Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-10-16 , DOI: 10.1016/j.jcmgh.2020.10.004 Chiara Lasconi 1 , Matthew C Pahl 1 , Diana L Cousminer 1 , Claudia A Doege 2 , Alessandra Chesi 1 , Kenyaita M Hodge 1 , Michelle E Leonard 1 , Sumei Lu 1 , Matthew E Johnson 1 , Chun Su 1 , Reza K Hammond 1 , James A Pippin 1 , Natalie A Terry 3 , Louis R Ghanem 3 , Rudolph L Leibel 2 , Andrew D Wells 4 , Struan F A Grant 5
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Background & Aims
Inflammatory bowel disease (IBD) is a polygenic disorder characterized principally by dysregulated inflammation impacting the gastrointestinal tract. However, there also is increasing evidence for a clinical association with stress and depression. Given the role of the hypothalamus in stress responses and in the pathogenesis of depression, useful insights could be gleaned from understanding its genetic role in IBD.
Methods
We conducted genetic correlation analyses on publicly available genome-wide association study summary statistics for depression and IBD traits to identify genetic commonalities. We used partitioned linkage disequilibrium score regression, leveraging our ATAC sequencing and promoter-focused Capture C data, to measure enrichment of IBD single-nucleotide polymorphisms within promoter-interacting open chromatin regions of human embryonic stem cell-derived hypothalamic-like neurons (HNs). Using the same data sets, we performed variant-to-gene mapping to implicate putative IBD effector genes in HNs. To contrast these results, we similarly analyzed 3-dimensional genomic data generated in epithelium-derived colonoids from rectal biopsy specimens from donors without pathologic disease noted at the time of colonoscopy. Finally, we conducted enrichment pathway analyses on the implicated genes to identify putative IBD dysfunctional pathways.
Results
We found significant genetic correlations (rg) of 0.122 with an adjusted P (Padj) = 1.4 × 10-4 for IBD: rg = 0.122; Padj = 2.5 × 10-3 for ulcerative colitis and genetic correlation (rg) = 0.094; Padj = 2.5 × 10-3 for Crohn’s disease, and significant approximately 4-fold (P = .005) and approximately 7-fold (P = .03) enrichment of IBD single-nucleotide polymorphisms in HNs and colonoids, respectively. We implicated 25 associated genes in HNs, among which CREM, CNTF, and RHOA encode key regulators of stress. Seven genes also additionally were implicated in the colonoids. We observed an overall enrichment for immune and hormonal signaling pathways, and a colonoid-specific enrichment for microbiota-relevant terms.
Conclusions
Our results suggest that the hypothalamus warrants further study in the context of IBD pathogenesis.
中文翻译：
变异基因图谱分析揭示下丘脑在炎症性肠病遗传易感性中的作用
背景与目标
炎症性肠病（IBD）是一种多基因疾病，其主要特征是影响胃肠道的炎症失调。然而，也有越来越多的证据表明其与压力和抑郁症存在临床关联。鉴于下丘脑在应激反应和抑郁症发病机制中的作用，可以通过了解其在 IBD 中的遗传作用来获得有用的见解。
方法
我们对公开的抑郁症和 IBD 特征的全基因组关联研究摘要统计数据进行了遗传相关性分析，以确定遗传共性。我们使用分区连锁不平衡评分回归，利用 ATAC 测序和以启动子为中心的 Capture C 数据，测量人胚胎干细胞来源的下丘脑样神经元 (HN) 的启动子相互作用开放染色质区域内 IBD 单核苷酸多态性的富集度。使用相同的数据集，我们进行了变异到基因的映射，以暗示 HN 中假定的 IBD 效应基因。为了对比这些结果，我们同样分析了在结肠镜检查时未发现病理性疾病的供体的直肠活检标本中产生的上皮衍生结肠样中产生的3维基因组数据。最后，我们对相关基因进行了富集途径分析，以确定假定的 IBD 功能障碍途径。
结果
我们发现 IBD 的显着遗传相关性 (rg) 为 0.122，调整后的P ( P adj ) = 1.4 × 10 -4 ：rg = 0.122；溃疡性结肠炎的P adj = 2.5 × 10 -3且遗传相关性 (rg) = 0.094；对于克罗恩病， P adj = 2.5 × 10 -3 ，并且 HN 和类结肠中 IBD 单核苷酸多态性分别显着约 4 倍 ( P = .005) 和约 7 倍 ( P = .03) 富集。我们涉及 HN 中的 25 个相关基因，其中CREM 、 CNTF和RHOA编码应激的关键调节因子。另外七个基因也与类集落有关。我们观察到免疫和激素信号通路的整体富集，以及微生物群相关术语的类集特异性富集。
结论
我们的结果表明下丘脑值得在 IBD 发病机制中进行进一步研究。
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