Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles
Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles
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DOI：
10.1212/wnl.0b013e3181a2e87d
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发表时间：
2009-04-28
期刊：
影响因子：
9.9
通讯作者：
Schneider, Julie A.
中科院分区：
文献类型：
--
作者：
Bennett, David A.;De Jager, Philip L.;Schneider, Julie A.
目的：阿尔茨海默病（Alzheimer disease，AD）易感基因的鉴定是一个重要的公共卫生问题。使用载脂蛋白E基因型（APOE），我们研究是否神经病理学中间表型，病理基础的临床AD，大概是中间的因果链，将增加权力的遗传associations.Methods：超过700名老年人进行年度评估和器官捐赠的一部分，宗教秩序的研究或拉什记忆和衰老项目。共536例临床AD或无痴呆的尸检患者进行了APOE基因分型和AD病理学定量测量分析。回归分析用于检验APOE与临床AD、接近死亡的认知功能水平以及AD神经病理学指标的关系。结果：APOE β 4与临床AD的几率增加相关（p = 3 x 10（-7）），与认知水平的相关性更强（p = 8 x 10（12））。然而，AD病理学定量测量的使用显著增强了相关性（p = 9 x 10（-24））。APOE β 2与AD（p = 0.69）或认知水平（p = 0.82）无关。然而，它与AD病理学的关联（p = 1 x 10（-5））足够强，如果在全基因组关联研究中发现，则有必要进行随访。功效计算表明，使用我们的AD病理学测量方法，需要625名受试者的样本量才能满足epsilon 2的全基因组显著性p = 5 x 10（-8）。结论：阿尔茨海默病易感基因座的发现工作可以受益于使用神经病理学中间表型作为其他方法的补充。神经病学（R）2009; 72：1495-1503
Objective: The identification of susceptibility alleles to risk of Alzheimer disease (AD) is a major public health priority. Using apolipoprotein E genotype (APOE), we examined whether neuropathologic intermediate phenotypes, the pathology underlying clinical AD that presumably lies intermediate in the causal chain, would increase power for genetic associations.Methods: More than 700 older persons underwent annual evaluation and organ donation as part of the Religious Orders Study or Rush Memory and Aging Project. A total of 536 autopsied persons with clinical AD or without dementia with APOE genotyping and a quantitative measure of AD pathology were analyzed. Regression analyses were used to examine the relation of APOE to clinical AD, to the level of cognitive function proximate to death, and to measures of AD neuropathology.Results: APOE epsilon 4 was associated with increased odds of clinical AD (p = 3 x 10(-7)), and its association with level of cognition was stronger (p = 8 x 10 (12)). However, the use of quantitative measures of AD pathology markedly enhanced the association (p = 9 x 10(-24)). The APOE epsilon 2 was not associated with either AD (p = 0.69) or level of cognition (p = 0.82). However, its association with AD pathology (p = 1 x 10(-5)) was sufficiently strong that it would have warranted follow-up if discovered in a genome-wide association study. Power calculations demonstrate that a sample size of 625 subjects with our measure of AD pathology would be required to meet genome-wide significance of p = 5 x 10(-8) for epsilon 2.Conclusion: Discovery efforts for susceptibility loci for Alzheimer disease could benefit from the use of neuropathologic intermediate phenotypes as a complement to other approaches. Neurology (R) 2009; 72: 1495-1503