Developmental And Genetic Regulation Of The Human Cortex Transcriptome In Schizophrenia
Andrew E. Jaffe,
Richard E Straub,
Joo Heon Shin,
Leonardo Collado Torres,
Hualin S Xi,
William S Ulrich,
Brady J. Maher,
The BrainSeq Consortium,
Nicholas J Brandon,
Jeffrey T. Leek,
Thomas M Hyde,
Joel E Kleinman,
Daniel R Weinberger
Posted 05 Apr 2017
bioRxiv DOI: 10.1101/124321 (published DOI: 10.1038/s41593-018-0197-y)
Posted 05 Apr 2017
GWAS have identified 108 loci that confer risk for schizophrenia, but risk mechanisms for individual loci are largely unknown. Using developmental, genetic, and illness-based RNA sequencing expression analysis, 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 post-natal 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 eQTL database to show that 48.1% of risk variants for schizophrenia associated with nearby expression. Within patients and controls, we implemented a novel algorithm for RNA quality adjustment, and identified 237 genes significantly associated with diagnosis that replicated in an independent case-control dataset. These genes implicated synaptic processes and were strongly regulated in early development (p < 10-20). These data offer new targets for modeling schizophrenia risk in cellular systems.
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