Abstract
Agonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Our study used gene expression data of 262 samples from ROSMAP with the detailed terminal state recorded for each donor, such as fever, infection, and unconsciousness. Fever and infection were the primary contributors to brain gene expression changes, brain cell-type-specific gene expression, and cell proportion changes. Furthermore, we also found that previous studies of gene expression in postmortem brains were confounded by agonal factors. Therefore, correction for agonal factors is important in the step of data preprocessing. 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.
Highlights
Postmortem brain samples are widely used for human genetic studies, primarily for the study of neuropsychiatric disorders such as schizophrenia, bipolar disorders and Alzheimer’s disease (Jaffe, 2016; Wang et al, 2019a)
Differential gene expression (DEG) analysis showed that only fever, infection and unconsciousness were significantly associated with various gene expressions
We present a transcriptomic data analysis of human postmortem brain from a public database, which provides a framework for understanding how different terminal states contribute to gene expression changes in postmortem brain tissue
Summary
Postmortem brain samples are widely used for human genetic studies, primarily for the study of neuropsychiatric disorders such as schizophrenia, bipolar disorders and Alzheimer’s disease (Jaffe, 2016; Wang et al, 2019a). Correcting for the extraneous environmental factors that influence gene expression in postmortem tissue (McCullumsmith et al, 2014) is critical to accurate data analyses One such category of environmental factors, agonal factors, describe the conditions that occur before death. We hypothesize that individual agonal factors uniquely alter postmortem brain gene expression and that successful adjustment of agonal-related variants within gene expression data is necessary and achievable. To investigate this matter, our study included 262 samples of postmortem human brain tissue from the Religious Orders Study and Memory and Aging Project (ROSMAP) study. We performed linear regression analysis to correct for agonal-related surrogate variables and hidden batch effects
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