title: Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects.
abstract: BACKGROUND
  Genetic variants at the CLU, CR1, and PICALM loci associate with risk for late-onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects.
  
  
  METHODS
  We pursued an association study between single nucleotide polymorphism genotypes at the CLU, CR1, and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at Mayo Clinic Minnesota (RS series: 372 with LOAD and 1690 control subjects) and Florida (JS series: 60 with LOAD and 529 control subjects). Single nucleotide polymorphisms at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361), and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall, Logical Memory delayed recall, Logical Memory percent retention, Visual Reproduction immediate recall, Visual Reproduction delayed recall, and Visual Reproduction percent retention scores from the Wechsler Memory Scale-Revised using multivariable linear regression analysis, adjusting for age at exam, sex, education, and apolipoprotein E ε4 dosage.
  
  
  RESULTS
  We identified nominally significant or suggestive associations between the LOAD-risky CR1 variants and worse Logical Memory immediate recall scores in blacks (P = .068-.046, β = -2.7 to -1.2). The LOAD-protective CLU variant is associated with better logical memory endophenotypes in white subjects (P = .099-.027, β = 0.31-0.93). The CR1 associations persisted when the control subjects from the AA series were assessed separately. The CLU associations appeared to be driven by one of the white series (RS) and were also observed when the control subset from RS was analyzed.
  
  
  CONCLUSIONS
  These results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD-protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.
authors: Mayo Clinic Florida, Department of Psychiatry and Psychology, Jacksonville, FL, USA.
authors: Otto
authors: O
authors: Pedraza
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Mariet
authors: M
authors: Allen
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Kyle
authors: K
authors: Jennette
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Minerva
authors: M
authors: Carrasquillo
authors: Mayo Clinic Florida, Biostatistics Unit, Jacksonville, FL, USA.
authors: Julia
authors: J
authors: Crook
authors: Mayo Clinic Florida, Biostatistics Unit, Jacksonville, FL, USA.
authors: Daniel
authors: D
authors: Serie
authors: Mayo Clinic Minnesota, Department of Biostatistics, Rochester, MN, USA.
authors: V Shane
authors: VS
authors: Pankratz
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Ryan
authors: R
authors: Palusak
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Thuy
authors: T
authors: Nguyen
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Kimberly
authors: K
authors: Malphrus
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Li
authors: L
authors: Ma
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Gina
authors: G
authors: Bisceglio
authors: Mayo Clinic Minnesota, Division of Epidemiology, Rochester, MN, USA.
authors: Rosebud O
authors: RO
authors: Roberts
authors: Mayo Clinic Florida, Department of Psychiatry and Psychology, Jacksonville, FL, USA.
authors: John A
authors: JA
authors: Lucas
authors: Mayo Clinic Minnesota, Department of Psychiatry and Psychology, Rochester, MN, USA.
authors: Robert J
authors: RJ
authors: Ivnik
authors: Mayo Clinic Minnesota, Department of Psychiatry and Psychology, Rochester, MN, USA.
authors: Glenn E
authors: GE
authors: Smith
authors: Mayo Clinic Florida, Department of Neurology, Jacksonville, FL, USA.
authors: Neill R
authors: NR
authors: Graff-Radford
authors: Mayo Clinic Minnesota, Department of Neurology, Rochester, MN, USA.
authors: Ronald C
authors: RC
authors: Petersen
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors: Steven G
authors: SG
authors: Younkin
authors: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA; Mayo Clinic Florida, Department of Neurology, Jacksonville, FL, USA. Electronic address: taner.nilufer@mayo.edu.
authors: Nilüfer
authors: N
authors: Ertekin-Taner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D044383:Black People / Q000235:genetics; D051152:Clusterin / Q000235:genetics*; D058068:Endophenotypes; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008568:Memory / Q000502:physiology*; D008875:Middle Aged; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D017463:Receptors, Complement 3b / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D053327:Apolipoprotein E4; C495242:CLU protein, human; C509991:CR1 protein, human; D051152:Clusterin; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D017463:Receptors, Complement 3b
keywords: Alzheimer's disease; Association; CLU; CR1; Endophenotypes; Genetic; Memory; PICALM
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