Human Variation in Alcohol Response Is Influenced by Variation in Neuronal Signaling Genes

Abstract

Background: Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person's level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs.Methods: A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected.Results: The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population.Conclusions: These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol's cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol's effects.

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

“…The present results are consistent with pharmacological data indicating that the protective effects of AMN082 on ethanol drinking are mediated by mGluR7. From clinical data, a human genome-wide association study that was performed on subjects characterized for alcohol level of response phenotypes has identified glutamate signaling, and mGluR7 (3p26.1-p25.1) in alcohol use disorders (Joslyn et al, 2010). Thus, pharmacological tools aimed at activating mGluR7 might be helpful for preventing excessive drinking of alcohol.…”

PTPRR (protein tyrosine phosphatase, receptor type, R)

“…Like for MDD, the heterogeneous etiology of alcohol use disorders (AUD) predicts a complex interplay of environmental and heritable factors and the latter may include impaired MAP kinase signaling circuits. By combining genome wide association studies (GWAS) and gene set enrichment analyses (GSEA) on subjects characterized for alcohol response level phenotypes, a set of 173 genes that appear relevant for the disorder, among which PTPRR, could be extracted (Joslyn et al, 2010). Several had a reported involvement in alcohol response and addiction, and a specific enrichment for neuronal signaling genes -especially the ones impacting on glutamate signaling -was apparent (Joslyn et al, 2010).…”

“…By combining genome wide association studies (GWAS) and gene set enrichment analyses (GSEA) on subjects characterized for alcohol response level phenotypes, a set of 173 genes that appear relevant for the disorder, among which PTPRR, could be extracted (Joslyn et al, 2010). Several had a reported involvement in alcohol response and addiction, and a specific enrichment for neuronal signaling genes -especially the ones impacting on glutamate signaling -was apparent (Joslyn et al, 2010). Analogous to STEP (Baum et al, 2010), PTPRR may modulate AMPA and NMDA receptor levels and as such is an appealing genetic component for the modulation of alcohol's effects.…”

Further Analyses of Genetic Association Between GRM8 and Alcohol Dependence Symptoms Among Young Adults

“…Many of these genes were found to contribute to the variation in the level of response to alcohol. The genes that were associated with variations in the level of response to alcohol showed enrichment for genes that were also involved in glutamate signaling, suggesting that this type of signaling may modulate the effects of alcohol (Joslyn et al, 2010).…”

“…GRM8 has emerged as a gene of interest with respect to a possible role in the development of alcohol dependence (Chen et al, 2009;Edenberg et al, 2010;Joslyn et al, 2010). GRM8 is a metabotropic glutamate receptor that maps to chromosome 7q31.3-q32, spanning over 800 kb, and is composed of 11 exons.…”