Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci.
Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci.
复制标题
DOI：
10.1016/j.jcmgh.2021.02.003
复制
发表时间：
2021
影响因子：
7.2
通讯作者：
Moreno V
中科院分区：
文献类型：
--
作者：
Díez-Obrero V;Dampier CH;Moratalla-Navarro F;Devall M;Plummer SJ;Díez-Villanueva A;Peters U;Bien S;Huyghe JR;Kundaje A;Ibáñez-Sanz G;Guinó E;Obón-Santacana M;Carreras-Torres R;Casey G;Moreno V
遗传变异与组织特异性基因表达和选择性剪接的关联指导复杂性状相关基因座的功能表征，并可能提示与疾病有关的新基因。在这方面，我们的目标如下：（1）生成结肠粘膜基因表达和可变剪接的参考谱，并在结肠亚位点之间比较它们（上行、横向和下行），（2）鉴定表达和剪接数量性状基因座（QTL），（3）发现鉴定的QTL有助于基于单核苷酸多态性（SNP）的遗传力的性状，（4）提出候选效应基因，和（5）提供基于网络的可视化资源。我们收集了485名健康成年人的结肠粘膜活检标本，并进行了批量RNA测序。我们对血液白细胞进行了全基因组SNP基因分型。统计方法和生物信息学软件用于QTL鉴定和下游分析。我们提供了一个完整的定量基因表达和选择性剪接跨结肠亚位点，并描述了它们的差异。我们鉴定了数千个表达和剪接QTL，并确定了它们在全基因组调控区域的富集。我们发现，影响结肠组织的疾病（如结直肠癌和炎症性肠病）以及影响其他组织的疾病（如精神疾病）的部分基于SNP的遗传性可以通过鉴定的QTL来解释。我们提供了多种表型的候选效应基因。最后，我们提供了Colon Transcriptome Explorer Web应用程序。我们提供了跨结肠亚位点的基因表达和剪接的大量表征。我们的研究结果提供了更大的病因学洞察复杂的性状和疾病的影响，在结肠组织中的转录组的变化。
The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)-based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource. We collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses. We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer web application. We provide a large characterization of gene expression and splicing across colon subsites. Our findings provide greater etiologic insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.
登录
查看更多内容
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
30.8
作者：
Huyghe, Jeroen R.;Bien, Stephanie A.;Peters, Ulrike
通讯作者：
Peters, Ulrike