Understanding gene regulation in schizophrenia-associated loci using high-throughput epigenetic CRISPR screens

ABSTRACT: Although schizophrenia (SCZ) is highly heritable, the genetic underpinnings of SCZ are largely unknown. Over the last decade, genome wide association (GWA) studies have made huge strides in identifying non-coding loci associated with increased risk of SCZ. However, our ability to interpret this data and identify causal variants has significantly lagged behind our ability to identify associations with this disorder. Work in our lab utilizes CRISPR-Cas9 technologies to dissect disease-associated variants and loci at large scale to determine if they function in gene regulation. Our current goal is to utilize high-throughput CRISPR screens to characterize SCZ-associated variants that map within regulatory elements and link them to their target genes. This proposal outlines the use of epigenetic CRISPR screens to dissect SCZ-associated loci that have been detected by both common variant GWA and rare variant whole exome sequencing (WES) studies, as well as loci that contain a single gene. Successful completion of this work will provide a mechanistic understanding of SCZ GWA regions and will provide an optimized strategy for tackling complex disease genetics.