Using Massively Parallel Reporter Assays to Investigate the Non-Coding Genetics of Brain Disorders

Genome-wide association studies (GWAS) have identified numerous genomic regions associated with psychiatric disorders, yet the vast majority of these loci are within non-coding regions, making it challenging to identify the true causal variants. These regions often span large blocks of linkage disequilibrium (LD), complicating efforts to assign function to individual variants. Massively parallel reporter assays (MPRA) provide a high-throughput method to functionally test thousands of regulatory sequences simultaneously, enabling systematic identification of regulatory variants that influence gene expression.In this dissertation, I apply MPRA to fine-mapped GWAS loci for schizophrenia, to a cross-disorder GWAS encompassing eight psychiatric disorders, and to cortical structure–associated variants using a response-MPRA approach. I use MPRA to prioritize variants with regulatory function and follow up with upstream analyses, such as chromatin accessibility and transcription factor binding motif disruption, and downstream analyses, including variant-gene mapping and CRISPR perturbation to validate gene regulatory relationships. By integrating MPRA with complementary functional genomic tools, this work advances our understanding of how non-coding variants contribute to the etiology of psychiatric disorders and highlights a scalable framework for identifying and validating causal regulatory variants across the genome. I end this dissertation by peering into the future of psychiatric genetics and MPRA.