Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium.
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Nat Commun. 2018 Jun 21;9(1):2427. doi: 10.1038/s41467-018-04365-8.
GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
GWAS 已经确定了 >200 个与炎症性肠病 (IBD) 相关的风险基因座。大多数疾病关联被认为是由调节变异驱动的。为了确定这些变异所干扰的潜在致病基因，我们生成了一个大型转录组数据集（九种与疾病相关的细胞类型），并鉴定了 23650 个顺式-eQTL。我们表明，这些由大约 9720 个调节模块决定，其中大约 3000 个在多种组织中起作用，大约 970 个在多个基因上起作用。我们确定了 63 个 200 个风险基因座中驱动疾病关联的调节模块，并表明这些模块在多基因模块中富集。基于这些分析，我们对 6600 例克罗恩病 (CD) 病例和 5500 例对照中的 45 个相应的 100 个候选基因进行了重测序，并通过负担测试表明它们包括可能的致病基因。我们的分析表明，使用这种方法来证明单个基因的因果关系，需要≥10 倍的更大样本量。
