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

The BrainSeq Consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1117-1125
Number of pages9
JournalNature Neuroscience
Volume21
Issue number8
DOIs
StatePublished - Aug 1 2018

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Medical Genetics
Transcriptome
Schizophrenia
Quantitative Trait Loci
RNA Sequence Analysis
Genome-Wide Association Study
Brain
Genes
Protein Isoforms
Databases

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. / The BrainSeq Consortium.

In: Nature Neuroscience, Vol. 21, No. 8, 01.08.2018, p. 1117-1125.

Research output: Contribution to journalArticle

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