PROJECT SUMMARY Although genome-wide association studies (GWAS) have been extremely successful in identifying numerous germline variants associated to risk for schizophrenia and bipolar disorder, at the vast majority of these loci, the causal mechanism between genetic variation and disease risk remains unknown. This limits the development of novel drug targets and/or personalized treatments. Schizophrenia and bipolar disorder share many genetic risk loci thus motivating approaches to gain insights into the shared molecular basis of these two diseases. Post-GWAS studies are experiencing a “big data” revolution driven by the exponentially decreasing costs of high-throughput genomic assays, including transcriptome levels, epigenetic modifications, and localization of tissue-specific regulatory sites, which are being collected in increasingly large cohorts of individuals. Here we propose a rigorous framework aimed at loci where shared or disease-specific risk for schizophrenia and bipolar disorder is mediated through alteration in gene expression levels, regulated via epigenetic control. To increase power for discovery while also facilitating validation of new findings, we will generate new disease-specific expression and chromatin variation data in subjects with known disease status. We propose to examine risk loci for schizophrenia and bipolar disorder to prioritize causal variants and genes and to validate them in functional assays.