title: Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.
abstract: 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.
  
  
  METHODS
  Case-control study with replication.
  
  
  METHODS
  Memory referral clinics in Canada and the United Kingdom.
  
  
  METHODS
  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 nondemented 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.
  
  
  METHODS
  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.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Hao
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authors.lastname: Li
authors.forename: Sally
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authors.initials: DD
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authors.lastname: Kertesz
authors.forename: Karen S
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authors.lastname: Lovestone
authors.forename: Inge
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authors.lastname: Loy-English
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authors.lastname: Plumpton
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authors.lastname: Pryse-Phillips
authors.forename: Rab K
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authors.lastname: Prinjha
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: Ann
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authors.lastname: Saunders
authors.forename: Andrew J
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authors.lastname: Slater
authors.forename: Peter H
authors.initials: PH
authors.lastname: St George-Hyslop
authors.forename: Sandra W
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authors.lastname: Stinnett
authors.forename: Jina E
authors.initials: JE
authors.lastname: Swartz
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Taylor
authors.forename: John
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authors.lastname: Wherrett
authors.forename: Julie
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authors.lastname: Williams
authors.forename: David P
authors.initials: DP
authors.lastname: Yarnall
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gibson
authors.forename: Michael C
authors.initials: MC
authors.lastname: Irizarry
authors.forename: Lefkos T
authors.initials: LT
authors.lastname: Middleton
authors.forename: Allen D
authors.initials: AD
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mesh_terms: D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002170:Canada / Q000453:epidemiology; D016022:Case-Control Studies; D016001:Confidence Intervals; D004493:Education; D005260:Female; D005602:France / Q000208:ethnology; D015894:Genome, Human / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D012042:Registries; D012737:Sex Factors; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D001057:Apolipoproteins E