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Deconvolving the contributions of cell-type heterogeneity on cortical gene expression

Author

Listed:
  • Ellis Patrick
  • Mariko Taga
  • Ayla Ergun
  • Bernard Ng
  • William Casazza
  • Maria Cimpean
  • Christina Yung
  • Julie A Schneider
  • David A Bennett
  • Chris Gaiteri
  • Philip L De Jager
  • Elizabeth M Bradshaw
  • Sara Mostafavi

Abstract

Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer’s disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs).Author summary: Gene expression data generated from a tissue sample reflects an average gene expression profile across heterogeneous populations of cells. Because composition of constituent cell-types can vary across individuals (due to technical or biological factors), differential gene expression analysis requires estimating and adjusting for such cellular heterogeneity. While many deconvolution algorithms for estimating cellular composition from tissue gene expression data have been tested extensively in blood, their performance when applied to brain tissue is unclear. To address this gap, we generated an immunohistochemistry (IHC) dataset for five major cell-types from brain, in order to apply and then assess deconvolution algorithms for application to brain gene expression datasets. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. Further, we show that adjusting for estimated cell-type proportions across individuals when conducting differential gene expression analysis is important in reducing false associations.

Suggested Citation

  • Ellis Patrick & Mariko Taga & Ayla Ergun & Bernard Ng & William Casazza & Maria Cimpean & Christina Yung & Julie A Schneider & David A Bennett & Chris Gaiteri & Philip L De Jager & Elizabeth M Bradsha, 2020. "Deconvolving the contributions of cell-type heterogeneity on cortical gene expression," PLOS Computational Biology, Public Library of Science, vol. 16(8), pages 1-17, August.
  • Handle: RePEc:plo:pcbi00:1008120
    DOI: 10.1371/journal.pcbi.1008120
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    Cited by:

    1. Yanshuo Chen & Yixuan Wang & Yuelong Chen & Yuqi Cheng & Yumeng Wei & Yunxiang Li & Jiuming Wang & Yingying Wei & Ting-Fung Chan & Yu Li, 2022. "Deep autoencoder for interpretable tissue-adaptive deconvolution and cell-type-specific gene analysis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Aletta M. R. Bosch & Marlijn Poel & Nina L. Fransen & Maria C. J. Vincenten & Anneleen M. Bobeldijk & Aldo Jongejan & Hendrik J. Engelenburg & Perry D. Moerland & Joost Smolders & Inge Huitinga & Jörg, 2024. "Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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