Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia

• Published in: Neuron (Cambridge, Mass.) Mass.), 2019-07, Vol.103 (2), p.203-216.e8
• Main Authors: Collado-Torres, Leonardo, Burke, Emily E., Peterson, Amy, Shin, JooHeon, Straub, Richard E., Rajpurohit, Anandita, Semick, Stephen A., Ulrich, William S., Price, Amanda J., Valencia, Cristian, Tao, Ran, Deep-Soboslay, Amy, Hyde, Thomas M., Kleinman, Joel E., Weinberger, Daniel R., Jaffe, Andrew E.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Adults; Age; Aged; Aged, 80 and over; brain; Brain research; Consortia; Cortex (frontal); Datasets; development; DNA methylation; Employees; eQTL; Female; Frontal Lobe - embryology; Frontal Lobe - growth & development; Frontal Lobe - metabolism; Gene expression; Gene Expression Regulation, Developmental - physiology; Gene Ontology; Gene regulation; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Genomics; Hippocampus; Hippocampus - embryology; Hippocampus - growth & development; Hippocampus - metabolism; human; Humans; Male; Medical examiners; Mental disorders; Middle Aged; Prefrontal cortex; Quality control; R&D; regional coherence; Research & development; Ribonucleic acid; RNA; RNA-seq; Sample size; Schizophrenia; Schizophrenia - genetics; Schizophrenia - pathology; Software; Transcription; TWAS; Young Adult
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.05.013

The hippocampus formation, although prominently implicated in schizophrenia pathogenesis, has been overlooked in large-scale genomics efforts in the schizophrenic brain. We performed RNA-seq in hippocampi and dorsolateral prefrontal cortices (DLPFCs) from 551 individuals (286 with schizophrenia). We identified substantial regional differences in gene expression and found widespread developmental differences that were independent of cellular composition. We identified 48 and 245 differentially expressed genes (DEGs) associated with schizophrenia within the hippocampus and DLPFC, with little overlap between the brain regions. 124 of 163 (76.6%) of schizophrenia GWAS risk loci contained eQTLs in any region. Transcriptome-wide association studies in each region identified many novel schizophrenia risk features that were brain region-specific. Last, we identified potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia and offer new insights into potentially causative biology. •Dorsolateral prefrontal cortex and hippocampus gene expression across development•Novel region-specific schizophrenia genetic risk features•Decreased regional functional coherence in schizophrenia•Public brain gene expression and eQTL resource at http://eqtl.brainseq.org/phase2 Collado-Torres et al. describe the BrainSeq Phase II gene expression resource encompassing two brain regions from 551 genotyped individuals spanning the entire human lifespan (286 with schizophrenia). This resource can answer region-specific questions about development and schizophrenia and its genetic risk.