Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE
Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE
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DOI：
10.1016/j.ajhg.2008.10.008
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发表时间：
2008-11-07
影响因子：
9.8
通讯作者：
Tanzi, Rudolph E.
中科院分区：
文献类型：
--
作者：
Bertram, Lars;Lange, Christoph;Tanzi, Rudolph E.
阿尔茨海默病（Alzheimer's disease，AD）是一种遗传复杂的异质性疾病。到目前为止，已经确定了四个基因导致早发性常染色体显性AD（APP，PSEN 1和PSEN 2（1-4））或增加晚发性AD的易感性（APOE）。然而，晚发性AD的遗传率高达80%，（6）并且迄今为止大部分表型变异仍然无法解释。我们使用484，522个单核苷酸多态性（SNP）对自报欧洲血统的AD家族的大样本（来自410个家族的1，376个样本）进行了全基因组关联（GWA）分析。我们确定了5个SNPs，它们显示出与多变量表型结合情感状态和发病年龄的显著或边缘显著的全基因组关联。其中一个信号（p = 5.7 x 10（-14））由SNP rs 4420638引起，可能反映了APOE-β 4，其定位于11 kb近端（r（2）= 0.78）。其他四个信号在另外三个独立的AD家族样本中进行了测试，这些样本由来自近900个家族的近2700名个体组成。这些SNP中的两个在复制样品中显示出显著关联（组合p值0.007和0.00002）。具有最强关联信号的SNP（rs 11159647，在染色体14 q31上）也显示出与在类似于1，400个AD病例和对照的独立样本中产生的GWA数据中的相同等位基因关联的证据（p = 0.04）。虽然潜在基因座（i）的确切身份仍然难以捉摸，但我们的研究提供了令人信服的证据，证明存在至少一种以前未描述的AD基因，如APOE-β 4，主要作为发病年龄的修饰剂。
Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either Cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE However, the heritability of late-onset AD is as high as 80%,(6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon 4, which maps 11 kb proximal (r(2) = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of similar to 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon 4, primarily acts as a modifier of onset age.