Utilizing circRNA transcriptomics for functional characterization of psychiatric GWAS

PROJECT SUMMARY/ABSTRACT Psychiatric disorders pose intricate challenges to individuals’ well-being, with their underlying molecular causes and pathophysiological mechanisms remaining elusive. Genome-wide association studies (GWAS) have provided valuable insights into the genetic associations of psychiatric disorders. However, translating these associations into specific causal driver variants and genes to unravel the underlying molecular mechanisms remains a significant challenge. Recent advancements in genetic-based imputation have enabled the inference of genetically- regulated components of trascriptomics from genome-wide genotype data. Our research team has successfully utilized brain-specific transcriptomic imputation approaches across psychiatric disorders to identify novel genes and pathways associated with risk. Here, we aim to further enhance our understanding of psychiatric disorders by performing transcriptome-wide association studies (TWAS) on circular RNAs (circRNA) transcriptomics. CircRNAs are formed through back splicing and exhibit functional importance. Their unique circular structure and enhanced stability make them intriguing candidates for studying gene expression regulation in physiological and pathological conditions. However, their involvement in psychiatric disorders is understudied and their integration with GWAS studies remains unexplored. In Aim 1, we will construct genetically regulated circRNA expression models using RNAseq ribo-depleted libraries of postmortem brain tissues, encompassing diverse ancestries and multiple brain regions. In Aim 2, we will integrate GWAS data with circRNA expression profiles using TWAS to identify disease-relevant genes and pathways influenced by circRNA dysregulation. This integrative approach will enhance our understanding of the molecular mechanisms underlying psychiatric disorders and provide valuable insights into the functional implications of circRNA dysregulation. Ultimately, this research has the potential to transform our understanding of the molecular basis of psychiatric disorders and pave the way for precision medicine strategies in psychiatric care.