The genetics of addiction.
The genetics of addiction.
复制标题
成瘾的遗传学。
DOI：
10.1007/s00439-012-1173-3
复制
发表时间：
2012
期刊：
影响因子：
5.3
通讯作者：
Muenke,Maximilian
中科院分区：
文献类型：
--
作者：
Volkow,NoraD;Muenke,Maximilian
Nichols和Hsiao（1967）在他们关于成功地选择性繁殖对吗啡成瘾具有高或低易感性的大鼠品系的报告的最后推测，尽管“我们还没有分离出导致成瘾易感性差异的因素，但其中一个因素似乎是代代相传的。尽管“一个因素”的概念非常乐观，但这项开创性的研究为成瘾的遗传性质提供了最早的实验证据之一。40年后，由于流行病学和遗传学研究的发现，成瘾“在家庭中运行”的一般概念是无可争议的，但对遗传对成瘾的贡献的时间，强度和偶然性的嘲弄仍然是具有挑战性的研究的焦点。通常很难在遗传/基因组变异与患复杂疾病的风险之间建立因果关系。造成这种情况的因素有很多：多种常见的基因变异，影响很小，遗传变异（上位性）和表型严重性之间的非线性相互作用，基因-基因相互作用的复杂网络，以及由不同基因变异引起的相似表型，仅举几例。在物质使用障碍（SUD）的情况下，复杂的环境因素对大脑过程发挥的强大调节作用，进一步混淆了图片，特别相关。这是因为，在没有药物暴露的情况下，这本身就是一个环境因素，即使存在压倒性的遗传负荷，特定的成瘾表型也会隐藏起来。另一方面，部分由遗传因素决定的大脑发育和结构可能会受到药物暴露的影响。这种双向互动突出了基因在人类大脑发育中的重要性，以及在随后出现的人格风格和情感和行为反应中的功能。事实上，多学科的证据表明，“成瘾遗传学”这个简单的概念掩盖了一系列密集的不同交织层的存在，基因、发育过程和环境因素相互作用，增加或减少SUD的风险（图1a）。在这期特刊中，我们试图将不同但互补的研究策略汇集在一起，其最终目标是更好地了解基因如何促成SUD，包括它们对决定成瘾疾病是否以及如何表现的各个层面的影响（图1 B）。在本介绍中，我们使用术语成瘾而不是DSM IV中描述的术语“依赖”，以避免与身体依赖混淆，后者在神经生物学和临床上与成瘾不同。我们把成瘾称为一种表现型，其特征是强迫性地服用药物，尽管对个体有不良后果，但对药物的摄入失去控制。请注意，虽然相关，但我们没有纳入关于基因在大脑发育中作用的论文;对该主题感兴趣的读者可以参考文献中的各种已发表评论（Toga and Thompson 2005; Hariri 2009; Jedema et al. 2010; Mochida and沃尔什2004）。
At the end of their report on the successful selective breeding of rat strains with either high or low susceptibilities to morphine addiction, Nichols and Hsiao (1967) conjecture that, although ‘‘we have not yet isolated the factors responsible for the difference in addiction liability, one factor seems to be passed on from generation to generation.’’That quaintly optimistic notion of ‘‘one factor’’notwithstanding, this seminal study offers one of the earliest pieces of experimental evidence for the hereditary nature of addiction. Forty years later, and thanks to the findings from epidemiology and genetics studies, the general concept that addiction ‘‘runs in families’’is beyond dispute, but teasing apart the timing, strength and contingent nature of the genetic contribution to addiction remains the focus of challenging research. It is typically difficult to establish causal relationships between genetic/genomic variation and the risk of suffering from complex diseases. The factors that contribute to this are many: multiple common gene variants with small effects, non-linear interactions between genetic variants (epistasis) and phenotype severity, complex networks of gene–gene interactions, and similar phenotypes arising from distinct gene variants, just to name a few. In the case of substance use disorders (SUD), the powerful modulatory role played by complex environmental factors on brain processes, which further muddle the picture, is particularly relevant. This is because, in the absence of drug exposure, itself an environmental factor, the specific addiction phenotype would remain hidden, even in the presence of an overwhelming genetic load. On the other hand, brain development and architecture, which are partly determined by genetic factors, can be affected by exposure to drugs. These two-way interactions highlight the importance of genes involved in human brain development and function in the subsequent emergence of personality styles and of emotional and behavioral reactivities. Indeed, multidisciplinary evidence reveals that the deceivingly simple concept of ‘‘genetics of addiction’’belies the existence of a dense array of different interwoven layers whereupon genes, developmental processes, and environmental factors interact to increase or decrease the risk for SUD (Fig. 1 a). In this special issue we have attempted to bring together different yet complementary research strategies whose ultimate goal is to better understand how genes contribute to SUD, including their effects on the various layers that determine whether and how the disease of addiction will be manifested (Fig. 1 b). In this introduction we use the term addiction rather than the term ‘‘dependence’’as described in DSM IV to avoid confusion with physical dependence, which is neurobiologically and clinically distinct from addiction. We refer to addiction as the phenotype characterized by the compulsive administration of the drug and the loss of control over its intake despite its adverse consequences to the individual. Note that, while relevant, we have not included a paper on the role of genes in brain development; readers interested in this topic are referred to various published reviews in the literature (Toga and Thompson 2005; Hariri 2009; Jedema et al. 2010; Mochida and Walsh 2004).