New Methods to Uncover Global Transcriptional Programs for Disease Risk Variants

描述（由申请人提供）：超过1，000个已发表的GWAS共同报告了约4，000个SNP与200多种性状/疾病的显著关联。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个包容性和有效的策略来解决这些变异赋予疾病易感性的分子基础。到目前为止，GWAS中指出的疾病表型的绝大多数关联都与位于基因沙漠中的变异有关，99%的基因组不编码已知的蛋白质，我们对功能后果和因果关系的理解充其量只是初步的。最近的研究结果表明，改变进化保守的非编码区的DNA序列可能与改变编码区一样有害。因此，致病的变异体将存在于基因沙漠区域也就不足为奇了。在“后GWAS”时代的最大挑战是了解基因沙漠区域的风险变异的调控原则和这些位点赋予风险的机制。该提案的目标是加速GWAS后的功能表征，通过关注功能改变，揭示疾病风险位点功能表征的初始全球原则 基于增强子RNA的作用。采用9 p21区域作为模型，我们将建立疾病相关的共同序列变异如何改变调控区的功能，并解决这些作用的分子机制。这些研究将整合疾病易感性相关的序列变异到新兴的长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改变，并探索增强子-RNA在GWAS基因座上携带序列变异的关键作用。主要意义将是发现一种新的功能性后果和疾病中GWAS位点的“表观基因组”分子机制，并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.