A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.
A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.
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DOI：
10.1186/1755-8794-1-44
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发表时间：
2008-09-29
影响因子：
2.7
通讯作者：
Kirov G
中科院分区：
文献类型：
--
作者：
Abraham R;Moskvina V;Sims R;Hollingworth P;Morgan A;Georgieva L;Dowzell K;Cichon S;Hillmer AM;O'Donovan MC;Williams J;Owen MJ;Kirov G
迟发性阿尔茨海默病（LOAD）是一种与年龄相关的神经退行性疾病，其发病率较高，在人口日益老龄化的社会中对医疗资源提出了重大需求。LOAD唯一可广泛重复的遗传风险因素是载脂蛋白E基因。为了确定其他遗传风险位点，我们在一个大型的LOAD病例 - 对照样本中进行了全基因组关联（GWA）研究，通过使用DNA混合池降低了成本。
从1082名LOAD患者和1239名对照个体中收集了DNA样本。发病年龄在60至95岁之间，对照个体在年龄（平均 = 76.53岁，标准差 = 33）、性别和种族方面进行了匹配。将等摩尔量的每个DNA样本添加到病例池或对照池中。使用Illumina HumanHap300和Illumina Sentrix HumanHap240S芯片对混合池进行基因分型，检测了561,494个单核苷酸多态性（SNP）。从混合池数据中确定了114个最佳命中的SNP，然后在用于构建混合池的病例 - 对照样本中对其进行单独基因分型。
在载脂蛋白E（APOE）位点观察到与LOAD高度显著的关联，证实了混合池基因分型方法的有效性。
对于APOE位点之外的109个SNP，在单独基因分型后，我们得到74个未经校正的p值≤0.05。为了进一步检验这些关联，我们添加了来自1958年出生队列的1400名受试者的对照数据，我们最强的发现rs727153的关联证据增加到3.4×10⁻⁶。
rs727153位于卵磷脂视黄醇酰基转移酶（磷脂酰胆碱 - 视黄醇O - 酰基转移酶，LRAT）转录起始点13kb处。为覆盖LRAT而选择的7个标签SNP中有5个显示与LOAD显著关联，其中LRAT内含子2中的一个SNP显示出最强的关联证据（rs201825，p值 = 6.1×10⁻⁷）。
我们通过确定APOE位点以及观察到显著关联的SNP的高度富集，验证了用于GWA研究的混合池方法。我们提供了LRAT作为LOAD的一个新的候选基因的证据。LRAT在维生素A级联反应中起着重要作用，而该系统先前已被认为与LOAD有关。
Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case – control sample, reducing costs through the use of DNA pooling. DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case – control sample used to construct the pools. Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach. For 109 SNPs outside the APOE locus, we obtained uncorrected p-values ≤ 0.05 for 74 after individual genotyping. To further test these associations, we added control data from 1400 subjects from the 1958 Birth Cohort with the evidence for association increasing to 3.4 × 10-6 for our strongest finding, rs727153. rs727153 lies 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine – retinol O-acyltransferase, LRAT). Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 × 10-7). We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD.
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影响因子：
4.4
作者：
Docherty SJ;Butcher LM;Schalkwyk LC;Plomin R
通讯作者：
Plomin R
影响因子：
9.9
作者：
Cummings, JL
通讯作者：
Cummings, JL
影响因子：
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作者：
Kirov, G;Nikolov, I;O'Donovan, MC
通讯作者：
O'Donovan, MC
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作者：
Norton, N;Williams, NM;O'Donovan, MC
通讯作者：
O'Donovan, MC
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作者：
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通讯作者：
Roses, Allen D.