Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368(1615):20120129. doi: 10.1098/rstb.2012.0129. Print 2013.
The familial nature of major depressive disorder (MDD) is now well recognized. We followed children and grandchildren of probands with and without MDD to examine transmission of depression over generations, and to identify early vulnerability markers prior to the onset of disease. The study now includes three generations and five completed assessment waves spanning 25 years, with a sixth wave underway. Beginning with the fourth wave, we collected measures of brain structure (magnetic resonance imaging, MRI) and physiology (electroencephalography, EEG) and DNA in order to examine at a biological level why the offspring of depressed parents were at higher risk. In this paper, we provide an overview of the study design, the main findings, including new data, and the role of the high-risk design in translational research. We demonstrate that offspring of depressed parents ('high-risk'), when compared with those of non-depressed parents ('low-risk'), were at increased risk for depressive and anxiety disorders, with anxiety appearing earlier and being a predisposing factor for MDD. Offspring with two generations previously affected were at greatest risk. Thinning of the cortical mantle (MRI) and reduced resting-state activity (EEG) within the right parieto-temporal hemisphere differentiated high- from low-risk offspring, regardless of whether the offspring had MDD, suggesting that these measures might serve as familial trait markers for depression and related syndromes. The high- and low-risk offspring also differed by serotonin transporter promoter length polymorphism genotypes, even though the same genotypes were not associated with the presence of MDD. The high-risk epidemiological design appears to be a particularly valuable asset in translational research as it allows targeting of biological processes that emerge prior to the onset of disease, and identifies individuals at high risk for the disorder who may carry the trait or marker but not yet be affected.
重度抑郁症（MDD）的家族性现在已得到充分认识。我们对 MDD 患者及其一级和二级亲属的后代进行了随访，以研究抑郁症在几代人之间的传递情况，并在疾病发作之前确定早期易损性标志物。该研究目前已进入第三代，共完成了五个评估阶段，跨度 25 年，第六个阶段正在进行中。从第四阶段开始，我们收集了大脑结构（磁共振成像，MRI）和生理学（脑电图，EEG）以及 DNA 的指标，以在生物学水平上研究为什么抑郁父母的子女患抑郁症的风险更高。在本文中，我们提供了研究设计、主要发现（包括新数据）的概述，以及高危设计在转化研究中的作用。我们证明，与非抑郁父母的子女（“低危”）相比，抑郁父母的子女（“高危”）患抑郁和焦虑障碍的风险更高，其中焦虑症出现更早，是 MDD 的一个诱发因素。两代之前都受影响的子女风险最高。与低危后代相比，皮质层（MRI）变薄和右顶颞叶静息状态活动（EEG）减少可区分高危和低危后代，而不论子女是否患有 MDD，这表明这些指标可能作为抑郁和相关综合征的家族特征标志物。高危和低危后代的 5-HTT 启动子长度多态性基因型也存在差异，尽管相同的基因型与 MDD 的存在无关。高危流行病学设计似乎是转化研究的一个特别有价值的资产，因为它可以针对疾病发作前出现的生物学过程进行靶向治疗，并识别出患有该疾病的高风险个体，这些个体可能携带特征或标志物，但尚未受到影响。
