Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease
Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease
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DOI：
10.1001/archneurol.2007.3
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发表时间：
2008-01-01
影响因子：
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通讯作者：
Roses, Allen D.
中科院分区：
文献类型：
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作者：
Li, Hao;Wetten, Sally;Roses, Allen D.
目的：在一项对469438个单核苷酸多态性（SNP）的全基因组关联研究中，确定与阿尔茨海默病（AD）发病风险和发病年龄相关的SNP。
设计：病例对照研究及重复验证。
地点：加拿大和英国的记忆转诊诊所。
参与者：产生假设的数据集包括753名符合美国国立神经疾病与中风研究所/阿尔茨海默病及相关疾病协会标准的阿尔茨海默病患者，这些患者来自加拿大的9家记忆转诊诊所，以及736名种族匹配的对照受试者；对照受试者从患者的非生物学亲属、朋友或配偶中招募，且通过病史或认知测试未表现出认知障碍。后续数据集包括来自英国医学研究理事会迟发性阿尔茨海默病遗传资源库的418例阿尔茨海默病病例和249例非痴呆对照病例，这些病例来自威尔士加的夫大学和英格兰伦敦国王学院的诊所。
主要观察指标：通过对年龄、性别、教育程度、研究地点和法裔加拿大人血统（针对加拿大数据集）进行调整的逻辑回归分析，计算SNP与阿尔茨海默病关联的比值比和95%置信区间。通过对类似协变量进行调整的考克斯比例风险回归分析，计算发病年龄的风险比和95%置信区间。
结果：未经调整时，载脂蛋白C1（APOC1）内的SNP RS4420638与阿尔茨海默病密切相关，这完全是由于与载脂蛋白E（APOE）的连锁不平衡。在多变量调整分析中，在加拿大数据集的逻辑分析中按P值排在前120位的3个SNP以及考克斯分析中的1个SNP为P值下的关联提供了额外证据。
Objective: To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs.Design: Case-control study with replication.Setting: Memory referral clinics in Canada and the United Kingdom.Participants: The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 non-demented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England.Main Outcome Measures: Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments.Results: Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P