Human Variation in Alcohol Response Is Influenced by Variation in Neuronal Signaling Genes
Human Variation in Alcohol Response Is Influenced by Variation in Neuronal Signaling Genes
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DOI：
10.1111/j.1530-0277.2010.01152.x
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发表时间：
2010-05-01
影响因子：
3.2
通讯作者：
White, Raymond L.
中科院分区：
文献类型：
--
作者：
Joslyn, Geoff;Ravindranathan, Ajay;White, Raymond L.
背景：酒精使用障碍（AUD）具有遗传复杂性的常见病症和疾病的共同特征。AUDs的病因是异质性的，涉及环境和遗传因素的大多数未知的相互作用。一个人对酒精的反应水平（LR）与家族史和AUD的发展呈负相关。作为一个AUD endophenotype，酒精LR被假设为基因复杂性较低，更接近AUDs的主要病因。方法：一个全基因组关联研究（GWAS）进行的主题，其特征在于酒精LR表型。进行GWAS数据的基因集富集分析（GSEA）以确定作为一组，参与共同生物学功能的基因是否结果：GSEA分析表明神经元信号基因的变异，尤其是谷氨酸信号基因的变异参与了人类群体中酒精LR的变异。结论：这些数据，再加上细胞和动物模型数据暗示神经元信号在酒精反应，支持神经元信号传导机制参与酒精的细胞和行为效应的结论。此外，这些数据表明，这些信号通路中的遗传变异有助于人类对酒精反应的变异。最后，细胞，动物和人类研究结果的一致性支持神经元信号传导，特别是谷氨酸信号传导，作为翻译研究的主要目标，以了解并最终调节酒精的影响。
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.