Schizophrenia and bipolar disorder are neuropsychiatric brain disorders that affect more than 2% of the population worldwide and cause enormous human suffering. Both disorders are highly heritable (>60-80%), but the 100+ loci that have been identified to date collectively do not account for a significant percentage of overall disease causation. A better understanding of gene expression patterns and the role of environmental factors in forming these patterns is crucial. Using cultured neuronal cells derived from olfactory neuroepithelium (CNON) from 50 patients with schizophrenia and 50 healthy controls, we will determine epigenetic chromatin marks in a sample with sufficient statistical power to discover mQTL and ChIP-QTL in developing neurons. Available long RNA-seq (strand-specific ncRNA and mRNA >100bp), small RNA-seq (piRNA and miRNA), and >30x whole genome sequence will be combined with data from NOMe-seq at >18X and ChIP-seq of H3K4me1, H3K4me3, and H3K27Ac. The in- vitro data will be complemented by data from analyses of high-quality, post-mortem adult brains derived from Caucasian males with schizophrenia (SCZ;n=8) or bipolar disorder (BPD;n=8) and normal controls (CTL;n=8). Analyses will include long RNA-seq (strand-specific ncRNA and mRNA >100bp), small RNA-seq (piRNA and miRNA), NOMe-seq at >18X and ChIP-seq of H3K4me1, H3K4me3, and H3K27Ac in dissected sections from the dorsal lateral prefrontal cortex (DLPFC), hippocampus (HIP), amygdala (AMY), dorsal caudate (DC), and the nucleus accumbens (NAc). We will map genomic, transcriptomic and epigenomic changes specific to either brain region or disease and develop an easy-to-use, web-based informatics framework for communication of the raw and computed data of this PsychENCODE project to other neuroscientists.

Public Health Relevance

Schizophrenia and bipolar disorder are highly heritable (genetic) neuropsychiatric brain disorders that affect more than 2% of the population worldwide and cause enormous human suffering. Although about 100 predisposing genes or gene regions have been identified, these account for only a fraction of disease liability. Our research will investigate the control of gene expression by identifying transcriptomic and epigenetic elements in cell lines and tissues derived from the brains of deceased individuals with schizophrenia or bipolar illness. By mapping these elements, we will provide knowledge of the patterns associated with the disorders and hope to begin to understand the cell types, brain regions, and periods of brain development that are impaired in these disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZMH1-ERB-C (03))
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Senthil, Geetha
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University of Southern California
Schools of Medicine
Los Angeles
United States
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