Discover novel disease-associated genes based on regulatory networks of long-range chromatin interactions.
Discover novel disease-associated genes based on regulatory networks of long-range chromatin interactions.
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DOI：
10.1016/j.ymeth.2020.10.010
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Wang H;Yang J;Zhang Y;Wang J
识别与复杂疾病及其潜在机制相关的基因和非编码基因变异是功能基因组学中最重要的问题之一。由于统计能力有限和缺乏机械建模，传统的全基因组关联研究(GWAS)受到限制，无法充分解决这一问题。在多组学数据集成的基础上，可以构建特定细胞类型的调控网络，以改进GWAS分析。在这项研究中，我们开发了一个新的计算基础设施，APRIL，将3D染色质相互作用纳入调控网络构建，该网络可以扩展到包括非编码GWASSNPs和靶基因之间的远程顺式调控链接。还推测了共同调节基因组的组合转录因子，以进一步扩大反式调节网络。今年4月，一套机器学习预测和统计测试被纳入，以基于扩大的监管网络预测新的疾病相关基因。非编码调控元件和遗传变异的重要特征在基于网络的预测中被优先考虑，提供了对与复杂疾病相关的转录调控失调机制的系统水平的洞察。
Identifying genes and non-coding genetic variants that are genetically associated with complex diseases and the underlying mechanisms is one of the most important questions in functional genomics. Due to the limited statistical power and the lack of mechanistic modeling, traditional genome-wide association studies (GWAS) is restricted to fully address this question. Based on multi-omics data integration, cell-type specific regulatory networks can be built to improve GWAS analysis. In this study, we developed a new computational infrastructure, APRIL, to incorporate 3D chromatin interactions into regulatory network construction, which can extend the networks to include long-range cis-regulatory links between non-coding GWAS SNPs and target genes. Combinatorial transcription factors that co-regulate groups of genes are also inferred to further expand the networks with trans-regulation. A suite of machine learning predictions and statistical tests are incorporated in APRIL to predict novel disease-associated genes based on the expanded regulatory networks. Important features of non-coding regulatory elements and genetic variants are prioritized in network-based predictions, providing systems-level insights on the mechanisms of transcriptional dysregulation associated with complex diseases.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
DOI：
10.1093/bioinformatics/btv301
发表时间：
2015-09-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gutiérrez-Sacristán A;Grosdidier S;Valverde O;Torrens M;Bravo À;Piñero J;Sanz F;Furlong LI
通讯作者：
Furlong LI
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P