Approaches for establishing the function of regulatory genetic variants involved in disease.
Approaches for establishing the function of regulatory genetic variants involved in disease.
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DOI：
10.1186/s13073-014-0092-4
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发表时间：
2014
期刊：
影响因子：
12.3
通讯作者：
Knight JC
中科院分区：
文献类型：
--
作者：
Knight JC
调控基因变异及其作用机制的多样性反映了基因调控的复杂性和背景特异性。调节变异在人类疾病中很重要，定义这种变异并建立机制对于解释疾病关联研究至关重要。这篇综述描述了识别和功能表征调控变异体的方法，并用常见疾病的例子加以说明。重点介绍了在解决变异体作用的功能性表观基因组调控图景方面的最新进展，展示了这如何使变异体的功能注释和关于作用机制的假说的产生成为可能。综述了在转录本、蛋白质和代谢物水平上的数量性状作图在确定特定基因与特定变异的关联以及进一步告知疾病关联方面的作用。建立作用机制是解决功能调控变异的关键步骤，本文综述了分析等位基因特异性表达、绘制染色质相互作用图的新方法以及基因组编辑的进展是如何促进这一过程的。最后，结合实例讨论了综合方法，强调了定义调节变量的作用机制和识别特定的调节基因如何能够最大限度地发挥全基因组关联研究的翻译效用，以了解疾病的发病机制，并发现新的药物靶点或机会，以改变现有药物的治疗目的。
The diversity of regulatory genetic variants and their mechanisms of action reflect the complexity and context-specificity of gene regulation. Regulatory variants are important in human disease and defining such variants and establishing mechanism is crucial to the interpretation of disease-association studies. This review describes approaches for identifying and functionally characterizing regulatory variants, illustrated using examples from common diseases. Insights from recent advances in resolving the functional epigenomic regulatory landscape in which variants act are highlighted, showing how this has enabled functional annotation of variants and the generation of hypotheses about mechanism of action. The utility of quantitative trait mapping at the transcript, protein and metabolite level to define association of specific genes with particular variants and further inform disease associations are reviewed. Establishing mechanism of action is an essential step in resolving functional regulatory variants, and this review describes how this is being facilitated by new methods for analyzing allele-specific expression, mapping chromatin interactions and advances in genome editing. Finally, integrative approaches are discussed together with examples highlighting how defining the mechanism of action of regulatory variants and identifying specific modulated genes can maximize the translational utility of genome-wide association studies to understand the pathogenesis of diseases and discover new drug targets or opportunities to repurpose existing drugs to treat them.
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影响因子：
30.8
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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
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Snyder M
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Koller D
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30.8
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Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
通讯作者：
Knight, Julian C.
影响因子：
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作者：
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通讯作者：
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