title: Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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 × 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 ϵ4-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 × 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
  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.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Columbia University, 630 W 168th St, New York, NY 10032, USA.
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authors.forename: Badri Narayan
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authors.forename: M Daniele
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authors.lastname: Go
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authors.lastname: Griffith
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authors.lastname: Obisesan
authors.forename: Jennifer J
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authors.lastname: Manly
authors.forename: Kathryn L
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authors.lastname: Lunetta
authors.forename: M Ilyas
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authors.lastname: Kamboh
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authors.lastname: Lopez
authors.forename: David A
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authors.lastname: Bennett
authors.forename: Hugh
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authors.lastname: Hendrie
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Hall
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Goldie S
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authors.lastname: Byrd
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kukull
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
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authors.initials: GD
authors.lastname: Schellenberg
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authors.lastname: Mayeux
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001741:Black or African American / Q000235:genetics*; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000208:ethnology* / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; D053327:Apolipoprotein E4