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Genetic control of gene expression and splicing in the developing human brain

Rebecca L. Walker, Gokul Ramaswami, Christopher Hartl, Nicholas Mancuso, Michael J. Gandal, Luis de la Torre-Ubieta, Bogdan Pasaniuc, Jason L. Stein, Daniel H. Geschwind
doi: https://doi.org/10.1101/471193
Rebecca L. Walker
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USAProgram in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USAInterdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Gokul Ramaswami
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Christopher Hartl
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USAInterdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Nicholas Mancuso
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, 90024
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Michael J. Gandal
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USADepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Luis de la Torre-Ubieta
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USADepartment of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Bogdan Pasaniuc
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, 90024Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Jason L. Stein
Department of Genetics & UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
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Daniel H. Geschwind
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USADepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Summary

Most genetic risk for human diseases lies within non-coding regions of the genome, which is predicted to regulate gene expression, often in a tissue and stage specific manner. This has motivated building of extensive eQTL resources to understand how human allelic variation affects gene expression and splicing throughout the body, focusing primarily on adult tissue. Given the importance of regulatory pathways during brain development, we characterize the genetic control of the developing human cerebral cortical transcriptome, including expression and splicing, in 201 mid-gestational human brains, to understand how common allelic variation affects gene regulation during development. We leverage expression and splice quantitative trait loci to identify genes and isoforms relevant to neuropsychiatric disorders and brain volume. These findings demonstrate genetic mechanisms by which early developmental events have a striking and widespread influence on adult anatomical and behavioral phenotypes, as well as the evolution of the human cerebral cortex.

Highlights

  • Genome wide map of human fetal brain eQTLs and sQTLs provides a new view of genetic control of expression and splicing.

  • There is substantial contrast between genetic control of transcript regulation in mature versus developing brain.

  • We identify novel regulatory regions specific to fetal brain development.

  • Integration of eQTLs and GWAS reveals specific relationships between expression and disease risk for neuropsychiatric diseases and relevant human brain phenotypes.

Copyright 
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 16, 2018.
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Genetic control of gene expression and splicing in the developing human brain
Rebecca L. Walker, Gokul Ramaswami, Christopher Hartl, Nicholas Mancuso, Michael J. Gandal, Luis de la Torre-Ubieta, Bogdan Pasaniuc, Jason L. Stein, Daniel H. Geschwind
bioRxiv 471193; doi: https://doi.org/10.1101/471193
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Genetic control of gene expression and splicing in the developing human brain
Rebecca L. Walker, Gokul Ramaswami, Christopher Hartl, Nicholas Mancuso, Michael J. Gandal, Luis de la Torre-Ubieta, Bogdan Pasaniuc, Jason L. Stein, Daniel H. Geschwind
bioRxiv 471193; doi: https://doi.org/10.1101/471193

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