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

doi:10.1016/j.celrep.2020.03.053

Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex

Cell Rep. 2020 Apr 7;31(1):107489. doi: 10.1016/j.celrep.2020.03.053.

Authors

Donna M Werling¹, Sirisha Pochareddy², Jinmyung Choi², Joon-Yong An³, Brooke Sheppard⁴, Minshi Peng⁵, Zhen Li⁶, Claudia Dastmalchi⁴, Gabriel Santpere⁷, André M M Sousa², Andrew T N Tebbenkamp², Navjot Kaur², Forrest O Gulden², Michael S Breen⁸, Lindsay Liang⁴, Michael C Gilson⁴, Xuefang Zhao⁹, Shan Dong⁴, Lambertus Klei¹⁰, A Ercument Cicek¹¹, Joseph D Buxbaum¹², Homa Adle-Biassette¹³, Jean-Leon Thomas¹⁴, Kimberly A Aldinger¹⁵, Diana R O'Day¹⁶, Ian A Glass¹⁶, Noah A Zaitlen¹⁷, Michael E Talkowski⁹, Kathryn Roeder¹⁸, Matthew W State¹⁹, Bernie Devlin¹⁰, Stephan J Sanders²⁰, Nenad Sestan²¹

Affiliations

¹ 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.
² Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
³ 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.
⁴ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
¹¹ Department of Computer Engineering, Bilkent University, Ankara 06800, Turkey; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
¹² 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.
¹³ Department of Pathology, Lariboisière Hospital, APHP, Biobank BB-0033-00064, and Université de Paris, 75006 Paris, France.
¹⁴ 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.
¹⁵ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
¹⁶ Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
¹⁷ Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁸ Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
¹⁹ 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.
²⁰ 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. Electronic address: stephan.sanders@ucsf.edu.
²¹ 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. Electronic address: nenad.sestan@yale.edu.

Abstract

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.

Keywords: BrainVar; DLPFC; LOC101926933 RP11-298I3.1 AL132780.1 ENSG00000257285; PsychENCODE; RHEBL1; dorsolateral prefrontal cortex; fetal transition; mTOR; prenatal eQTL.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Base Sequence / genetics
Brain / embryology*
Brain / growth & development
Brain / metabolism
Computational Biology / methods*
Databases, Genetic
Exome Sequencing / methods
Genetic Predisposition to Disease / genetics
Genetic Variation / genetics
Genome-Wide Association Study / methods
Genomics / methods
Humans
Phenotype
Polymorphism, Single Nucleotide / genetics
Prefrontal Cortex / metabolism*
Quantitative Trait Loci / genetics
Sequence Analysis, RNA / methods
Transcriptome / genetics
Whole Genome Sequencing / methods

Abstract

Publication types

MeSH terms

Grants and funding