Open AccessCross-species alcohol dependence-associated gene networks: Co-analysis of mouse brain gene expression and human genome-wide association data
Author(s) -
Kristin M. Mignogna,
SilviuAlin Bacanu,
Brien P. Riley,
Aaron R. Wolen,
Michael F. Miles
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0202063
Subject(s) - genome wide association study , biology , gene , genetics , genetic association , gene regulatory network , alcohol dependence , genome , ventral tegmental area , regulation of gene expression , gene expression , computational biology , neuroscience , single nucleotide polymorphism , alcohol , dopamine , dopaminergic , biochemistry , genotype
Genome-wide association studies on alcohol dependence, by themselves, have yet to account for the estimated heritability of the disorder and provide incomplete mechanistic understanding of this complex trait. Integrating brain ethanol-responsive gene expression networks from model organisms with human genetic data on alcohol dependence could aid in identifying dependence-associated genes and functional networks in which they are involved. This study used a modification of the Edge-Weighted Dense Module Searching for genome-wide association studies (EW-dmGWAS) approach to co-analyze whole-genome gene expression data from ethanol-exposed mouse brain tissue, human protein-protein interaction databases and alcohol dependence-related genome-wide association studies. Results revealed novel ethanol-responsive and alcohol dependence-associated gene networks in prefrontal cortex, nucleus accumbens, and ventral tegmental area. Three of these networks were overrepresented with genome-wide association signals from an independent dataset. These networks were significantly overrepresented for gene ontology categories involving several mechanisms, including actin filament-based activity, transcript regulation, Wnt and Syndecan-mediated signaling, and ubiquitination. Together, these studies provide novel insight for brain mechanisms contributing to alcohol dependence.