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Developmental and genetic regulation of the human cortex transcriptome in schizophrenia

Andrew E Jaffe, Richard E Straub, Joo Heon Shin, Ran Tao, Yuan Gao, Leonardo Collado Torres, Tony Kam-Thong, Hualin S Xi, Jie Quan, Qiang Chen, Carlo Colantuoni, William S Ulrich, Brady J. Maher, Amy Deep-Soboslay, The BrainSeq Consortium, Alan Cross, Nicholas J. Brandon, Jeffrey T Leek, Thomas M. Hyde, Joel E. Kleinman, Daniel R Weinberger
doi: https://doi.org/10.1101/124321
Andrew E Jaffe
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
3Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
4Center for Computational Biology, Johns Hopkins University, Baltimore MD 21205 USA
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  • For correspondence: andrew.jaffe@libd.org
Richard E Straub
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Joo Heon Shin
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Ran Tao
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Yuan Gao
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Leonardo Collado Torres
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
3Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
4Center for Computational Biology, Johns Hopkins University, Baltimore MD 21205 USA
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Tony Kam-Thong
5Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
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Hualin S Xi
6Computational Sciences, Pfizer Inc, Cambridge, MA 02140
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Jie Quan
6Computational Sciences, Pfizer Inc, Cambridge, MA 02140
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Qiang Chen
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Carlo Colantuoni
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
7Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
8Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
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William S Ulrich
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Brady J. Maher
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
9Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
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Amy Deep-Soboslay
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
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Alan Cross
10AstraZeneca Neuroscience iMed, IMED Biotech Unit, Cambridge, MA, 02139 USA
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Nicholas J. Brandon
10AstraZeneca Neuroscience iMed, IMED Biotech Unit, Cambridge, MA, 02139 USA
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Jeffrey T Leek
3Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
4Center for Computational Biology, Johns Hopkins University, Baltimore MD 21205 USA
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Thomas M. Hyde
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
7Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
9Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
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Joel E. Kleinman
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
7Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
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Daniel R Weinberger
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA
8Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
9Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
11McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
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  • For correspondence: drweinberger@libd.org
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Summary

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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 22, 2017.
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Developmental and genetic regulation of the human cortex transcriptome in schizophrenia
Andrew E Jaffe, Richard E Straub, Joo Heon Shin, Ran Tao, Yuan Gao, Leonardo Collado Torres, Tony Kam-Thong, Hualin S Xi, Jie Quan, Qiang Chen, Carlo Colantuoni, William S Ulrich, Brady J. Maher, Amy Deep-Soboslay, The BrainSeq Consortium, Alan Cross, Nicholas J. Brandon, Jeffrey T Leek, Thomas M. Hyde, Joel E. Kleinman, Daniel R Weinberger
bioRxiv 124321; doi: https://doi.org/10.1101/124321
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Developmental and genetic regulation of the human cortex transcriptome in schizophrenia
Andrew E Jaffe, Richard E Straub, Joo Heon Shin, Ran Tao, Yuan Gao, Leonardo Collado Torres, Tony Kam-Thong, Hualin S Xi, Jie Quan, Qiang Chen, Carlo Colantuoni, William S Ulrich, Brady J. Maher, Amy Deep-Soboslay, The BrainSeq Consortium, Alan Cross, Nicholas J. Brandon, Jeffrey T Leek, Thomas M. Hyde, Joel E. Kleinman, Daniel R Weinberger
bioRxiv 124321; doi: https://doi.org/10.1101/124321

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