PROJECT SUMMARY Serious mental illness (SMI) that includes schizophrenia (SCZ) and bipolar disorder (BD) are common, complex and debilitating psychiatric disorders that together affect over 2% of the population and carry considerable morbidity, mortality, and personal and societal cost. Over the last decade, large-scale genome wide association studies (GWAS) have identified hundreds of loci contributing to the risk of SCZ and BD. Advancing these statistical associations to causal mechanisms for SMIs is very challenging due to incomplete understanding of the non-coding regulatory mechanisms in the human brain tissue and the local correlation of risk variants. Therefore, a systematic analysis that performs fine-mapping to jointly identify and validate a credible set of causal variants in SMI and molecular features that includes transcripts and regulatory sequences, in relevant tissues and cell types is a critical next step. The overarching goal of our proposal is to leverage genomics and multiscale functional omics (gene expression and epigenome regulation) data and perform fine mapping to detect and validate causal variants, transcripts and regulatory sequences in SMI. In Aim 1, we will perform large-scale trans- ancestry GWAS of SCZ and BD to expand the current repertoire of risk (and resilience) loci and refine the credible sets of causal variants underlying genome-wide significant associations. In Aim 2, we will integrate putative causal variants with multiscale functional omics data from human brain tissue that capture gene expression and epigenome regulation at the bulk, cell type-specific and single cell level to identify credible sets of transcripts and regulatory sequences. In Aim 3, we will functionally validate putative causal variants and regulatory sequences, by using novel approaches that combine massively parallel reporter assays and genome editing in excitatory and inhibitory neurons derived from human induced pluripotent stem cells. Our computational and experimental aims bridge the gap between the fine-mapping of causal variants, the molecular gene- regulatory effects of risk variants on enhancer activity and gene expression and their biological effects at the cellular level. If successful, our project can elucidate the genes, pathways, and mechanisms underlying SCZ and BD, and provide new insights and avenues for therapeutic development.