Cell Reports (Apr 2020)
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,
- André 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
Affiliations
- Donna M. Werling
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA
- Sirisha Pochareddy
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Jinmyung Choi
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Joon-Yong An
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Integrated Biomedical and Life Science, Korea University, Seoul 02841, Republic of Korea; School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul 02841, Republic of Korea
- Brooke Sheppard
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Minshi Peng
- Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Zhen Li
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurosciences, University of California, San Diego, San Diego, CA 92093, USA
- Claudia Dastmalchi
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Gabriel Santpere
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Neurogenomics Group, Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain
- André M.M. Sousa
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Andrew T.N. Tebbenkamp
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Navjot Kaur
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Forrest O. Gulden
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
- Michael S. Breen
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Lindsay Liang
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Michael C. Gilson
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Xuefang Zhao
- Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA
- Shan Dong
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Lambertus Klei
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- A. Ercument Cicek
- Department of Computer Engineering, Bilkent University, Ankara 06800, Turkey; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Joseph D. Buxbaum
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Homa Adle-Biassette
- Department of Pathology, Lariboisière Hospital, APHP, Biobank BB-0033-00064, and Université de Paris, 75006 Paris, France
- Jean-Leon Thomas
- Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA; UMRS1127, Sorbonne Université, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France
- Kimberly A. Aldinger
- Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
- Diana R. O’Day
- Department of Pediatrics, University of Washington, Seattle, WA 98105, USA
- Ian A. Glass
- Department of Pediatrics, University of Washington, Seattle, WA 98105, USA
- Noah A. Zaitlen
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
- Michael E. Talkowski
- Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA
- Kathryn Roeder
- Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Matthew W. State
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94158, USA
- Bernie Devlin
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Stephan J. Sanders
- Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
- Nenad Sestan
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Comparative Medicine, Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration, and Repair and Yale Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Corresponding author
- Journal volume & issue
-
Vol. 31,
no. 1
Abstract
Summary: Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology. : Werling et al. analyze gene expression across the span of human cerebral cortical development and profile the trajectories of individual genes, coordinated groups of genes, and their relationships to disorders. Integration of genetic variation identifies quantitative trait loci that implicate specific genes in loci associated with neuropsychiatric traits and disorders. Keywords: dorsolateral prefrontal cortex, DLPFC, fetal transition, BrainVar, PsychENCODE, prenatal eQTL, RHEBL1, mTOR, LOC101926933 RP11-298I3.1 AL132780.1 ENSG00000257285
