BRAIN Laboratory, Department of Psychology, Washington University in St. Louis, Box 1125, One Brookings Drive, St. Louis, MO 63130, USA.
Neurobiol Dis. 2013 Apr;52:12-23. doi: 10.1016/j.nbd.2012.05.007. Epub 2012 Jun 1.
Major depressive disorder (MDD) is etiologically complex and has a heterogeneous presentation. This heterogeneity hinders the ability of molecular genetic research to reliably detect the small effects conferred by common genetic variation. As a result, significant research efforts have been directed at investigating more homogenous intermediate phenotypes believed to be more proximal to gene function and lie between genes and/or environmental effects and disease processes. In the current review we survey and integrate research on two promising intermediate phenotypes linked to depression: reward processing and stress sensitivity. A synthesis of this burgeoning literature indicates that a molecular genetic approach focused on intermediate phenotypes holds significant promise to fundamentally improve our understanding of the pathophysiology and etiology of depression, which will be required for improved diagnostic definitions and the development of novel and more efficacious treatment and prevention strategies. We conclude by highlighting challenges facing intermediate phenotype research and future development that will be required to propel this pivotal research into new directions.
重度抑郁症(MDD)的病因复杂,临床表现异质性大。这种异质性阻碍了分子遗传学研究可靠地检测常见遗传变异所带来的微小影响。因此,大量的研究工作都集中在研究被认为更接近基因功能的、更同质的中间表型上,这些中间表型位于基因和/或环境效应与疾病过程之间。在本综述中,我们调查并整合了与抑郁相关的两种有前途的中间表型的研究:奖励处理和应激敏感性。对这一不断涌现的文献的综合分析表明,专注于中间表型的分子遗传学方法具有很大的前景,可以从根本上提高我们对抑郁症病理生理学和病因学的理解,这对于改进诊断定义以及开发新的、更有效的治疗和预防策略是必需的。最后,我们强调了中间表型研究所面临的挑战,以及推动这一关键研究向新方向发展所需的未来发展。