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 CicekJoseph 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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Article number107489
JournalCell Reports
Volume31
Issue number1
DOIs
Publication statusPublished - 2020 Apr 7

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Werling, D. M., Pochareddy, S., Choi, J., An, J. Y., Sheppard, B., Peng, M., Li, Z., Dastmalchi, C., Santpere, G., Sousa, A. M. M., Tebbenkamp, A. T. N., Kaur, N., Gulden, F. O., Breen, M. S., Liang, L., Gilson, M. C., Zhao, X., Dong, S., Klei, L., ... Sestan, N. (2020). Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex. Cell Reports, 31(1), [107489]. https://doi.org/10.1016/j.celrep.2020.03.053