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Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits

View ORCID ProfileNil Aygün, Angela L. Elwell, Dan Liang, Michael J. Lafferty, Kerry E. Cheek, Kenan P. Courtney, Jessica Mory, Ellie Hadden-Ford, Oleh Krupa, Luis de la Torre-Ubieta, Daniel H. Geschwind, Michael I. Love, View ORCID ProfileJason L. Stein
doi: https://doi.org/10.1101/2020.10.21.349019
Nil Aygün
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • ORCID record for Nil Aygün
Angela L. Elwell
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Dan Liang
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Michael J. Lafferty
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Kerry E. Cheek
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Kenan P. Courtney
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Jessica Mory
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Ellie Hadden-Ford
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Oleh Krupa
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Luis de la Torre-Ubieta
3Neurogenetics Program, Department of Neurology, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095, USA
4Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095, USA
5Department of Human Genetics, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095, USA
6Department of Psychiatry and Biobehavioral Sciences, Semel Institute, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095, USA
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Daniel H. Geschwind
3Neurogenetics Program, Department of Neurology, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095, USA
4Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095, USA
5Department of Human Genetics, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095, USA
6Department of Psychiatry and Biobehavioral Sciences, Semel Institute, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095, USA
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Michael I. Love
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
7Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Jason L. Stein
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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  • ORCID record for Jason L. Stein
  • For correspondence: jason_stein@med.unc.edu
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Summary

Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing is mainly performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements of cells present during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs and allele specific expression in primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74). Using colocalization and TWAS, we uncover cell-type specific regulatory mechanisms underlying risk for these traits.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵8 Lead Contact: jason_stein{at}med.unc.edu

  • Author affiliations updated Supplementary table 8 updated Main text for Figure 7 updated Supplementary Figure 7B updated Three references included

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 4.0 International license.
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Posted October 28, 2020.
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Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits
Nil Aygün, Angela L. Elwell, Dan Liang, Michael J. Lafferty, Kerry E. Cheek, Kenan P. Courtney, Jessica Mory, Ellie Hadden-Ford, Oleh Krupa, Luis de la Torre-Ubieta, Daniel H. Geschwind, Michael I. Love, Jason L. Stein
bioRxiv 2020.10.21.349019; doi: https://doi.org/10.1101/2020.10.21.349019
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Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits
Nil Aygün, Angela L. Elwell, Dan Liang, Michael J. Lafferty, Kerry E. Cheek, Kenan P. Courtney, Jessica Mory, Ellie Hadden-Ford, Oleh Krupa, Luis de la Torre-Ubieta, Daniel H. Geschwind, Michael I. Love, Jason L. Stein
bioRxiv 2020.10.21.349019; doi: https://doi.org/10.1101/2020.10.21.349019

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