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PLoS One. 2018 Jul 17;13(7):e0200003. doi: 10.1371/journal.pone.0200003. eCollection 2018.

Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis.

Author information

1
Molecular and Behavioral Neuroscience Institute. University of Michigan, Ann Arbor, MI, United States of America.
2
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, United States of America.
3
Genetics, University of Michigan, Ann Arbor, MI, United States of America.
4
University of California Irvine, Irvine, CA, United States of America.
5
HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America.
6
Stanford University, Palo Alto, CA, United States of America.
7
Cornell University, New York, NY, United States of America.

Abstract

Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.

PMID:
30016334
PMCID:
PMC6049916
DOI:
10.1371/journal.pone.0200003
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors are members of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by Pritzker Neuropsychiatric Disorders Research Fund, LLC. A shared intellectual property agreement exists between the academic and philanthropic entities of the consortium. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no competing interests exist.

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