Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects

Otto D Pedraza, Mariet Allen, Kyle Jennette, Minerva M Carrasquillo, Juliana Crook, Daniel Serie, V. Shane Pankratz, Ryan Palusak, Thuy Nguyen, Kimberly Malphrus, Li Ma, Gina Bisceglio, Rosebud O Roberts, John A Lucas, Robert J. Ivnik, Glenn E. Smith, Neill R Graff Radford, Ronald Carl Petersen, Steven G Younkin, Nilufer Taner

Research output: Contribution to journalArticle

29 Citations (Scopus)

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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)205-213
Number of pages9
JournalAlzheimer's and Dementia
Volume10
Issue number2
DOIs
StatePublished - 2014

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Endophenotypes
Alzheimer Disease
Short-Term Memory
Reproduction
Single Nucleotide Polymorphism
hydroquinone
Repression (Psychology)
Apolipoprotein E4
Wechsler Scales
Sex Education
Linear Models

Keywords

  • Alzheimer's disease
  • Association
  • CLU
  • CR1
  • Endophenotypes
  • Genetic
  • Memory
  • PICALM

ASJC Scopus subject areas

  • Clinical Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Epidemiology
  • Health Policy

Cite this

Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects. / Pedraza, Otto D; Allen, Mariet; Jennette, Kyle; Carrasquillo, Minerva M; Crook, Juliana; Serie, Daniel; Pankratz, V. Shane; Palusak, Ryan; Nguyen, Thuy; Malphrus, Kimberly; Ma, Li; Bisceglio, Gina; Roberts, Rosebud O; Lucas, John A; Ivnik, Robert J.; Smith, Glenn E.; Graff Radford, Neill R; Petersen, Ronald Carl; Younkin, Steven G; Taner, Nilufer.

In: Alzheimer's and Dementia, Vol. 10, No. 2, 2014, p. 205-213.

Research output: Contribution to journalArticle

Pedraza, Otto D ; Allen, Mariet ; Jennette, Kyle ; Carrasquillo, Minerva M ; Crook, Juliana ; Serie, Daniel ; Pankratz, V. Shane ; Palusak, Ryan ; Nguyen, Thuy ; Malphrus, Kimberly ; Ma, Li ; Bisceglio, Gina ; Roberts, Rosebud O ; Lucas, John A ; Ivnik, Robert J. ; Smith, Glenn E. ; Graff Radford, Neill R ; Petersen, Ronald Carl ; Younkin, Steven G ; Taner, Nilufer. / Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects. In: Alzheimer's and Dementia. 2014 ; Vol. 10, No. 2. pp. 205-213.
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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. Conclusion: 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.",
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TY - JOUR

T1 - Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects

AU - Pedraza, Otto D

AU - Allen, Mariet

AU - Jennette, Kyle

AU - Carrasquillo, Minerva M

AU - Crook, Juliana

AU - Serie, Daniel

AU - Pankratz, V. Shane

AU - Palusak, Ryan

AU - Nguyen, Thuy

AU - Malphrus, Kimberly

AU - Ma, Li

AU - Bisceglio, Gina

AU - Roberts, Rosebud O

AU - Lucas, John A

AU - Ivnik, Robert J.

AU - Smith, Glenn E.

AU - Graff Radford, Neill R

AU - Petersen, Ronald Carl

AU - Younkin, Steven G

AU - Taner, Nilufer

PY - 2014

Y1 - 2014

N2 - 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. Conclusion: 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.

AB - 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. Conclusion: 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.

KW - Alzheimer's disease

KW - Association

KW - CLU

KW - CR1

KW - Endophenotypes

KW - Genetic

KW - Memory

KW - PICALM

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