Abstract
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.
Highlights
Alcohol Use Disorder (AUD) is a highly prevalent and costly syndrome with few effective treatments [1,2,3]
Blood gene expression data were used to train classifiers, which were highly accurate at predicting alcohol dependence status. These results suggest that gene expression profiles from peripheral blood samples contain a biological signature of alcohol dependence that can discriminate between chronic intermittent ethanol (CIE) and Air subjects
Recent evidence in mice suggests that brain gene expression profiles can predict disease status as well as predict drugs effective for treating alcoholism
Summary
Alcohol Use Disorder (AUD) is a highly prevalent and costly syndrome with few effective treatments [1,2,3]. AUD like other psychiatric disorders is diagnosed by evaluating a patient’s symptoms and behaviors over time as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM5) [4]. Patients meeting two or more criteria within the last year are considered to have AUD with different degrees of severity. Adding molecular-based criteria would provide useful objective data to refine diagnosis and possibly afford earlier detection of problematic drinking before detrimental medical, legal, or social consequences of AUD appear. There are currently three FDA-approved treatments for AUD: disulfiram, acamprosate, and naltrexone, none of which are effective for all patients. There are no reliable prognostic indicators that predict responses to therapeutic intervention
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