TY - JOUR
T1 - Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects
AU - Pedraza, Otto
AU - Allen, Mariet
AU - Jennette, Kyle
AU - Carrasquillo, Minerva
AU - Crook, Julia
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 C.
AU - Younkin, Steven G.
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
N. R. Graff-Radford has served as a consultant to Codman and received grant support from Janssen Alzheimer Immunotherapy, Pfizer Pharmaceuticals, Medivation, and Forrest . He has served as Chair of the data safety monitoring board in clinical trials sponsored by Baxter. R. C. Petersen has been a consultant to GE Healthcare and Elan Pharmaceuticals , has served on a data safety monitoring board in clinical trials sponsored by Pfizer Incorporated and Janssen Alzheimer Immunotherapy , and gave a Continuing Medical Education (CME) lecture at Novartis Incorporated.
Funding Information:
Support for this research was provided by the National Institutes of Health grants ( National Institute on Aging [ R01 AG032990 to N. E. T. and R01 AG018023 to N. R. G.-R. and S. G. Y.]), Mayo Alzheimer's Disease Research Center ( P50 AG016574 to R. C. P., N. R. G.-R., S. G. Y., and N. E. T.), Mayo Alzheimer's Disease Patient Registry ( U01 AG006786 to R. C. P.), and K01 AG028573 (to R. O. R.). N. E. T. is the recipient of National Institutes of Health ( KL2 RR024151 ) and Siragusa Foundation grants. This project was also generously supported by the Robert and Clarice Smith, and Abigail Van Buren Alzheimer's Disease Research Program (to R. C. P. and S. G. Y.), and by the Palumbo Professorship in Alzheimer's Disease Research (to S. G. Y.). M. M. C. is supported in part by a GHR Foundation grant. We thank the patients and their families for their participation, without whom these studies will not have been possible.
PY - 2014/3
Y1 - 2014/3
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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U2 - 10.1016/j.jalz.2013.01.016
DO - 10.1016/j.jalz.2013.01.016
M3 - Article
C2 - 23643458
AN - SCOPUS:84897516307
SN - 1552-5260
VL - 10
SP - 205
EP - 213
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 2
ER -