SA109: CROSS-SPECIES ANALYSIS OF ALCOHOL-REGULATED AND DEPENDENCE-ASSOCIATED GENE NETWORKS IN THE VENTRAL TEGMENTAL AREA

Abstract

Background Despite studies suggesting that Alcohol Dependence (AD) is moderately heritable, Genome-Wide Association Studies (GWAS) on AD lack power for detecting the small contribution of individual genes to risk, and the ability to determine their mechanistic role in this complex disorder. Gene co-expression networks provide information about the mechanistic framework through which genetic variants take their effects on AD. Studying gene expression in human brains can be problematic. However, studies have identified significantly ethanol-associated gene networks in mice. Direct integration of human GWAS and Protein-Protein Interaction (PPI) data with mouse gene expression data has the potential to identify novel associated loci and the mechanistic frameworks through which they function. We therefore believe that this co-analysis will identify such loci and networks, and that these networks will reflect results of other GWAS s. Methods The present analysis used Edge-Weighted dense module searching for Genome-Wide Association Studies (EW-dmGWAS) to co-analyze GWAS data from the Irish Affected Sib-Pair Study of Alcohol Dependence, human PPI data, and acute-ethanol-exposed mouse gene expression data, to identify and prioritize ethanol-regulated gene networks (i.e. modules) with respect to AD risk contribution. Expression data was obtained from the Ventral Tegmental Area (VTA), due to its role in reward pathways, and previous findings of significantly ethanol-regulated networks in this region. To validate our results, we tested modules for overrepresentation of genes with nominal GWAS p-values from an alternative GWAS dataset (Avon Longitudinal Study of Parents and Children; ALSPAC). To determine the functional relatedness of genes within significantly overrepresented modules, we analyzed their functional enrichment using ToppGene. Finally, to specifically assess the prioritization of modules, we examined the association of module scores with ALSPAC p-values. Results Of the 276 significantly alcohol-associated modules, 25 of them contained at least one gene with nominal significance in ALSPAC. One of these modules showed significant overrepresentation of these genes, after correction for multiple testing (p=0.006). This module showed functional enrichment for genes associated with ubiquitination, abnormal glial and muscle cell morphology, and neuron degeneration. Finally, module scores was significantly, negatively associated with ALSPAC p-value (β=-2.05, p=0.003) (meaning higher module scores indicated smaller p-values). Discussion The results indicate that integration of mouse gene expression data and human genetic data via EW-dmGWAS allows identification of novel alcohol-associated gene networks in the VTA, and that the resulting scores successfully prioritize these modules with respect to association with risk for AD. This suggests that these modules are bridging the gap between the disparate results of independent GWAS s, and that some of the relevant mechanisms involve dopaminergic reward pathways relevant to the early stages of AD development. One of these modules was significantly overrepresented with nominally significant genes from that dataset, indicating that it is of particular importance. The functional enrichment of its constituent genes suggests that the Ventral Tegmental Area is associated with AD by way of alcohol-regulated pathways involving neuron degeneration via ubiquitination.