抑郁症的影像遗传学研究:探索基因与环境的交互作用

Imaging Genetics of Major Depression Disorder: Exploring Gene-Environment Interactions

抑郁症具有中等的遗传度。通过影像遗传学方法探讨抑郁相关基因的多态性对神经活动的影响,发现编码五羟色胺、促肾上腺素释放激素受体、多巴胺等神经递质或受体的基因多态性会影响杏仁核、前扣带等情绪加工脑区的功能或结构,且多数基因与压力生活经历发生交互作用。表明基因与环境的交互作用在抑郁症发病机理中扮演重要角色。未来的研究应拓展遗传和神经影像分析方法,重视环境因素的测量,通过整合遗传、神经影像及环境变量构建抑郁病理模型。

Major Depression Disorder （MDD） is a complex mental disorder characterized by various symptoms including motor, cognitive, and affective abnormalities. It is one of the world＇s leading causes of disability, lifetime prevalence estimates vary from 8% to 12%. MDD is moderately heritable, identification of genes that underlie susceptibility to MDD will be a major advance in our understanding of its pathophysiological mechanisms, and lead to improved prevention and the development of new and more effective therapies. Although hundreds of behavioral and pharmacogenetic association studies have been performed, clinical association studies still suffer from a lack of replication. Effects of single genes suspected to be linked to MDD have proven to be much smaller than originally expected and their pathogenetic influence is further complicated by gene--gene interactions, gene-environment interactions and disease heterogeneity. In order to address these issues, many have advocated for the use of the intermediate phenotype approach. Intermediate phenotypes describe neurobiological or neuropsychological traits that are linked to both genetic heritability and clinical disorder, they are presumably not only more specific, quantifiable, and reliable than diagnostic phenotypes, but also more proximal to gene function. Neural intermediate phenotypes measured by modem neuroimaging techniques are thought to more directly index the underlying neurobiology of complex phenotypes and hence have the intrinsic potential to bridge the gap between genes and psychiatric diagnostic phenotypes. The rapidly growing field of imaging genetics utilizes neuroimaging as tools to detect the subtle neural impact of genetic variants. More and more researchers are using the imaging genetic approach to investigate how depression-related genetic polymorphisms influence neural activities. Recent research shows that variants of genes are involved in the serotoninergic fimetion （i.e.5-HTTLPR, HTR1A, MAOA, TPH2） associated with alterations of emotion-related neural activity or structure in the amygdala, anterior cingulate cortex, hippocampus, hypothalamus and functional connectivity between them. These regions are thought to be core regions in the pathophysiology of MDD. Other variants of genes that control such biochemicals as dopamine, CRH, BDNF, NPY, FKBP5 impact the function of brain regions that underlie the reward processing and stress responses. Research also found that most of these genes interact with life stressors, suggesting that gene-environment interactions played an important role in the pathogenesis of MDD. Future studies should focus on the following aspects： （1） To address the complex nature of the human genome, researchers should move beyond candidate gene studies, using genome-wide approach to overcome the selection bias. （2） At the neural level, future imaging genetics studies in MDD may combine biochemical measures （e.g., PET and MRS） with fMRI and genetic measures, and integrate structural and functional imaging data. （3） Researchers should attach great importance to the measurement of environmental factors, use observational measures and multiple well-validated measures to make the measurements more reliable. Moreover, future researchers may want to investigate the GxE interaction in the framework of the ＂differential susceptibility model＂. （4） To further understand the causes and development of MDD, future studies should integrate neuroimaging, genetic, personality and social environmental factors, using the longitudinal study paradigm to construct a comprehensive model of MDD.