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Transcriptome organization for chronic alcohol abuse in human brain

Molecular Psychiatry volume 20, pages 1438–1447 (2015)Cite this article

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Abstract

Alcohol dependence is a heterogeneous psychiatric disorder characterized by high genetic heritability and neuroadaptations occurring from repeated drug exposure. Through an integrated systems approach we observed consistent differences in transcriptome organization within postmortem human brain tissue associated with the lifetime consumption of alcohol. Molecular networks, determined using high-throughput RNA sequencing, for drinking behavior were dominated by neurophysiological targets and signaling mechanisms of alcohol. The systematic structure of gene sets demonstrates a novel alliance of multiple ion channels, and related processes, underlying lifetime alcohol consumption. Coordinate expression of these transcripts was enriched for genome-wide association signals in alcohol dependence and a meta-analysis of alcohol self-administration in mice. Further dissection of genes within alcohol consumption networks revealed the potential interaction of alternatively spliced transcripts. For example, expression of a human-specific isoform of the voltage-gated sodium channel subunit SCN4B was significantly correlated to lifetime alcohol consumption. Overall, our work demonstrates novel convergent evidence for biological networks related to excessive alcohol consumption, which may prove fundamentally important in the development of pharmacotherapies for alcohol dependence.

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Acknowledgements

The authors acknowledge the Texas Advanced Computing Center (TACC) at the University of Texas at Austin for providing computing resources. The authors are grateful to the New South Wales Tissue Resource Centre at the University of Sydney for providing human brain samples; the Centre is supported by the National Health and Medical Research Council of Australia, Schizophrenia Research Institute and National Institute on Alcohol Abuse and Alcoholism (NIH/NIAAA R24AA012725). This work was supported by funding through the National Institute on Alcohol Abuse and Alcoholism and the Integrative Neuroscience Initiative on Alcoholism (INIA-West): AA013517, AA012404, AA020926, AA019382 and AA007471.

Author Contributions

SPF analyzed data and wrote the manuscript; DA, SH-S and RDM performed sequencing and mapping of collected sequence reads; and RAH and RDM assisted in experimental design, manuscript writing, and coordination of the collection and preparation for all experimental samples.

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Authors and Affiliations

  1. Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA

    S P Farris, R A Harris & R D Mayfield

  2. Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX, USA

    D Arasappan

  3. Genomic Sequencing and Analysis Facility, University of Texas at Austin, Austin, TX, USA

    S Hunicke-Smith

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Correspondence to R D Mayfield.

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Submission Classification: Biological Sciences—Neuroscience, Medical Sciences, Genetics.

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Farris, S., Arasappan, D., Hunicke-Smith, S. et al. Transcriptome organization for chronic alcohol abuse in human brain. Mol Psychiatry 20, 1438–1447 (2015). https://doi.org/10.1038/mp.2014.159

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