Human Genetics Ph.D. Program, Virginia Commonwealth University, Richmond, Virginia.
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
Alcohol Clin Exp Res. 2019 Sep;43(9):1872-1886. doi: 10.1111/acer.14138. Epub 2019 Jul 16.
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.
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.
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.
Our studies indicate that MEF2B influences SRE in humans and that Mef2 impacts EtOH sedation in Drosophila.
自我评估酒精效应（SRE）测量人类对乙醇（EtOH）的反应水平。有趣的是，SRE 与酗酒风险呈正相关，这表明 SRE 与酗酒之间存在机制联系。
为了确定在 SRE 和更广泛的酒精相关行为中起作用的候选基因，我们将人类遗传分析与果蝇（Drosophila melanogaster）研究相结合。我们首先对 SRE 在雅芳纵向父母与子女研究样本中的全基因组关联研究（GWAS）汇总统计数据进行基于基因的分析。基于人类的先前发现、与苍蝇基因的同源性以及遗传试剂的可用性，我们选择了这些基因中的一部分进行了关于果蝇乙醇行为的研究。
我们在 SRE GWAS 中发现了 37 个具有名义关联的基因。我们探索了 6 个同源基因在果蝇乙醇镇静和快速耐受中的作用。我们发现转录因子 Mef2 是果蝇正常乙醇镇静所必需的。2 个独立的 Mef2 RNAi 转基因的全神经元表达显著降低了 Mef2 的表达，使果蝇对乙醇镇静产生抗性。此外，具有多个独立 Mef2 突变等位基因的果蝇也对乙醇镇静产生抗性，证实了 Mef2 在这种行为中的作用。Mef2 的表达改变并没有改变乙醇快速耐受或导致内部乙醇浓度的净变化。
我们的研究表明，MEF2B 影响人类的 SRE，而 Mef2 影响果蝇的乙醇镇静。
