Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits.
Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits.
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DOI：
10.1176/appi.ajp.2010.09101452
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发表时间：
2010-05
期刊：
影响因子：
--
通讯作者：
Moffitt TE
中科院分区：
文献类型：
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作者：
Caspi A;Hariri AR;Holmes A;Uher R;Moffitt TE
暴露在相同环境风险下的人的反应有明显差异的证据表明，遗传易感性的个体差异可能在起作用。这种基因-环境(G×E)相互作用的研究已经获得了势头。在这篇文章中，作者综述了最广泛的研究领域之一：5-羟色胺转运体基因(SLC6A4；也称为5-HTT)启动子区的变异及其对应激敏感性的贡献。这一领域的研究既促进了基础科学的发展，也为研究复杂的疾病和特征提供了更广泛的经验教训。作者评估了关于5-HTT应激敏感性假说的四条证据：1)关于5-HTTLPR(5-HTTLPR)、应激敏感性和人类抑郁症的观察性研究；2)关于5-HTTLPR和与人类应激反应相关的生物学表型的神经科学实验研究；3)非人类灵长类动物中5-HTT变异和应激敏感性的研究；以及4)啮齿类动物的应激敏感性和基因工程5-HTT突变的研究。在此基础上，对G×E研究提出了建议。作者讨论了G×E互作假说如何在大样本和小样本中检验，G×E研究如何在重复基因发现之前和之后进行，G×E研究作为基因发现工具的使用，结构验证在评估G×E研究中的重要性，以及G×E研究对公众理解遗传科学的贡献。
Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (G×E) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for G×E research. The authors discuss how G×E interaction hypotheses can be tested with large and small samples, how G×E research can be carried out before as well as after replicated gene discovery, the uses of G×E research as a tool for gene discovery, the importance of construct validation in evaluating G×E research, and the contribution of G×E research to the public understanding of genetic science.