Rebecca E Schmitt1, Brandon C Shell2, Kristen M Lee3, Keith L Shelton4, Laura D Mathies4,5, Alexis C Edwards5,6,7, Mike Grotewiel1,2,3,5. 1. Human Genetics Ph.D. Program, Virginia Commonwealth University, Richmond, Virginia. 2. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. 3. Neuroscience Ph.D. Program, Virginia Commonwealth University, Richmond, Virginia. 4. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia. 5. Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia. 6. Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia. 7. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.
Abstract
BACKGROUND: Self-Rating of the Effects of Alcohol (SRE) measures level of response to ethanol (EtOH) in humans. Interestingly, there is a positive relationship between the SRE and risk for abusing alcohol, suggesting mechanistic connections between SRE and alcohol abuse. METHODS: To identify candidate genes with a role in SRE and alcohol-related behavior more generally, we coupled human genetic analyses with studies in Drosophila melanogaster. We first performed a gene-based analysis of Genomewide association studies (GWAS) summary statistics for SRE in the Avon Longitudinal Study of Parents and Children sample. Based on prior findings in humans, orthology to fly genes, and the availability of genetic reagents, we selected a subset of these genes for studies on EtOH behavior in Drosophila. RESULTS: We found 37 genes with nominal associations in our SRE GWAS. We explored the role of 6 orthologous genes in Drosophila EtOH sedation and rapid tolerance. We found that the transcription factor Mef2 is required for normal EtOH sedation in flies. Pan-neuronal expression of 2 independent Mef2 RNAi transgenes significantly reduced Mef2 expression and made flies resistant to EtOH sedation. Additionally, flies with multiple independent mutant alleles of Mef2 were also resistant to EtOH sedation, confirming a role for Mef2 in this behavior. Altered expression of Mef2 did not change EtOH rapid tolerance or cause a net change in internal EtOH concentrations. CONCLUSIONS: Our studies indicate that MEF2B influences SRE in humans and that Mef2 impacts EtOH sedation in Drosophila.
BACKGROUND: Self-Rating of the Effects of Alcohol (SRE) measures level of response to ethanol (EtOH) in humans. Interestingly, there is a positive relationship between the SRE and risk for abusing alcohol, suggesting mechanistic connections between SRE and alcohol abuse. METHODS: To identify candidate genes with a role in SRE and alcohol-related behavior more generally, we coupled human genetic analyses with studies in Drosophila melanogaster. We first performed a gene-based analysis of Genomewide association studies (GWAS) summary statistics for SRE in the Avon Longitudinal Study of Parents and Children sample. Based on prior findings in humans, orthology to fly genes, and the availability of genetic reagents, we selected a subset of these genes for studies on EtOH behavior in Drosophila. RESULTS: We found 37 genes with nominal associations in our SRE GWAS. We explored the role of 6 orthologous genes in Drosophila EtOH sedation and rapid tolerance. We found that the transcription factor Mef2 is required for normal EtOH sedation in flies. Pan-neuronal expression of 2 independent Mef2 RNAi transgenes significantly reduced Mef2 expression and made flies resistant to EtOH sedation. Additionally, flies with multiple independent mutant alleles of Mef2 were also resistant to EtOH sedation, confirming a role for Mef2 in this behavior. Altered expression of Mef2 did not change EtOH rapid tolerance or cause a net change in internal EtOH concentrations. CONCLUSIONS: Our studies indicate that MEF2B influences SRE in humans and that Mef2 impacts EtOH sedation in Drosophila.
Authors: Stephen F Altschul; John C Wootton; E Michael Gertz; Richa Agarwala; Aleksandr Morgulis; Alejandro A Schäffer; Yi-Kuo Yu Journal: FEBS J Date: 2005-10 Impact factor: 5.542