Interpreting GWAS associations in schizophrenia using genome-wide chromatin mapping

 描述(由申请人提供) 在这个项目中，候选人提议从胎儿和成人大脑中构建第一个大脑特定染色质相互作用的全面地图。在这两个时间点生成高质量和高分辨率的染色质相互作用数据集，将有助于解释和区分精神分裂症(SCZ)GWAS的发现。首先，我们将使用Hi-C(分辨率~40kb)在全基因组水平上识别大脑特定的和发育相关的染色质相互作用。其次，我们将使用这些结果来指导使用捕获Hi-C(分辨率~1kb)对单个SCZ Gwas基因座的染色质相互作用进行有针对性的询问。我们将进一步整合来自CommonMind和mental ENCODE等来源的大脑特定信息，希望将SCZ Gwas基因座的子集与特定基因联系起来。第三，我们将整合Hi-C，Capture Hi-C，和SCZ Gwas结果，以确定SNP-基因对的优先顺序，并将使用STAR-SEQ(自转录活性调节区测序)分析来从功能上表征这些分析，并确定关联的方向。这些都是解释SCZ GWAS调查结果的必要实验。除了这项工作固有的科学益处外，该项目还为候选人提供了统计遗传学和功能基因组学方面的广泛培训计划。培训计划增加了朱斯蒂-罗德里格斯博士的神经科学培训，包括技能制作、分析和使用“组学”数据，使她能够跟踪SCZ基因组的发现。此外，该项目将为后续的R01提供丰富的初步数据。

 DESCRIPTION (provided by applicant) In this project, the candidate proposes to construct the first comprehensive map of brain-specific chromatin interactions from fetal and adult brains. Generating high-quality and high-resolution datasets of chromatin interactions at these two time-points will facilitate the interpretation and prioritization of schizophrenia (SCZ) GWAS findings. First, we will identify brain-specific and developmentally-relevant chromatin interactions at a genome-wide level using Hi-C (resolution ~40 kb). Second, we will use these results to guide the targeted interrogation of chromatin interactions at individual SCZ GWAS loci using Capture Hi-C (resolution ~1kb). We will further integrate brain-specific information from sources such as CommonMind and psychENCODE in the hope to connect a subset of SCZ GWAS loci to specific genes. Third, we will integrate Hi-C, Capture Hi-C, and SCZ GWAS results to prioritize SNP-gene pairs, and will use STARR-seq (self-transcribing active regulatory region sequencing) assays to functionally characterize these and identify a direction of association. These are essential experiments for the interpretation of SCZ GWAS findings. In addition to the scientific benefits inherent in this work, this project also provides an extensive training program in statistical genetics and functional genomics for the candidate. The training plan augments Dr. Giusti-Rodríguez' neuroscience training with skills making, analyzing, and using "omics" data to enable her to follow-up SCZ genomic findings. Furthermore, this project will provide a wealth of preliminary data for a subsequent R01.