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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, Bill 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
Lieber Institute for Brain Development;
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  • For correspondence: andrew.jaffe@libd.org
Richard E Straub
Lieber Institute for Brain Development;
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Joo Heon Shin
Lieber Institute for Brain Development;
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Ran Tao
Lieber Institute for Brain Development;
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Yuan Gao
Lieber Institute for Brain Development;
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Leonardo Collado Torres
Lieber Institute for Brain Development;
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Tony Kam-Thong
Roche;
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Hualin S Xi
Pfizer;
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Jie Quan
Pfizer;
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Qiang Chen
Lieber Institute for Brain Development;
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Carlo Colantuoni
Lieber Institute for Brain Development;
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Bill Ulrich
Lieber Institute for Brain Development;
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Brady J Maher
Lieber Institute for Brain Development;
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Amy Deep-Soboslay
Lieber Institute for Brain Development;
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Alan Cross
AstraZeneca;
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Nicholas J Brandon
AstraZeneca;
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Jeffrey T Leek
Johns Hopkins University
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Thomas M Hyde
Lieber Institute for Brain Development;
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Joel E Kleinman
Lieber Institute for Brain Development;
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Daniel R Weinberger
Lieber Institute for Brain Development;
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Abstract

GWAS have identified over 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. 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). Lastly, we found 42.5% of risk variants associate with nearby genes and diverse transcript features that converge on developmental regulation and subsequent dysregulation in illness and 34 loci show convergent directionality with illness association implicating specific causative transcripts. 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 April 05, 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, Bill 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, Bill 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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