cardiff, S Glam, Wales

[13] Kings Coll London, MRC, Ctr Neurodegenerat Res, Inst Psychiat, London WC2R 2LS, England

[14] GlaxoSmithKline Res & Dev Ltd, Clin Imaging Ctr, London, England

[15] Hammersmith Hosp, Dept Clin Neurosci, Univ London Imperial Coll Sci Technol & Med, London, England

来源：

ARCHIVES OF NEUROLOGY | 2008年 / 65卷 / 01期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

D O I：

10.1001/archneurol.2007.3

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs. Design: Case-control study with replication. Setting: Memory referral clinics in Canada and the United Kingdom. Participants: The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 non-demented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England. Main Outcome Measures: Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments. Results: Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P <.05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2). Conclusions: Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.

引用

页码：45 / 53

页数：9

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