Hall F Scott, Chen Yu, Resendiz-Gutierrez Federico
Department of Pharmacology and Experimental Therapeutics, College of Pharmacology and Pharmacological Science, University of Toledo, Toledo, Ohio, USA.
Brain Behav Evol. 2020;95(5):230-246. doi: 10.1159/000516169. Epub 2021 Apr 13.
Drug dependence has long been thought to have a genetic component. Research seeking to identify the genetic basis of addiction has gone through important transitions over its history, in part based upon the emergence of new technologies, but also as the result of changing perspectives. Early research approaches were largely dictated by available technology, with technological advancements having highly transformative effects on genetic research, but the limitations of technology also affected modes of thinking about the genetic causes of disease. This review explores these transitions in thinking about the genetic causes of addiction in terms of the "streetlight effect," which is a type of observational bias whereby people search for something only where it is easiest to search. In this way, the genes that were initially studied in the field of addiction genetics were chosen because they were the most "obvious," and formed current understanding of the biological mechanisms underlying the actions of drugs of abuse and drug dependence. The problem with this emphasis is that prior to the genomic era the vast majority of genes and proteins had yet to be identified, much less studied. This review considers how these initial choices, as well as subsequent choices that were also driven by technological limitations, shaped the study of the genetic basis of drug dependence. While genome-wide approaches overcame the initial biases regarding which genes to choose to study inherent in candidate gene studies and other approaches, genome-wide approaches necessitated other assumptions. These included additive genetic causation and limited allelic heterogeneity, which both appear to be incorrect. Thus, the next stage of advancement in this field must overcome these shortcomings through approaches that allow the examination of complex interactive effects, both gene × gene and gene × environment interactions. Techniques for these sorts of studies have recently been developed and represent the next step in our understanding of the genetic basis of drug dependence.
长期以来，人们一直认为药物依赖具有遗传成分。旨在确定成瘾遗传基础的研究在其发展历程中经历了重要转变，部分是基于新技术的出现，也是观念转变的结果。早期的研究方法很大程度上受制于现有技术，技术进步对基因研究产生了极具变革性的影响，但技术的局限性也影响了对疾病遗传病因的思考方式。本综述从“路灯效应”的角度探讨了在成瘾遗传病因思考方面的这些转变，“路灯效应”是一种观察性偏差，即人们只在最容易寻找的地方寻找某物。通过这种方式，成瘾遗传学领域最初研究的基因是因为它们最“明显”而被选择的，并形成了对滥用药物作用和药物依赖背后生物学机制的当前理解。这种强调的问题在于，在基因组时代之前，绝大多数基因和蛋白质尚未被鉴定出来，更不用说研究了。本综述考虑了这些最初的选择以及同样由技术限制驱动的后续选择如何塑造了药物依赖遗传基础的研究。虽然全基因组方法克服了候选基因研究和其他方法中固有的关于选择哪些基因进行研究的初始偏差，但全基因组方法需要其他假设。这些假设包括加性遗传因果关系和有限的等位基因异质性，而这两者似乎都是不正确的。因此，该领域的下一阶段进展必须通过允许检查复杂交互作用的方法来克服这些缺点，包括基因×基因和基因×环境相互作用。最近已经开发出用于这类研究的技术，它们代表了我们对药物依赖遗传基础理解的下一步。
