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-Rodrguez' 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.
The goal of this study is to generate high-resolution chromatin interaction data from fetal and adult brain in order to interpret and prioritize findings from schizophrenia genome-wide association studies (GWAS). Large- scale connection of GWAS regions to specific genes could yield 'actionable' findings, which may lead to the development of more targeted therapies.
