1000 Genomes-based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium phase 1 Data
1000 Genomes-based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium phase 1 Data
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DOI：
10.1038/ejhg.2012.3
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发表时间：
2012-07-01
影响因子：
5.2
通讯作者：
Li, Yun
中科院分区：
文献类型：
--
作者：
Huang, Jie;Ellinghaus, David;Li, Yun
我们假设，基于1000个基因组计划数据的插补可以在全基因组范围内识别新的关联信号，这是由于密集的标记图和大量的单倍型。为了检验假设，Wellcome Trust Case Control Consortium（WTCCC）I期基因型数据使用1000个基因组作为参考（20100804 EUR）进行插补，并使用插补剂量进行7项病例/对照关联研究。我们观察到两个“遗漏”的疾病相关变异，这些变异在最初的WTCCC分析中无法检测到，但在2007年WTCCC出版后的后续研究中被报道。一个在IL 2 RA基因内，与1型糖尿病相关，另一个在CDKN 2B基因附近，与2型糖尿病相关。我们还确定了两个精炼的关联。一个是IL 23 R外显子9中的SNP rs 11209026，与克罗恩病相关，预测其可能被PolyPhen 2破坏。另一个改进的变异是在与1型糖尿病相关的CUX 2基因区域，其中新鉴定的最高SNP rs 1265564的相关P值为1.68 x 10（-16）。两个精确位点的新的前导SNP为疾病关联提供了更合理的解释。我们证明，基于1000个基因组的插补确实可以识别新的（在我们的情况下，“错过”，因为它们在2007年之后的研究中被检测和复制）和精炼的信号。我们预计这项研究的结果将在个别群体和联盟开始进行基于1000个基因组的估算时提供及时的信息。European Journal of Human Genetics（2012）20，801-805; doi：10.1038/ejhg.2012.3; 2012年2月1日在线发表
We hypothesize that imputation based on data from the 1000 Genomes Project can identify novel association signals on a genome-wide scale due to the dense marker map and the large number of haplotypes. To test the hypothesis, the Wellcome Trust Case Control Consortium (WTCCC) Phase I genotype data were imputed using 1000 genomes as reference (20100804 EUR), and seven case/control association studies were performed using imputed dosages. We observed two 'missed' disease-associated variants that were undetectable by the original WTCCC analysis, but were reported by later studies after the 2007 WTCCC publication. One is within the IL2RA gene for association with type 1 diabetes and the other in proximity with the CDKN2B gene for association with type 2 diabetes. We also identified two refined associations. One is SNP rs11209026 in exon 9 of IL23R for association with Crohn's disease, which is predicted to be probably damaging by PolyPhen2. The other refined variant is in the CUX2 gene region for association with type 1 diabetes, where the newly identified top SNP rs1265564 has an association P-value of 1.68 x 10(-16). The new lead SNP for the two refined loci provides a more plausible explanation for the disease association. We demonstrated that 1000 Genomes-based imputation could indeed identify both novel (in our case, 'missed' because they were detected and replicated by studies after 2007) and refined signals. We anticipate the findings derived from this study to provide timely information when individual groups and consortia are beginning to engage in 1000 genomes-based imputation. European Journal of Human Genetics (2012) 20, 801-805; doi: 10.1038/ejhg.2012.3; published online 1 February 2012