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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH103346-03
Application #
9095441
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Senthil, Geetha
Project Start
2014-06-15
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Southern California
Department
Psychiatry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
Khan, Atlas; Liu, Qian; Wang, Kai (2018) iMEGES: integrated mental-disorder GEnome score by deep neural network for prioritizing the susceptibility genes for mental disorders in personal genomes. BMC Bioinformatics 19:501
Zhu, Ying; Sousa, André M M; Gao, Tianliuyun et al. (2018) Spatiotemporal transcriptomic divergence across human and macaque brain development. Science 362:
Amiri, Anahita; Coppola, Gianfilippo; Scuderi, Soraya et al. (2018) Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science 362:
Rhie, Suhn K; Schreiner, Shannon; Witt, Heather et al. (2018) Using 3D epigenomic maps of primary olfactory neuronal cells from living individuals to understand gene regulation. Sci Adv 4:eaav8550
Toker, Lilah; Mancarci, Burak Ogan; Tripathy, Shreejoy et al. (2018) Transcriptomic Evidence for Alterations in Astrocytes and Parvalbumin Interneurons in Subjects With Bipolar Disorder and Schizophrenia. Biol Psychiatry 84:787-796
Wang, Daifeng; Liu, Shuang; Warrell, Jonathan et al. (2018) Comprehensive functional genomic resource and integrative model for the human brain. Science 362:
Li, Mingfeng; Santpere, Gabriel; Imamura Kawasawa, Yuka et al. (2018) Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science 362:
Bryois, Julien; Garrett, Melanie E; Song, Lingyun et al. (2018) Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nat Commun 9:3121
Gusev, Alexander; Mancuso, Nicholas; Won, Hyejung et al. (2018) Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet 50:538-548
An, Joon-Yong; Lin, Kevin; Zhu, Lingxue et al. (2018) Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science 362:

Showing the most recent 10 out of 19 publications