Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
PLoS Genet. 2011 Jan 27;7(1):e1001283. doi: 10.1371/journal.pgen.1001283.
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 x 10⁻⁵ in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value < 1 x 10⁻² in CelD and < 1 x 10⁻³ in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37 x 10⁻⁸ and 6.39 x 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 x 10⁻¹⁰ and 1.38 x 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.
克罗恩病（CD）和乳糜泻（CelD）是慢性肠道炎症性疾病，其发病机制涉及遗传和环境因素。这两种疾病在家族中可能同时发生，并且研究表明 CelD 患者比一般人群更容易患 CD。这些观察结果表明 CD 和 CelD 可能具有共同的遗传风险基因座。已经在这两种疾病中独立鉴定出两个这样的共同基因座，即 IL18RAP 和 PTPN2。我们的研究目的是通过合并 CD 和 CelD 的全基因组关联研究（GWAS）数据集的结果来明确鉴定这些疾病的共同风险基因座。具体来说，在一项荟萃分析中合并了 CelD（768 例，1422 例对照）和 CD（3230 例，4829 例对照）的 GWAS 结果。在该荟萃分析中，有 9 个独立区域的名义关联 p 值<1.0×10⁻⁵，并且在原始扫描中显示出与个体疾病的关联证据（在 CelD 中 p 值<1×10⁻²，在 CD 中 p 值<1×10⁻³）。这些区域包括先前报道的两个共同基因座，IL18RAP 和 PTPN2，在荟萃分析中的 p 值分别为 3.37×10⁻⁸和 6.39×10⁻⁹。另外七个区域以前没有被报道为共同基因座，因此在另外的 CelD（3149 例和 4714 例对照）和 CD（1835 例和 1669 例对照）队列中进行了测试。这两个区域中的两个，TAGAP 和 PUS10，在 CelD 和 CD 复制队列的联合复制中显示出显著的复制证据（经 Bonferroni 校正的 p 值<0.0071），并被确定为具有全基因组意义的共同风险基因座，总体合并 p 值分别为 1.55×10⁻¹⁰和 1.38×10⁻¹¹。通过对 CD 和 CelD 的 GWAS 数据进行荟萃分析，我们已经确定了四个共同风险基因座：PTPN2、IL18RAP、TAGAP 和 PUS10。两个数据集的联合分析提供了在单个疾病的 GWAS 中缺乏的检测具有较小影响的共同基因座的能力。
