Goltser-Dubner Tanya, Galili-Weisstub Esti, Segman Ronnen H
Department of Psychiatry, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Isr J Psychiatry Relat Sci. 2010;47(1):72-82.
Major depressive disorder (MDD) is a heterogeneous, highly prevalent, and moderately heritable disorder. A complex and diverse genetic-environmental interplay converges to set apart a significant minority that is susceptible to MDD, from among those who experience shorter lived and less recurrent intensive and incapacitating forms of sadness. The major technological advances of deciphering the human genome reference sequence and its common gene variations are beginning to allow cost effective genetic studies of unprecedented scale, applying increasingly denser genome wide mapping to increasingly larger case control samples. This effort is now at the initial stages of unraveling the genetic architecture of several complex phenotypes. Despite a tardy beginning, MDD genetic research is maturing from modest scale candidate gene association studies to include family-based linkage studies, and will soon allow genome wide case control association studies. Replicated risk conferring gene variants discovered so far exert a modest effect size that appears to contribute to overt phenotype expression in the context of a highly intricate concert of interrelated epigenetic and epistatic modifiers. The unraveling of additional previously unimplicated MDD risk conferring genes, that will throw light on molecular mechanisms mediating such susceptibilities, is necessary for progressing beyond current generation monoamine modulating antidepressant drugs. The review outlines basic concepts and current progress briefly overviews major replicated gene findings that to date mostly stem from hypotheses driven candidates, and ends with a discussion of current directives, including sample size and phenotype considerations and advancement of systematic studies of the functional significance of implicated gene variants, beyond their current exploratory stage.
重度抑郁症（MDD）是一种异质性、高度流行且具有中度遗传性的疾病。复杂多样的基因 - 环境相互作用使得少数易患MDD的人从那些经历短暂且较少复发的强烈且使人丧失能力的悲伤情绪的人群中区分出来。解读人类基因组参考序列及其常见基因变异的重大技术进步开始使得开展前所未有的大规模且具有成本效益的基因研究成为可能，即将越来越密集的全基因组图谱应用于越来越大的病例对照样本。这项工作目前正处于揭示几种复杂表型的遗传结构的初始阶段。尽管起步较晚，但MDD基因研究正从适度规模的候选基因关联研究发展到包括基于家系的连锁研究，并且很快将允许进行全基因组病例对照关联研究。迄今为止发现的经复制的赋予风险的基因变异产生的效应大小适中，在高度复杂的相关表观遗传和上位性修饰因子协同作用的背景下，似乎对明显的表型表达有贡献。揭示更多以前未涉及的赋予MDD风险的基因，以阐明介导这种易感性的分子机制，对于超越当前一代单胺调节抗抑郁药物的发展是必要的。本综述概述了基本概念和当前进展，简要回顾了主要的经复制的基因研究结果，这些结果迄今为止大多源于假设驱动的候选基因，并以对当前指导方针的讨论作为结尾，包括样本量和表型考虑因素，以及对所涉及基因变异功能意义的系统研究的进展，目前这些研究已超越探索阶段。
