A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease.
A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease.
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DOI：
10.1371/journal.pgen.1001283
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发表时间：
2011-01-27
期刊：
影响因子：
4.5
通讯作者：
Rioux JD
中科院分区：
文献类型：
--
作者：
Festen EA;Goyette P;Green T;Boucher G;Beauchamp C;Trynka G;Dubois PC;Lagacé C;Stokkers PC;Hommes DW;Barisani D;Palmieri O;Annese V;van Heel DA;Weersma RK;Daly MJ;Wijmenga C;Rioux JD
克罗恩病（CD）和腹腔疾病（CELD）是慢性肠道炎症性疾病，涉及两种疾病的遗传和环境因素可以同时发生。一般人群。在这两种疾病中已经独立鉴定，我们的研究的目的是通过将CD和CELD的CD的数据集（GWAS）数据集结合在一起，以明确地识别这些疾病的共享风险。在荟萃分析中合并了768例，1,422个对照）和CD（3,230例，4,829个对照）。在此荟萃分析中<1.0×10-5显示了与原始扫描中各个疾病的关联的证据（p值<1×10-2，在CD中<1×10-3）两个先前报道的共享位置IL18RAP和PTPN2，p值分别为3.37×10-8和6.39×10-9在额外的CELD中测试（3,149病例和4,714个对照）和CD（1,835例和1,669个对照组），其中两个基因座，TAGAP和PUS10，在合并的CELD和CD复制队列和CD复制队列中显示了重复的重要证据首先以全基因组显着性的共享风险位置确定，总体p值分别为1.55×10-10和1.38×10-11来自CD和CELD的GWAS数据的荟萃分析，我们已经确定了四个共享风险基因座：PTPN2，IL18RAP，TAGAP和PUS10。共享局部效果相对较小。
腹腔疾病和克罗恩病是消化道的慢性炎症性疾病。对于这些疾病。通过比较CD和CELD的独立GWA研究的结果，发现了两个遗传风险基因座：PTPN2基因座和IL18RAP基因座，因此，为了直接测试其他共同的遗传风险因素，我们将GWA结合起来。两项大型研究的持续研究基本上是与CD或CELD进行编码的任何人的结合表型。 celd和cd的同龄人可以在此分析中显示共同的风险基因座，而对两种疾病中的任何一种的风险基因座的信号应稀释。 IL18 RAP两个基因座携带TAGAP和PUS10作为克罗恩病和腹腔疾病的共同风险基因座，具有全基因组意义。
Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect. Celiac disease and Crohn's disease are both chronic inflammatory diseases of the digestive tract. Both of these diseases are complex genetic traits with multiple genetic and non-genetic risk factors. Recent genome-wide association (GWA) studies have identified some of the genetic risk factors for these diseases. Interestingly, in addition to some similarities in phenotype, these studies have shown that CelD and CD share some genetic risk factors. Specifically, by comparing the results of independent GWA studies of CD and CelD, two genetic risk loci were found in common: the PTPN2 locus and the IL18RAP locus. Therefore, in order to directly test for additional shared genetic risk factors, we combined the GWA results from two large studies of CelD and CD, essentially creating a combined phenotype with anyone with CD or CelD being coded as affected. Association results were then replicated in additional cohorts of CelD and CD. It is expected that shared risk loci should show association in this analysis, whereas the signal of risk loci specific to either of the two diseases should be diluted. With this method of meta-analysis, we identified next to PTPN2 and IL18 RAP two loci harbouring TAGAP and PUS10 as shared risk loci for Crohn's disease and celiac disease at genome-wide significance.
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