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

Autor: Jaffe AE; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. andrew.jaffe@libd.org.; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. andrew.jaffe@libd.org.; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. andrew.jaffe@libd.org.; Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA. andrew.jaffe@libd.org.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. andrew.jaffe@libd.org.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA. andrew.jaffe@libd.org., Straub RE; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA., Shin JH; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA., Tao R; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA., Gao Y; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA., Collado-Torres L; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.; Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA., Kam-Thong T; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Xi HS; Computational Sciences, Pfizer Inc, Cambridge, MA, USA., Quan J; Computational Sciences, Pfizer Inc, Cambridge, MA, USA., Chen Q; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA., Colantuoni C; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA., Ulrich WS; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA., Maher BJ; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA., Deep-Soboslay A; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA., Cross AJ; Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA, USA., Brandon NJ; Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA, USA., Leek JT; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.; Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA., Hyde TM; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Kleinman JE; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA., Weinberger DR; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. drweinberger@libd.org.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2018 Aug; Vol. 21 (8), pp. 1117-1125. Date of Electronic Publication: 2018 Jul 26.
DOI: 10.1038/s41593-018-0197-y
Abstrakt: 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 .
Databáze: MEDLINE
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