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

Abstract

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 .

Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex

“…Functional genomic analyses of the developing human brain have revealed highly dynamic spatiotemporal patterns of gene expression and epigenetic changes during prenatal and early postnatal development (Kang et al, 2011;Li et al, 2018). In contrast, these metrics are comparatively stable over several decades of adulthood (Colantuoni et al, 2011;Jaffe et al, 2018;Kang et al, 2011;Li et al, 2018;Pletikos et al, 2014). Disruptions of these developmentally dynamic regulatory processes are likely to be important contributors to multiple neurodevelopmental and neuropsychiatric disorders (Birnbaum and Weinberger, 2017;Breen et al, 2016;Geschwind and Flint, 2015;McCarroll and Hyman, 2013;Rosti et al, 2014;Sestan and State, 2018;Turner and Eichler, 2018).…”

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

“…Consistent with this hypothesis, at a global level, cellular studies emphasise RNA splicing as a key mechanism mediating the effect of disease-associated, non-coding variants in complex disorders, including schizophrenia 6 . Similarly, in human brain, genomic regions associated with schizophrenia are enriched for genes that show differential isoform usage across neurodevelopment 7 , implicating many schizophrenia-associated risk loci in the regulation of the expression of specific RNA transcripts. Consistent with these findings, examples of associations between psychiatric risk-associated loci and the abundance of novel, alternatively spliced transcripts are beginning to emerge [8][9][10] , complementing numerous reports of altered splicing patterns in the brains of psychiatric cases, compared to controls [11][12][13] .…”

Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes

“…A growing body of evidence indicates that genetic variants associated with ASD and SZ manifest their risk during critical periods of early brain development (8,(51)(52)(53).…”