OP08 Multi-ancestry genome-wide association study of inflammatory bowel disease identifies 125 novel loci and directly implicates new genes in disease susceptibility
OP08 Multi-ancestry genome-wide association study of inflammatory bowel disease identifies 125 novel loci and directly implicates new genes in disease susceptibility
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OP08 炎症性肠病的多祖先全基因组关联研究确定了 125 个新基因座并直接暗示了疾病易感性中的新基因
DOI：
10.1093/ecco-jcc/jjad212.0008
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Fachal L
中科院分区：
文献类型：
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作者：
Fachal L
背景全基因组关联研究（GWASs）已经确定了320个与炎症性肠病（IBD）相关的基因座。这些基因座中约有15%包括位于目前批准用于治疗IBD的药物靶向途径中的基因。因此，确定新的基因座不仅可以提供进一步的见解，因果生物学，但也揭示了新的治疗targets.MethodsWe进行了多祖先GWAS荟萃分析67个队列，从欧洲，东亚和南亚人口。最终数据集包括125，992名IBD患者（59，734名CD患者; 57，565名UC患者）和超过120万名人群对照（图1）。使用TOPMed多样化人群组进行基因型插补，并使用REGENIE进行关联检验。通过Metal使用固定效应荟萃分析对结果进行荟萃分析。为了优先考虑效应基因并产生治疗假设，我们将我们的结果与来自相关组织和细胞类型的大量和单细胞转录组数据进行了整合。通过共定位分析，我们确定了这些信号驱动附近的基因（顺eQTL）的表达，这表明这些基因的异常表达的基础association.ResultsWe确定了290个新的独立的疾病易感性关联信号。其中，125个新的信号位于任何先前报道的基因座> 1 Mb。6个新的单基因综合征相关基因位点，包括结肠炎GUCY 2C、G6 PC 3、NFKBIA、PIK 3CD、PIK 3R 1、ZBTB 24。例如，一种与UC风险增加相关的新变异（P= 8 × 10 -14）降低了T细胞、B细胞、巨噬细胞和横结肠中跨膜线粒体蛋白TSPO 3的表达。促炎性巨噬细胞表现出一致的TSPO下调。小鼠中TSP 0的丧失导致DSS诱导的结肠炎加重。正在进行的临床试验正在评估靶向该基因是否可以改善多发性硬化症患者的免疫反应。我们还发现了一种新的CD易感性变异体（P= 3x 10 -16），与单核细胞和巨噬细胞中WNK 1表达增加有关。而小鼠中WNK 1的缺失显示响应于NLRP 3炎性体激活的IL-1B表达增加;它还通过PI 3 KC 3复合物的上调刺激自噬。受损的自噬已被证明是关键，在促进CD susceptibility.ConclusionIntegrating从多种细胞类型和条件的分子数据，不仅扩大了我们的能力，以确定新的候选致病基因，它也提供了额外的证据，遗传学作为一种工具，以指导开发新的治疗药物或现有分子的再利用。
BackgroundGenome-wide association studies (GWASs) have identified 320 loci associated with inflammatory bowel disease (IBD). About 15% of these loci include genes that lie in pathways targeted by drugs currently approved to treat IBD. Thus, identifying new loci can not only provide further insights into causal biology but also reveal novel therapeutic targets.MethodsWe performed a multi-ancestry GWAS meta-analysis of 67 cohorts, from European, East Asian and South Asian populations. The final dataset included 125,992 IBD patients (59,734 with CD; 57,565 with UC) and more than 1.2 million population controls (Fig 1).Genotype imputation was undertaken using the TOPMed diverse population panel and association tests were performed using REGENIE. The results were meta-analysed using a fixed effects meta-analysis via Metal.To prioritise effector genes and generate therapeutic hypotheses, we integrated our results with bulk and single cell transcriptome data from relevant tissues and cell types. Through colocalization analyses we identified those signals driving the expression of nearby genes (cis-eQTL), suggesting that aberrant expression of these genes underpins the association.ResultsWe identified 290 new independent disease susceptibility association signals. Out of these, 125 new signals are located >1Mb from any previously reported loci. Six new loci contain genes implicated in monogenic syndromes that include colitisGUCY2C, G6PC3, NFKBIA, PIK3CD, PIK3R1, ZBTB24.Up to 40% of all disease susceptibility association signals colocalize with a cis-eQTL. For instance, a new variant associated with increased risk of UC (P=8x10-14) decreases the expression of the transmembrane mitochondrial proteinTSPOin T cells, B cells, macrophages, and transverse colon. Pro-inflammatory macrophages show consistentTSPOdownregulation. Loss ofTSPOin mice causes exacerbated DSS-induced colitis. Ongoing clinical trials are evaluating whether targeting this gene could ameliorate the immune response in multiple sclerosis patients. We also identified a new CD susceptibility variant (P=3x10-16) associated with increased expression ofWNK1in monocytes and macrophages. Whereas loss ofWNK1in mice show increased expression of IL-1B in response to NLRP3 inflammasome activation; it also stimulates autophagy through the upregulation of the PI3KC3 complex. Impaired autophagy has shown to be key in promoting CD susceptibility.ConclusionIntegrating molecular data from multiple cell types and conditions not only expands our ability to determine novel candidate causal genes, it also provides additional evidence of the utility of genetics as an instrument to guide the development of new therapeutic drugs or the repurposing of existing molecules.