title: Genetic variability in CLU and its association with Alzheimer's disease.
abstract: BACKGROUND
  Recently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU.
  
  
  RESULTS
  To further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD.
  
  
  CONCLUSIONS
  We conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Guerreiro
authors.forename: John
authors.initials: J
authors.lastname: Beck
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Isabel
authors.initials: I
authors.lastname: Santana
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Helena
authors.initials: H
authors.lastname: Ribeiro
authors.forename: Beatriz
authors.initials: B
authors.lastname: Santiago
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.forename: Catarina
authors.initials: C
authors.lastname: Oliveira
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: John
authors.initials: J
authors.lastname: Hardy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001921:Brain / Q000473:pathology; D051152:Clusterin / Q000235:genetics* / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: C495242:CLU protein, human; D051152:Clusterin