Uher R
Institute of Psychiatry, King's College London, London, UK.
Mol Psychiatry. 2008 Dec;13(12):1070-8. doi: 10.1038/mp.2008.92. Epub 2008 Aug 5.
In a number of human diseases, including depression, interactions between genetic and environmental factors have been identified in the absence of direct genotype-disorder associations. The lack of genes with major direct pathogenic effect suggests that genotype-specific vulnerabilities are balanced by adaptive advantages and implies aetiological heterogeneity. A model of depression is proposed that incorporates the interacting genetic and environmental factors over the life course and provides an explanatory framework for the heterogeneous aetiology of depression. Early environmental influences act on the genome to shape the adaptability to environmental changes in later life. The possibility is explored that genotype- and epigenotype-related traits can be harnessed to develop personalized therapeutic interventions. As diagnosis of depression alone is a weak predictor of response to specific treatments, aetiological subtypes can be used to inform the choice between treatments. As a specific application of this notion, a hypothesis is proposed regarding relative responsiveness of aetiological subtypes of depression to psychological treatment and antidepressant medication. Other testable predictions are likely to emerge from the general framework of interacting genetic, epigenetic and environmental mechanisms in depression.
在包括抑郁症在内的多种人类疾病中，在缺乏直接的基因型与疾病关联的情况下，已确定了遗传因素与环境因素之间的相互作用。缺乏具有主要直接致病作用的基因表明，基因型特异性易感性由适应性优势所平衡，这意味着病因具有异质性。本文提出了一种抑郁症模型，该模型纳入了生命过程中相互作用的遗传和环境因素，并为抑郁症的异质性病因提供了一个解释框架。早期环境影响作用于基因组，以塑造对晚年环境变化的适应能力。本文探讨了利用与基因型和表观基因型相关的特征来开发个性化治疗干预措施的可能性。由于仅抑郁症诊断对特定治疗反应的预测能力较弱，病因亚型可用于指导治疗选择。作为这一概念的具体应用，本文提出了一个关于抑郁症病因亚型对心理治疗和抗抑郁药物相对反应性的假设。抑郁症中遗传、表观遗传和环境机制相互作用的一般框架可能会产生其他可检验的预测。
