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Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex

View ORCID ProfileDonna M. Werling, View ORCID ProfileSirisha Pochareddy, View ORCID ProfileJinmyung Choi, View ORCID ProfileJoon-Yong An, View ORCID ProfileBrooke Sheppard, Minshi Peng, Zhen Li, Claudia Dastmalchi, Gabriel Santpere, Andre M. M. Sousa, View ORCID ProfileAndrew T. N. Tebbenkamp, Navjot Kaur, View ORCID ProfileForrest O. Gulden, View ORCID ProfileMichael S. Breen, Lindsay Liang, Michael C. Gilson, Xuefang Zhao, Shan Dong, View ORCID ProfileLambertus Klei, View ORCID ProfileA. Ercument Cicek, View ORCID ProfileJoseph D. Buxbaum, View ORCID ProfileHoma Adle-Biassette, View ORCID ProfileJean-Leon Thomas, View ORCID ProfileKimberly A. Aldinger, Diana R. O’Day, Ian A. Glass, Noah A. Zaitlen, View ORCID ProfileMichael E. Talkowski, View ORCID ProfileKathryn Roeder, View ORCID ProfileMatthew W. State, View ORCID ProfileBernie Devlin, View ORCID ProfileStephan J. Sanders, View ORCID ProfileNenad Sestan
doi: https://doi.org/10.1101/585430
Donna M. Werling
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
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Sirisha Pochareddy
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
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  • ORCID record for Sirisha Pochareddy
Jinmyung Choi
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
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Joon-Yong An
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
3Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea
4School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea
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Brooke Sheppard
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
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Minshi Peng
5Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Zhen Li
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
6Department of Neurosciences, University of California, San Diego, San Diego, CA 92093, USA
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Claudia Dastmalchi
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
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Gabriel Santpere
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
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Andre M. M. Sousa
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
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Andrew T. N. Tebbenkamp
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
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Navjot Kaur
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
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Forrest O. Gulden
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
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Michael S. Breen
7Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
8Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
9Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Lindsay Liang
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
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Michael C. Gilson
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
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Xuefang Zhao
10Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
11Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
12Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA
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Shan Dong
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
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Lambertus Klei
13Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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  • ORCID record for Lambertus Klei
A. Ercument Cicek
14Department of Computer Engineering, Bilkent University, Ankara, 06800, Turkey
15Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Joseph D. Buxbaum
7Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
8Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
9Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
16Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Homa Adle-Biassette
17Department of Pathology, Lariboisière Hospital, APHP and Paris Diderot University, Sorbonne Paris Cité, Paris, France
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Jean-Leon Thomas
18Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA
19UMRS1127, Sorbonne Université, Institut du Cerveau et de la Moelle épinière, 7, Boulevard de l’Hôpital, 75013 Paris, France
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Kimberly A. Aldinger
20Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA
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Diana R. O’Day
21Department of Pediatrics, the University of Washington, Seattle, WA 98105, USA
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Ian A. Glass
21Department of Pediatrics, the University of Washington, Seattle, WA 98105, USA
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Noah A. Zaitlen
22Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
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Michael E. Talkowski
10Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
11Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
12Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA
23Departments of Pathology and Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
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Kathryn Roeder
5Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
15Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Matthew W. State
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
24Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
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Bernie Devlin
13Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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  • ORCID record for Bernie Devlin
Stephan J. Sanders
1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
24Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
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  • For correspondence: stephan.sanders@ucsf.edu nenad.sestan@yale.edu
Nenad Sestan
2Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
25Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA
26Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
27Department of Comparative Medicine, Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06510, USA
28Program in Cellular Neuroscience, Neurodegeneration, and Repair and Yale Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA
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  • For correspondence: stephan.sanders@ucsf.edu nenad.sestan@yale.edu
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Summary

Variation in gene expression underlies neurotypical development, while genomic variants contribute to neuropsychiatric disorders. BrainVar is a unique resource of paired whole-genome sequencing and bulk-tissue RNA-sequencing from the human dorsolateral prefrontal cortex of 176 neurotypical individuals across prenatal and postnatal development, providing the opportunity to assay genomic and transcriptomic variation in tandem. Leveraging this resource, we identified rare premature stop codons with commensurate reduced and allele-specific expression of corresponding genes, and common variants that alter gene expression (expression quantitative trait loci, eQTLs). Categorizing eQTLs by prenatal and postnatal effect, genes affected by temporally-specific eQTLs, compared to constitutive eQTLs, are enriched for haploinsufficiency, protein-protein interactions, and neuropsychiatric disorder risk loci. Expression levels of over 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell type specific genes and neuropsychiatric disorder loci, underscoring the importance of cataloguing developmental trajectories in understanding cortical physiology and pathology.

Highlights

  • Whole-genome and RNA-sequencing across human prefrontal cortex development in BrainVar

  • Gene-specific developmental trajectories characterize the late-fetal transition

  • Identification of constitutive, prenatal-specific, postnatal-specific, and rare eQTLs

  • Integrated analysis reveals genetic and developmental influences on CNS traits and disorders

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 4.0 International license.
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Posted March 22, 2019.
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Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex
Donna M. Werling, Sirisha Pochareddy, Jinmyung Choi, Joon-Yong An, Brooke Sheppard, Minshi Peng, Zhen Li, Claudia Dastmalchi, Gabriel Santpere, Andre M. M. Sousa, Andrew T. N. Tebbenkamp, Navjot Kaur, Forrest O. Gulden, Michael S. Breen, Lindsay Liang, Michael C. Gilson, Xuefang Zhao, Shan Dong, Lambertus Klei, A. Ercument Cicek, Joseph D. Buxbaum, Homa Adle-Biassette, Jean-Leon Thomas, Kimberly A. Aldinger, Diana R. O’Day, Ian A. Glass, Noah A. Zaitlen, Michael E. Talkowski, Kathryn Roeder, Matthew W. State, Bernie Devlin, Stephan J. Sanders, Nenad Sestan
bioRxiv 585430; doi: https://doi.org/10.1101/585430
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Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex
Donna M. Werling, Sirisha Pochareddy, Jinmyung Choi, Joon-Yong An, Brooke Sheppard, Minshi Peng, Zhen Li, Claudia Dastmalchi, Gabriel Santpere, Andre M. M. Sousa, Andrew T. N. Tebbenkamp, Navjot Kaur, Forrest O. Gulden, Michael S. Breen, Lindsay Liang, Michael C. Gilson, Xuefang Zhao, Shan Dong, Lambertus Klei, A. Ercument Cicek, Joseph D. Buxbaum, Homa Adle-Biassette, Jean-Leon Thomas, Kimberly A. Aldinger, Diana R. O’Day, Ian A. Glass, Noah A. Zaitlen, Michael E. Talkowski, Kathryn Roeder, Matthew W. State, Bernie Devlin, Stephan J. Sanders, Nenad Sestan
bioRxiv 585430; doi: https://doi.org/10.1101/585430

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