Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease
Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease
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DOI：
10.1016/j.ajhg.2008.12.008
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发表时间：
2009-01-09
影响因子：
9.8
通讯作者：
Pericak-Vance, Margaret A.
中科院分区：
文献类型：
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作者：
Beecham, Gary W.;Martin, Eden R.;Pericak-Vance, Margaret A.
只有载脂蛋白E多态性一直与迟发性阿尔茨海默病（LOAD）的风险相关，但它们只代表了潜在遗传效应的一小部分。为了确定额外的LOAD风险位点，我们使用Illumina公司的HumanHap550头芯片对492例LOAD病例和498例认知对照进行了全基因组关联研究（GWAS）。另外238例病例和220例对照作为验证数据集，以确定满足全基因组显著性的单核苷酸多态性（snp）。为了验证其他相关snp （p < 0.0001）和名义上相关的候选基因，我们使用先前发表的LOAD GWAS(1)和IMPUTE程序从GWAS中输入snp。采用Cochran-Armitage趋势检验和logistic回归进行相关性检验，采用错误发现率- β均匀混合法确定全基因组显著性。在样品和SNP水平上进行了广泛的质量控制方法。GWAS证实了已知的APOE关联，并鉴定出与12q13位点的关联具有全基因组显著性；12q13位点在我们的验证数据集中得到了确认。另外四个高度相关的信号（1q42, 4q28, 6q14, 19q13）通过使用输入的数据集被复制，并且六个候选基因在GWAS和联合输入的数据集中都具有名义关联的snp。这些结果有助于进一步确定LOAD的遗传结构。
Only Apolipoprotein E polymorphisms have been consistently associated with the risk of late-onset Alzheimer disease (LOAD), but they represent only a minority of the underlying genetic effect. To identify additional LOAD risk loci, we performed a genome-wide association study (GWAS) on 492 LOAD cases and 498 cognitive controls using Illumina's HumanHap550 beadchip. An additional 238 cases and 220 controls were used as a validation data set for single-nucleotide polymorphisms (SNPs) that met genome-wide significance. To validate additional associated SNPs (p < 0.0001) and nominally associated candidate genes, we imputed SNPs from our GWAS using a previously published LOAD GWAS(1) and the IMPUTE program. Association testing was performed with the Cochran-Armitage trend test and logistic regression, and genome-wide significance was determined with the False Discovery Rate-Beta Uniform Mixture method. Extensive quality-control methods were performed at both the sample and the SNP level. The GWAS confirmed the known APOE association and identified association with a 12q13 locus at genome-wide significance; the 12q13 locus was confirmed in our validation data set. Four additional highly associated signals (1q42, 4q28, 6q14, 19q13) were replicated with the use of the imputed data set, and six candidate genes had SNPs with nominal association in both the GWAS and the joint imputated data set. These results help to further define the genetic architecture of LOAD.