Pedraza Otto, Allen Mariet, Jennette Kyle, Carrasquillo Minerva, Crook Julia, 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 C, Younkin Steven G, Ertekin-Taner Nilüfer
Mayo Clinic Florida, Department of Psychiatry and Psychology, Jacksonville, FL, USA.
Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
Alzheimers Dement. 2014 Mar;10(2):205-13. doi: 10.1016/j.jalz.2013.01.016. Epub 2013 May 2.
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.
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.
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.
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.
在全基因组关联研究中，CLU、CR1和PICALM基因座的遗传变异与晚发性阿尔茨海默病（LOAD）风险相关。在本研究中，我们的目的是确定这三个基因座的LOAD风险变异是否会影响黑人和白人受试者的记忆内表型。
我们对CLU、CR1和PICALM基因座的单核苷酸多态性基因型与记忆内表型进行了关联研究。我们评估了在佛罗里达州梅奥诊所招募的黑人受试者（AA系列：44例LOAD患者和224例对照受试者）以及在明尼苏达州梅奥诊所（RS系列：372例LOAD患者和1690例对照受试者）和佛罗里达州（JS系列：60例LOAD患者和529例对照受试者）招募的白人受试者。对LOAD风险基因座CLU（rs11136000）、CR1（rs6656401、rs3818361）和PICALM（rs3851179）的单核苷酸多态性进行基因分型，并使用多变量线性回归分析测试其与韦氏记忆量表修订版中的逻辑记忆即刻回忆、逻辑记忆延迟回忆、逻辑记忆保留百分比、视觉再现即刻回忆、视觉再现延迟回忆和视觉再现保留百分比得分的关联，同时对检查时的年龄、性别、教育程度和载脂蛋白E ε4剂量进行校正。
我们在黑人中发现LOAD风险CR1变异与较差的逻辑记忆即刻回忆得分之间存在名义上显著或提示性的关联（P = 0.068 - 0.046，β = -2.7至-1.2）。LOAD保护性CLU变异与白人受试者更好的逻辑记忆内表型相关（P = 0.099 - 0.027，β = 0.31 - 0.93）。当分别评估AA系列的对照受试者时，CR1的关联仍然存在。CLU的关联似乎由其中一个白人系列（RS）驱动，并且在分析RS的对照亚组时也观察到了。
这些结果首次表明CR1的LOAD风险变异可能影响黑人的记忆内表型。此外，CLU的LOAD保护性变异可能使白人的记忆力增强。尽管在进行严格的多重检验校正后这些结果不再显著，但在与它们具有生物学一致性的LOAD关联背景下需要考虑这些结果。它们还提供了对记忆内表型效应大小的估计，可指导未来的研究。在临床正常受试者中检测到这些变异对记忆的影响，意味着这些LOAD风险基因座可能在AD临床诊断之前就改变了记忆。
