Gene x Environment Interactions Predicting an Endophenotype for Depression

描述（由申请人提供）：本提案的总体目标是通过研究与抑郁症内表型相关的基因-环境相互作用来推进儿童和青少年抑郁症发展的知识。了解基因和环境如何相互作用来预测内表型将有助于增加对由遗传脆弱性引发的抑郁症的发育途径的认识。具体来说，理论表明，与消极情绪/气质相关的表型可能是候选基因与抑郁症之间的中间性状（Caspi, Hariri, Holmes, Uher, & Moffitt, 2010）。然而，到目前为止，还没有研究检查基因与环境的相互作用预测在实验室中引起的青少年观察到的情绪反应。此外，考虑到青少年发病的抑郁症与成年后复发的可能性增加2-7倍相关，对青少年抑郁症发展的研究尤为重要（Rutter, Kim-Cohen, & Maughan, 2006）。因此，重要的是在青少年抑郁复发之前预测青少年抑郁的发生。对抑郁症发展途径的研究与美国国家心理健康研究所的使命是一致的，即了解精神疾病的发展轨迹，从而帮助确定如何最好地进行干预。此外，拟议的项目将针对NIMH发展转化研究部门的高优先级领域：1)专注于识别反映情绪调节/消极情绪的行为表型，这将有助于发现潜在的遗传脆弱性；2)测试一个结合遗传学、消极情绪和实验/环境因素在抑郁症发展中的模型；3)采用纵向设计来检查抑郁的途径和增加抑郁的轨迹。此外，本建议试图通过采用多方法、多信息、多波设计来仔细评估365名三、六、九年级学生的环境变量（慢性压力）以及抑郁诊断和症状，并在18个月的时间里每3个月定期随访一次。此外，拟议的研究将采用强有力的方法，通过观察在实验室冲突讨论中引起的情绪来评估负面情绪的潜在内在表型。最后，该研究将检查3个精心挑选的、理论上有动机的候选基因：血清素转运基因（5-HTTLPR）、多巴胺D2受体基因（DRD2）和单胺氧化酶A （MAOA）。这项研究将测试关于这些候选基因可能影响抑郁症的发育途径的先验假设。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to advance knowledge on the development of depression in children and adolescents by investigating gene-environment interplay associated with endophenotypes for depression. Understanding how genes and the environment interact to predict endophenotypes will help to increase knowledge on developmental pathways to depression initiated by genetic vulnerabilities. Specifically, theory suggests that phenotypes related to negative emotionality/temperament may be an intermediate trait between candidate genes and depression (Caspi, Hariri, Holmes, Uher, & Moffitt, 2010). Yet, no study to date has examined gene x environment (g x e) interactions predicting observed emotional responses elicited in the laboratory among adolescents. Furthermore, the study of the development of depression among youth is especially important given that adolescent-onset depression is associated with a 2-7 times increased likelihood of recurrence in adulthood (Rutter, Kim-Cohen, & Maughan, 2006). Therefore, to inform prevention efforts it is important to predict adolescent-onset depression before recurrent episodes occur. The study of developmental pathways to depression is consistent with the mission of the National Institute of Mental Health to understand trajectories of mental illness that can help determine how best to intervene. In addition, the proposed project will target the NIMH Division of Developmental Translational Research areas of high priority by 1) focusing on identifying behavioral phenotypes reflecting mood regulation/negative emotionality that will help to discover underlying genetic vulnerabilities, 2) testing a model that incorporates genetics, negative emotionality, and experiental/environmental factors in the development of depression, and 3) employing a longitudinal design to examine pathways for depression and trajectories of increasing depression. Additionally, this proposal seeks to address limitations of prior g x e studies of depression by employing a multi-method, multi-informant, multi-wave design to carefully assess environmental variables (chronic stress) as well as depression diagnoses and symptoms among 365 3rd, 6th, and 9th graders across 7 waves of data with regular follow-ups every 3 months over a period of 18 months. Moreover, the proposed research will employ strong methodology to assess the potential endophenotype of negative emotionality by observing emotions [elicited in the laboratory during a conflict discussion.] Finally, the research will examine 3 carefully selected and theoretically motivated candidate genes: the serotonin transporter gene (5-HTTLPR), the dopamine D2 receptor gene (DRD2), and monoamine oxidase A (MAOA). The research will test clear a priori hypotheses about the developmental pathways through which these candidate genes may influence depression.