Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice

• Published in: PLoS computational biology 2022-02, Vol.18 (2), p.e1009800-e1009800
• Main Authors: Ferguson, Laura B, Roberts, Amanda J, Mayfield, R Dayne, Messing, Robert O
• Format: Article
• Language: English
• Subjects: Alcohol; Alcohol Drinking - genetics; Alcohol use; Alcohol, Denatured; Alcohols; Amygdala; Animals; Antigen presentation; Antigens; Behavior; Biology and Life Sciences; Biomarkers; Blood; Brain; Cell signaling; Dependence; Diagnosis; Discriminant analysis; DNA microarrays; Drug dependence; Drug withdrawal; Ethanol; Ethanol - administration & dosage; Females; Gene Expression; Genetic aspects; Genomes; Glutamic acid receptors; Health aspects; Hypothalamus; Immune response; Laboratory tests; Males; Medical prognosis; Medicine and Health Sciences; Mental disorders; Mice; Mice, Inbred C57BL; Mitochondria; Oxidative phosphorylation; Patients; Peripheral blood; Phosphorylation; Physical Sciences; Physiological aspects; Prefrontal cortex; Ribonucleic acid; RNA; Signaling; Signs and symptoms; Social Sciences; Transcription; Transcriptomes; Ubiquitination; γ-Aminobutyric acid
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1009800

Alcohol Use Disorder (AUD) is a chronic, relapsing syndrome diagnosed by a heterogeneous set of behavioral signs and symptoms. There are no laboratory tests that provide direct objective evidence for diagnosis. Microarray and RNA-Seq technologies enable genome-wide transcriptome profiling at low costs and provide an opportunity to identify biomarkers to facilitate diagnosis, prognosis, and treatment of patients. However, access to brain tissue in living patients is not possible. Blood contains cellular and extracellular RNAs that provide disease-relevant information for some brain diseases. We hypothesized that blood gene expression profiles can be used to diagnose AUD. We profiled brain (prefrontal cortex, amygdala, and hypothalamus) and blood gene expression levels in C57BL/6J mice using RNA-seq one week after chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. We found a high degree of preservation (rho range: [0.50, 0.67]) between blood and brain transcript levels. There was small overlap between blood and brain DEGs, and considerable overlap of gene networks perturbed after CIE related to cell-cell signaling (e.g., GABA and glutamate receptor signaling), immune responses (e.g., antigen presentation), and protein processing / mitochondrial functioning (e.g., ubiquitination, oxidative phosphorylation). Blood gene expression data were used to train classifiers (logistic regression, random forest, and partial least squares discriminant analysis), which were highly accurate at predicting alcohol dependence status (maximum AUC: 90.1%). These results suggest that gene expression profiles from peripheral blood samples contain a biological signature of alcohol dependence that can discriminate between CIE and Air subjects.