New Methods to Uncover Global Transcriptional Programs for Disease Risk Variants

描述(由申请人提供)：已发表的1,000多篇GWA报告了200多种性状/疾病的~4,000个SNP的显著关联。挑战是将SNP关联转移到生物学见解，然后转化这些见解，实现更好的临床结果。这一雄心勃勃的目标需要一种包容和有效的战略来解决这些变异导致疾病易感性的分子基础。到目前为止，GWAs中提到的绝大多数疾病表型的关联都与位于基因沙漠中的变异有关，基因沙漠中99%的基因组不编码已知蛋白质，我们对功能后果和因果关系的了解充其量也是最基本的。最近的发现表明，改变进化上保守的非编码区的DNA序列可能与改变编码区一样有害。因此，致病变异将存在于基因沙漠区域也就不足为奇了。在“后GWAS”时代，最大的挑战是理解基因沙漠地区风险变异的调控原则，以及这些基因座潜在的风险机制。这项建议的目标是加速GWA后的功能表征，揭示通过关注改变的功能来描述疾病风险基因座功能的初始全球原则 在基于增强子RNA的作用的转录中。以9p21区域为模型，我们将建立与疾病相关的常见序列变体如何改变调节区的功能，并解决这些影响的分子机制。这些研究将把与疾病易感性相关的序列变异整合到新出现的远距离基因组区域相互作用的三维网络中，建立基因转录的局部和全局变化，并探索在GWAS基因座具有序列变异的增强子-RNA的关键作用。主要的意义将是发现一种新的功能后果和疾病中Gwas基因座背后的“表观基因组”分子机制，有机会利用这些新的机制和治疗见解来预防与衰老相关的慢性疾病。

DESCRIPTION (provided by applicant): More than 1,000 published GWAS have collectively reported significant associations of ~4,000 SNPs for more than 200 traits/diseases. The challenge is to move SNP associations to biological insights and then to translate these insights, achieving better clinical outcomes. This ambitious goal requires an inclusive and effective strategy to solve the molecular basis by which these variants confer disease susceptibility. To date, the vast majority of the associations noted in GWAS for disease phenotypes have been with variants located within gene deserts, the 99% of the genome that does not encode known proteins and where our understanding of functional consequences and causality is at best rudimentary. Recent findings indicate that altering DNA sequence in evolutionarily conserved non-coding regions can be as deleterious as altering coding regions. Therefore, it is not surprising that disease-causing variants will reside in the gene desert regions. The greatest challenge in the "post-GWAS" era is to understand the regulatory principles of risk variants in gene desert regions and the mechanisms underlying the risk conferred by these loci. The goal of this proposal is to accelerate post-GWAS functional characterization, uncovering initial global principles for the functional characterization of disease risk loci by focusing on altered function in transcription based on the actions of enhancer RNAs. Employing the 9p21 region as a model, we will establish how disease-associated common sequence variants alter the functions of regulatory regions and address the molecular mechanisms by which these effects are exerted. These studies will integrate disease susceptibility-associated sequence variations into the emerging three-dimensional network of long-distance genomic region interactions, establish local and global alterations in gene transcription, and explore the key role of enhancer-RNAs harboring sequence variations at GWAS loci. The primary significance will be the discovery of a novel functional consequences and an "epigenomic" molecular mechanism underlying GWAS loci in disease, with the opportunity for exploiting these new mechanistic and therapeutic insights for preventative approaches to the chronic diseases associated with aging.