Dataset Information

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

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.

SUBMITTER: Werling DM

PROVIDER: S-EPMC7295160 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Werling Donna M DM Pochareddy Sirisha S Choi Jinmyung J An Joon-Yong JY Sheppard Brooke B Peng Minshi M Li Zhen Z Dastmalchi Claudia C Santpere Gabriel G Sousa André M M AMM Tebbenkamp Andrew T N ATN Kaur Navjot N Gulden Forrest O FO Breen Michael S MS Liang Lindsay L Gilson Michael C MC Zhao Xuefang X Dong Shan S Klei Lambertus L Cicek A Ercument AE Buxbaum Joseph D JD Adle-Biassette Homa H Thomas Jean-Leon JL Aldinger Kimberly A KA O'Day Diana R DR Glass Ian A IA Zaitlen Noah A NA Talkowski Michael E ME Roeder Kathryn K State Matthew W MW Devlin Bernie B Sanders Stephan J SJ Sestan Nenad N

Cell reports 20200401 1

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 ...[more]

PMID: 32268104

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Project description:Regional cellular heterogeneity is a fundamental feature of the human neocortex; however, details of this heterogeneity are still undefined. We used single-nucleus RNA-sequencing to examine cell-specific transcriptional features in the dorsolateral PFC (DLPFC) and the subgenual anterior cingulate cortex (sgACC), regions implicated in major psychiatric disorders. Droplet-based nuclei-capture and library preparation were performed on replicate samples from 8 male donors without history of psychiatric or neurologic disorder. Unsupervised clustering identified major neural cell classes. Subsequent iterative clustering of neurons further revealed 20 excitatory and 22 inhibitory subclasses. Inhibitory cells were consistently more abundant in the sgACC and excitatory neuron subclusters exhibited considerable variability across brain regions. Excitatory cell subclasses also exhibited greater within-class transcriptional differences between the two regions. We used these molecular definitions to determine which cell classes might be enriched in loci carrying a genetic signal in genome-wide association studies or for differentially expressed genes in mental illness. We found that the heritable signals of psychiatric disorders were enriched in neurons and that, while the gene expression changes detected in bulk-RNA-sequencing studies were dominated by glial cells, some alterations could be identified in specific classes of excitatory and inhibitory neurons. Intriguingly, only two excitatory cell classes exhibited concomitant region-specific enrichment for both genome-wide association study loci and transcriptional dysregulation. In sum, by detailing the molecular and cellular diversity of the DLPFC and sgACC, we were able to generate hypotheses on regional and cell-specific dysfunctions that may contribute to the development of mental illness.SIGNIFICANCE STATEMENT Dysfunction of the subgenual anterior cingulate cortex has been implicated in mood disorders, particularly major depressive disorder, and the dorsolateral PFC, a subsection of the PFC involved in executive functioning, has been implicated in schizophrenia. Understanding the cellular composition of these regions is critical to elucidating the neurobiology underlying psychiatric and neurologic disorders. We studied cell type diversity of the subgenual anterior cingulate cortex and dorsolateral PFC of humans with no neuropsychiatric illness using a clustering analysis of single-nuclei RNA-sequencing data. Defining the transcriptomic profile of cellular subpopulations in these cortical regions is a first step to demystifying the cellular and molecular pathways involved in psychiatric disorders.

Dataset Information

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

Publications

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

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