INFERNO: inferring the molecular mechanisms of noncoding genetic variants.
INFERNO: inferring the molecular mechanisms of noncoding genetic variants.
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DOI：
10.1093/nar/gky686
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发表时间：
2018-09-28
影响因子：
14.9
通讯作者：
Wang LS
中科院分区：
文献类型：
--
作者：
Amlie-Wolf A;Tang M;Mlynarski EE;Kuksa PP;Valladares O;Katanic Z;Tsuang D;Brown CD;Schellenberg GD;Wang LS
通过全基因组关联研究（GWAS）鉴定的大多数变体存在于非编码基因组中，影响包括转录增强子在内的调控元件。然而，表征它们的作用需要将GWAS结果与上下文特异性调控活性和连锁不平衡注释相结合，以确定非编码关联信号和调控元件，组织背景和它们影响的靶基因的因果变异。我们提出了INFERNO，一种新的方法，它集成了数百个功能基因组数据集，包括增强子活性，转录因子结合位点和表达数量性状位点与GWAS汇总统计。INFERNO包括新的统计方法来量化组织特异性增强子重叠的经验富集，并确定失调的长非编码RNA（lncRNA）的共调控网络。我们将INFERNO应用于两项大型GWAS研究。对于精神分裂症（36，989例，113，075例对照），INFERNO确定了影响已知精神分裂症相关基因的大脑增强子的pupillary因果变异。对于炎症性肠病（IBD）（12，882例，21，770例对照），INFERNO发现了免疫和消化增强剂以及参与调节适应性免疫反应的lncRNA的富集。总之，INFERNO全面推断了因果非编码变异的分子机制，为GWAS后分析提供了敏感的假设生成方法。该软件可作为开源管道和Web服务器使用。
The majority of variants identified by genome-wide association studies (GWAS) reside in the noncoding genome, affecting regulatory elements including transcriptional enhancers. However, characterizing their effects requires the integration of GWAS results with context-specific regulatory activity and linkage disequilibrium annotations to identify causal variants underlying noncoding association signals and the regulatory elements, tissue contexts, and target genes they affect. We propose INFERNO, a novel method which integrates hundreds of functional genomics datasets spanning enhancer activity, transcription factor binding sites, and expression quantitative trait loci with GWAS summary statistics. INFERNO includes novel statistical methods to quantify empirical enrichments of tissue-specific enhancer overlap and to identify co-regulatory networks of dysregulated long noncoding RNAs (lncRNAs). We applied INFERNO to two large GWAS studies. For schizophrenia (36,989 cases, 113,075 controls), INFERNO identified putatively causal variants affecting brain enhancers for known schizophrenia-related genes. For inflammatory bowel disease (IBD) (12,882 cases, 21,770 controls), INFERNO found enrichments of immune and digestive enhancers and lncRNAs involved in regulation of the adaptive immune response. In summary, INFERNO comprehensively infers the molecular mechanisms of causal noncoding variants, providing a sensitive hypothesis generation method for post-GWAS analysis. The software is available as an open source pipeline and a web server.
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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：
10.12659/msm.899595
发表时间：
2017-01-26
期刊：
Medical science monitor : international medical journal of experimental and clinical research
影响因子：
--
作者：
Dai X;Dong M;Yu H;Xie Y;Yu Y;Cao Y;Kong Z;Zhou B;Xu Y;Yang T;Li K
通讯作者：
Li K
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：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M