Implications of genome wide association studies for addiction: are our a priori assumptions all wrong?
Implications of genome wide association studies for addiction: are our a priori assumptions all wrong?
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DOI：
10.1016/j.pharmthera.2013.07.006
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发表时间：
2013-12
影响因子：
13.5
通讯作者：
Uhl, George R.
中科院分区：
文献类型：
--
作者：
Hall, F. Scott;Drgonova, Jana;Jain, Siddharth;Uhl, George R.
来自双胞胎研究、连锁研究、候选基因关联研究和最近的全基因组关联研究（GWAS）的数据支持了成瘾易感性的大量遗传贡献。与此同时，动物研究试图确定可能有助于对成瘾药物和成瘾倾向的反应的基因，最初集中在主要滥用药物的靶基因上。这些研究确定了影响药物滥用反应的基因/蛋白质;然而，这并不一定意味着这些基因的变异有助于成瘾倾向的遗传成分。最初的连锁和候选基因研究的主要问题之一是基于已知的蛋白质对药物作用的贡献，先验地关注被认为与成瘾有关的基因，使得不太可能识别新基因。GWAS的方法是系统的，不可知的这样一个先验假设。从已经完成的大量GWAS中可以得出几个结论：（1）成瘾是高度多基因的;每个等位基因变异都以一种小的、加性的方式对成瘾易感性做出贡献;（2）与我们的先验假设相比，出乎意料的是，基因类别在解释成瘾易感性方面是最重要的;（3）尽管存在大量的遗传异质性，但在特定基因上存在大量的GWAS信号的收敛。本文回顾了这项研究的历史，从最初的基于候选基因和连锁研究的转基因小鼠模型，通过GWAS成瘾和尼古丁戒断的进展，到目前的人类和转基因小鼠研究后GWAS。
Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS.
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