Interpreting GWAS associations in schizophrenia using genome-wide chromatin mapping

 描述（由申请人提供） 在这个项目中，候选人建议构建第一个胎儿和成人大脑脑特异性染色质相互作用的综合图谱。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优先考虑精神分裂症（SCZ）GWAS结果。首先，我们将使用Hi-C（分辨率约40 kb）在全基因组水平上识别脑特异性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Capture Hi-C（分辨率约1 kb）在单个SCZ GWAS基因座处靶向询问染色质相互作用。我们将进一步整合来自CommonMind和psychENCODE等来源的大脑特异性信息，希望将SCZ GWAS位点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，以优先考虑SNP-基因对，并将使用STARR-seq（自转录活性调控区测序）分析来功能性表征这些基因并确定关联方向。这些是解释SCZ GWAS发现的必要实验。除了这项工作所固有的科学优势外，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Giusti-Rodríguez博士的神经科学培训，包括制作，分析和使用“组学”数据的技能，使她能够跟进SCZ基因组发现。此外，该项目将为后续R 01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.