Project Summary/Abstract The candidate for this Mentored Career Development Award is a board certified psychiatrist with a Ph.D. in Biochemistry and Molecular Genetics, with extensive training in the theory of molecular genetics and its application to the treatment and research of psychiatric disorders. To achieve independence, the candidate requires training in statistics and bioinformatics, and this proposal will allow him to achieve his short-term career goal of developing expertise in these fields. Through research experience, formal study, and mentorship under Drs. Manolis Kellis, Francine Benes, Joseph Coyle, Schahram Akbarian, and Chris Cowan, the candidate will develop the expertise needed to achieve his long-term goal of developing and maintaining a successful independent research program investigating the epigenomic causes and potential treatments of schizophrenia (SZ) and bipolar disorder (BD). SZ and BD are highly prevalent illnesses that strike individuals in their early adulthood and often result in a lifetime of severe disability, placing an enormous burden on individuals, families, and society as a whole. The studies proposed here will improve our understanding of the mechanisms that cause these disorders, with the goal of discovering more effective treatments. GABAergic neurotransmission is dysfunctional in these disorders, and this dysfunction is specific to discrete locations within the hippocampus of affected individuals. Recent work shows that changes in DNA methylation of particular genes are involved with this site-specific GABAergic dysfunction. The current proposal will test the hypothesis that these DNA methylation changes are specific to neurons (as opposed to non-neuronal cells) within affected circuits, and that histone modification is also a factor in these phenomena. To test these hypotheses, the candidate will perform experiments using the Illumina MethylationEPIC BeadChip and methylated histone chromatin immunoprecipitation sequencing. These methods will be used to measure changes in DNA methylation and histone methylation in chromatin samples specific to neurons or non-neuronal cells collected from discrete loci within the circuitry of postmortem human hippocampus of individuals with SZ, BD, or healthy control subjects. These highly refined samples will be generated using microscopic dissection to obtain tissue from specific regions of the hippocampus, and then fluorescence- activated cell sorting to isolate neuronal and non-neuronal nuclei prior to chromatin extraction. Genome-wide DNA and histone methylation datasets will be made publicly available. These studies will be conducted at McLean Hospital, a psychiatric hospital affiliated with Harvard Medical School. McLean Hospital is the top-ranked psychiatric hospital in the nation (US News & World Report 2015), and hosts a world-class research program, as well as the Harvard Brain Tissue Resource Center, a national resource that will provide tissue for these studies. McLean Hospital, Harvard Medical School, and the Boston area host a wide array of resources that the candidate will make use of to maximize the opportunities afforded by this Career Development Award.