Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis

• Published in: Nature neuroscience Vol. 21; no. 8; pp. 1117 - 1125
• Main Authors: Jaffe, Andrew E., Straub, Richard E., Shin, Joo Heon, Tao, Ran, Gao, Yuan, Collado-Torres, Leonardo, Kam-Thong, Tony, Xi, Hualin S., Quan, Jie, Chen, Qiang, Colantuoni, Carlo, Ulrich, William S., Maher, Brady J., Deep-Soboslay, Amy, Cross, Alan J., Brandon, Nicholas J., Leek, Jeffrey T., Hyde, Thomas M., Kleinman, Joel E., Weinberger, Daniel R.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2018; Nature Publishing Group
• Subjects: 38; 38/91; 45; 45/91; 631/337/2019; 631/378/340; 631/61/514/1949; Adolescent; Adult; Animal Genetics and Genomics; Autopsy; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Cerebral cortex; Child; Child, Preschool; Chronic Disease; Databases, Genetic; Development and progression; Female; Gene expression; Gene Expression Regulation, Developmental - genetics; Gene sequencing; Genes; Genetic analysis; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic regulation; Genetic Variation; Genetics; Genome-wide association studies; Genomes; Genomics; Genotype; Genotype & phenotype; Health aspects; Humans; Infant; Male; Medical schools; Mental disorders; Neurobiology; Neurosciences; Pathogenesis; Polymorphism, Single Nucleotide; Prefrontal Cortex - growth & development; Prefrontal Cortex - physiopathology; Pregnancy; Quantitative genetics; Quantitative trait loci; Resource; Ribonucleic acid; Risk; Risk factors; RNA; RNA sequencing; Schizophrenia; Schizophrenia - genetics; Schizophrenia - physiopathology; Sequence Analysis, RNA; Transcription; Transcriptome - genetics
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-018-0197-y

Genome-wide association studies have identified 108 schizophrenia risk loci, but biological mechanisms for individual loci are largely unknown. Using developmental, genetic and illness-based RNA sequencing expression analysis in human brain, we characterized the human brain transcriptome around these loci and found enrichment for developmentally regulated genes with novel examples of shifting isoform usage across pre- and postnatal life. We found widespread expression quantitative trait loci (eQTLs), including many with transcript specificity and previously unannotated sequence that were independently replicated. We leveraged this general eQTL database to show that 48.1% of risk variants for schizophrenia associate with nearby expression. We lastly found 237 genes significantly differentially expressed between patients and controls, which replicated in an independent dataset, implicated synaptic processes, and were strongly regulated in early development. These findings together offer genetics- and diagnosis-related targets for better modeling of schizophrenia risk. This resource is publicly available at http://eqtl.brainseq.org/phase1 . The authors surveyed gene expression across cortical development and in individuals with schizophrenia. Three-fold more risk variants influenced expression than known. Risk genes showed developmental regulation, while diagnosis changes implicated largely treatment effects.