title: Role of ABCA7 loss-of-function variant in Alzheimer's disease: a replication study in European-Americans.
abstract: BACKGROUND
  A recent study found a significant increase of ABCA7 loss-of-function variants in Alzheimer's disease (AD) cases compared to controls. Some variants were located on noncoding regions, but it was demonstrated that they affect splicing. Here, we try to replicate the association between AD risk and ABCA7 loss-of-function variants at both the single-variant and gene level in a large and well-characterized European American dataset.
  
  
  METHODS
  We genotyped the GWAS common variant and four rare variants previously reported for ABCA7 in 3476 European-Americans.
  
  
  RESULTS
  We were not able to replicate the association at the single-variant level, likely due to a lower effect size on the European American population which led to limited statistical power. However, we did replicate the association at the gene level; we found a significant enrichment of ABCA7 loss-of-function variants in AD cases compared to controls (P = 0.0388; odds ratio =1.54). We also confirmed that the association of the loss-of-function variants is independent of the previously reported genome-wide association study signal.
  
  
  CONCLUSIONS
  Although the effect size for the association of ABCA7 loss-of-function variants with AD risk is lower in our study (odds ratio = 1.54) compared to the original report (odds ratio = 2.2), the replication of the findings of the original report provides a stronger foundation for future functional applications. The data indicate that different independent signals that modify risk for complex traits may exist on the same locus. Additionally, our results suggest that replication of rare-variant studies should be performed at the gene level rather than focusing on a single variant.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Del-Aguila
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Fernández
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jimenez
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Black
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: Shengmei
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: Yuetiva
authors.initials: Y
authors.lastname: Deming
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Saef
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: Bill
authors.initials: B
authors.lastname: Howells
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA.
authors.forename: John
authors.initials: J
authors.lastname: Budde
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.|The Hope Center for Neurological Disorders, BJC Institute of Health, 425 S. Euclid Ave, St. Louis, MO, 63110, USA. ccruchaga@wustl.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D012306:Risk; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters