title: Genome-wide analysis of genetic loci associated with Alzheimer disease.
abstract: BACKGROUND
  Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).
  
  
  OBJECTIVE
  To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).
  
  
  METHODS
  In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.
  
  
  METHODS
  Presence of Alzheimer disease.
  
  
  RESULTS
  Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).
  
  
  CONCLUSIONS
  Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Sudha
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authors.lastname: Seshadri
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authors.lastname: Dartigues
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authors.lastname: Hollingworth
authors.forename: Thor
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authors.lastname: Aspelund
authors.forename: Isabel
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authors.lastname: Hernandez
authors.forename: Alexa
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authors.lastname: Beiser
authors.forename: Lewis H
authors.initials: LH
authors.lastname: Kuller
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Koudstaal
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Christophe
authors.initials: C
authors.lastname: Tzourio
authors.forename: Richard
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authors.lastname: Abraham
authors.forename: Carmen
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authors.lastname: Antunez
authors.forename: Yangchun
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authors.lastname: Du
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Claudine
authors.initials: C
authors.lastname: Berr
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Jesus
authors.initials: J
authors.lastname: Lopez-Arrieta
authors.forename: Badri N
authors.initials: BN
authors.lastname: Varadarajan
authors.forename: James T
authors.initials: JT
authors.lastname: Becker
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Sanford
authors.initials: S
authors.lastname: Auerbach
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rice
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Palmi V
authors.initials: PV
authors.lastname: Jonsson
authors.forename: Helena
authors.initials: H
authors.lastname: Schmidt
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Mosley
authors.forename: Rhoda
authors.initials: R
authors.lastname: Au
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.forename: Agustin
authors.initials: A
authors.lastname: Ruiz
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.forename: Steve G
authors.initials: SG
authors.lastname: Younkin
authors.forename: Philip A
authors.initials: PA
authors.lastname: Wolf
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Lopez
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
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authors.lastname: Breteler
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide
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