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Agonal factors distort gene-expression patterns in human postmortem brains
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2020-07-12
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2020_07_liu.pdf
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Agonal factors, the conditions that occur just prior to death, can impact the molecular quality of
postmortem brains, influencing gene expression results. Nevertheless, study designs using
postmortem brain tissue rarely, if ever, account for these factors, and previous studies had not
documented nor adjusted for agonal factors. Our study used gene expression data of 262 samples
from ROSMAP with the following terminal states recorded for each donor: surgery, fever, infection,
unconsciousness, difficulty breathing, and mechanical ventilation. Performed differential gene
expression and weighted gene co-expression network analyses (WGCNA), fever and infection were
the primary contributors to brain gene expression changes. Fever and infection also contributed to
brain cell-type specific gene expression and cell proportion changes. Furthermore, the gene
expression patterns implicated in fever and infection were unique to other agonal factors. We also
found that previous studies of gene expression in postmortem brains were confounded by variables
of hypoxia or oxygen level pathways. Therefore, correction for agonal factors through probabilistic
estimation of expression residuals (PEER) or surrogate variable analysis (SVA) is recommended to
control for unknown agonal factors. Our analyses revealed fever and infection contributing to gene
expression changes in postmortem brains and emphasized the necessity of study designs that
document and account for agonal factors.