Comorbidities, Confounders, and the White Matter Transcriptome in Chronic Alcoholism
Version of Record online: 24 JAN 2014
Copyright © 2014 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 38, Issue 4, pages 994–1001, April 2014
How to Cite
Sutherland, G. T., Sheedy, D., Sheahan, P. J., Kaplan, W. and Kril, J. J. (2014), Comorbidities, Confounders, and the White Matter Transcriptome in Chronic Alcoholism. Alcoholism: Clinical and Experimental Research, 38: 994–1001. doi: 10.1111/acer.12341
- Issue online: 9 APR 2014
- Version of Record online: 24 JAN 2014
- Manuscript Accepted: 18 NOV 2013
- Manuscript Received: 11 SEP 2013
- NIAAA. Grant Number: R24AA012725
- NHMRC. Grant Number: #401551
- University of Sydney
- Schizophrenia Research Institute
- NSW Department of Health
- Human Postmortem Brain Tissue;
- Hepatic Encephalopathy;
- RNA Quality
Alcohol abuse is the world's third leading cause of disease and disability, and one potential sequel of chronic abuse is alcohol-related brain damage (ARBD). This clinically manifests as cognitive dysfunction and pathologically as atrophy of white matter (WM) in particular. The mechanism linking chronic alcohol intoxication with ARBD remains largely unknown but it is also complicated by common comorbidities such as liver damage and nutritional deficiencies. Liver cirrhosis, in particular, often leads to hepatic encephalopathy (HE), a primary glial disease.
In a novel transcriptomic study, we targeted the WM only of chronic alcoholics in an attempt to tease apart the pathogenesis of ARBD. Specifically, in alcoholics with and without HE, we explored both the prefrontal and primary motor cortices, 2 regions that experience differential levels of neuronal loss.
Our results suggest that HE, along with 2 confounders, gray matter contamination, and low RNA quality are major drivers of gene expression in ARBD. All 3 exceeded the effects of alcohol itself. In particular, low-quality RNA samples were characterized by an up-regulation of translation machinery, while HE was associated with a down-regulation of mitochondrial energy metabolism pathways.
The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non-HE alcoholics had widespread but only subtle changes in gene expression in their WM. Notwithstanding the latter result, this study demonstrates that significant confounders in transcriptomic studies of human postmortem brain tissue can be identified, quantified, and “removed” to reveal disease-specific signals.