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Nat Neurosci. 2018 Aug;21(8):1117-1125. doi: 10.1038/s41593-018-0197-y. Epub 2018 Jul 26.

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

Author information

1
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. andrew.jaffe@libd.org.
2
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. andrew.jaffe@libd.org.
3
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. andrew.jaffe@libd.org.
4
Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA. andrew.jaffe@libd.org.
5
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. andrew.jaffe@libd.org.
6
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA. andrew.jaffe@libd.org.
7
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
8
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
9
Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA.
10
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
11
Computational Sciences, Pfizer Inc, Cambridge, MA, USA.
12
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
13
Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
14
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
15
Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA, USA.
16
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. drweinberger@libd.org.
17
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
18
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
19
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
20
Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.

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 .

PMID:
30050107
PMCID:
PMC6438700
DOI:
10.1038/s41593-018-0197-y
[Indexed for MEDLINE]
Free PMC Article

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