From GWAS variant to function: A study of ∼148,000 variants for blood cell traits.
From GWAS variant to function: A study of ∼148,000 variants for blood cell traits.
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DOI：
10.1016/j.xhgg.2021.100063
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发表时间：
2022-01-13
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Sun Q;Crowley CA;Huang L;Wen J;Chen J;Bao EL;Auer PL;Lettre G;Reiner AP;Sankaran VG;Raffield LM;Li Y
全基因组关联研究(GWAS)已经确定了数十万个与复杂疾病和特征相关的遗传变异。然而，大多数变种都是非编码的，并且与基因没有明显的联系，这使得解释这些GWAS信号具有挑战性。我们提出了一项系统的从变异到功能的研究，优先选择基因组中最有可能的功能元件进行实验后续研究，发现148,000个变异具有血液学特征。具体地说，我们开发了吸血鬼：指向有趣的监管效果的变体注释方法，这是一个用R shiny实现的交互式Web应用程序。该工具有效地集成和显示来自多个互补来源的信息，包括与血细胞相关的组织或细胞的表观基因组签名、功能和保守性总结分数、对蛋白质和基因表达的变异影响、染色质构象信息以及公开可用的GWAS和表观基因组范围关联研究(PheWAS)结果。利用独立执行的功能验证实验产生的数据，我们证明了我们优先处理的变体、基因或变体-基因链接更有可能得到实验验证。这项研究不仅对系统和有效地揭示血液学变异背后的功能机制具有重要意义，而且还提供了一个可以适应许多其他复杂特征的原型，为有效的变异到功能(V2F)分析铺平了道路。我们开发了吸血鬼：指向有趣的规则效果的变体注释方法，这是一个用R shiny实现的交互式Web应用程序。吸血鬼高效地集成和显示来自多个互补来源的信息。使用来自各种功能实验的数据，我们证明了吸血鬼优先的变体更有可能扮演功能角色。
Genome-wide association studies (GWASs) have identified hundreds of thousands of genetic variants associated with complex diseases and traits. However, most variants are noncoding and not clearly linked to genes, making it challenging to interpret these GWAS signals. We present a systematic variant-to-function study, prioritizing the most likely functional elements of the genome for experimental follow-up, for >148,000 variants identified for hematological traits. Specifically, we developed VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny. This tool efficiently integrates and displays information from multiple complementary sources, including epigenomic signatures from blood-cell-relevant tissues or cells, functional and conservation summary scores, variant impact on protein and gene expression, chromatin conformation information, as well as publicly available GWAS and phenome-wide association study (PheWAS) results. Leveraging data generated from independently performed functional validation experiments, we demonstrate that our prioritized variants, genes, or variant-gene links are significantly more likely to be experimentally validated. This study not only has important implications for systematic and efficient revelation of functional mechanisms underlying GWAS variants for hematological traits but also provides a prototype that can be adapted to many other complex traits, paving the path for efficient variant-to-function (V2F) analyses. We developed VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny. VAMPIRE efficiently integrates and displays information from multiple complementary sources. Using data from various functional experiments, we demonstrated that VAMPIRE-prioritized variants are more likely to play functional roles.
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影响因子：
6
作者：
Crowley C;Yang Y;Qiu Y;Hu B;Abnousi A;Lipiński J;Plewczyński D;Wu D;Won H;Ren B;Hu M;Li Y
通讯作者：
Li Y
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