title: Transcriptome organization for chronic alcohol abuse in human brain.
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.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Farris
authors.affiliation: Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Arasappan
authors.affiliation: Genomic Sequencing and Analysis Facility, University of Texas at Austin, Austin, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hunicke-Smith
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Mayfield
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics; D000437:Alcoholism / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000473:pathology; D002908:Chronic Disease; D019295:Computational Biology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D011180:Postmortem Changes; D059467:Transcriptome / Q000502:physiology*; D062585:Voltage-Gated Sodium Channel beta-4 Subunit / Q000235:genetics*
chemical_list: C477263:SCN4B protein, human; D062585:Voltage-Gated Sodium Channel beta-4 Subunit