Blood and Intestine eQTLs from an Anti-TNF-Resistant Crohn's Disease Cohort Inform IBD Genetic Association Loci.
Blood and Intestine eQTLs from an Anti-TNF-Resistant Crohn's Disease Cohort Inform IBD Genetic Association Loci.
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DOI：
10.1038/ctg.2016.34
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发表时间：
2016-06-23
影响因子：
3.6
通讯作者：
Hao K
中科院分区：
文献类型：
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作者：
Di Narzo AF;Peters LA;Argmann C;Stojmirovic A;Perrigoue J;Li K;Telesco S;Kidd B;Walker J;Dudley J;Cho J;Schadt EE;Kasarskis A;Curran M;Dobrin R;Hao K
全基因组关联研究 (GWAS) 已确定与炎症性肠病 (IBD) 和其他免疫介导疾病可重复相关的基因座；然而，大多数遗传易感性的分子机制仍不清楚。可以利用疾病相关组织的表达数量性状基因座（eQTL）来阐明受疾病特异性遗传变异影响的基因和途径。在这项研究中，我们针对抗肿瘤坏死因子耐药的克罗恩病 (CD) 患者的人全血和肠组织导出了 eQTL。我们在已发表的 IBD GWAS 命中中解释了这些 eQTL，以了解疾病过程。以 10% 的错误发现率，我们发现血液中的 5,174 个基因和肠道中的 2,063 个基因由附近的单核苷酸多态性 (SNP)（即 cis-eQTL）控制，其中 1,360 个基因在两种组织之间共享。大部分已识别的 eQTL 得到了 regulomeDB 数据库的支持，表明 eQTL 存在于调控元件中（比值比；血液和肠道 eQTL 的 OR=3.44 和 3.24），而不是蛋白质编码区域。已发表的 IBD GWAS 命中结果总体上富集了血液和肠道 eQTL（OR=2.88 和 2.05；P 值分别=2.51E-9 和 0.013），从而将遗传易感性与这些组织中基因表达的控制联系起来。通过系统检索，我们使用 eQTL 数据获取了国家人类基因组研究所目录中记录的 372 个 IBD GWAS SNP 中的 109 个，并根据 eQTL 影响的基因根据其功能进行了分类。其中许多基因已通过实验验证了在导致肠道炎症的特定细胞类型中的作用。本研究中描述的血液和肠道 eQTL 是将 GWAS 位点与调节功能联系起来的强大工具，从而阐明与 IBD 和相关病症相关的遗传位点的潜在机制。总体而言，我们的 eQTL 发现方法根据经验识别了与疾病相关的变异，包括它们对疾病相关细胞途径中表达变化的方向和程度的影响，以便推断遗传易感性这一方面的功能结果。
Genome-wide association studies (GWAS) have identified loci reproducibly associated with inflammatory bowel disease (IBD) and other immune-mediated diseases; however, the molecular mechanisms underlying most of genetic susceptibility remain undefined. Expressional quantitative trait loci (eQTL) of disease-relevant tissue can be employed in order to elucidate the genes and pathways affected by disease-specific genetic variance. In this study, we derived eQTLs for human whole blood and intestine tissues of anti-tumor necrosis factor-resistant Crohn's disease (CD) patients. We interpreted these eQTLs in the context of published IBD GWAS hits to inform on the disease process. At 10% false discovery rate, we discovered that 5,174 genes in blood and 2,063 genes in the intestine were controlled by a nearby single-nucleotide polymorphism (SNP) (i.e., cis-eQTL), among which 1,360 were shared between the two tissues. A large fraction of the identified eQTLs were supported by the regulomeDB database, showing that the eQTLs reside in regulatory elements (odds ratio; OR=3.44 and 3.24 for blood and intestine eQTLs, respectively) as opposed to protein-coding regions. Published IBD GWAS hits as a whole were enriched for blood and intestine eQTLs (OR=2.88 and 2.05; and P value=2.51E-9 and 0.013, respectively), thereby linking genetic susceptibility to control of gene expression in these tissues. Through a systematic search, we used eQTL data to inform 109 out of 372 IBD GWAS SNPs documented in National Human Genome Research Institute catalog, and we categorized the genes influenced by eQTLs according to their functions. Many of these genes have experimentally validated roles in specific cell types contributing to intestinal inflammation. The blood and intestine eQTLs described in this study represent a powerful tool to link GWAS loci to a regulatory function and thus elucidate the mechanisms underlying the genetic loci associated with IBD and related conditions. Overall, our eQTL discovery approach empirically identifies the disease-associated variants including their impact on the direction and extent of expression changes in the context of disease-relevant cellular pathways in order to infer the functional outcome of this aspect of genetic susceptibility.