Gene x Environment Interactions Predicting an Endophenotype for Depression

描述(由申请人提供)：这项建议的总体目标是通过研究与抑郁症的内在表型相关的基因-环境相互作用来促进对儿童和青少年抑郁症发展的了解。了解基因和环境如何相互作用来预测内表型，将有助于增加对遗传易感性引发抑郁症的发育途径的了解。具体地说，理论表明，与消极情绪性/气质相关的表型可能是候选基因和抑郁症之间的中间特征(Caspi，Hariri，Holmes，Uher，&Moffitt，2010)。然而，到目前为止，还没有研究检查基因x环境(G X E)的交互作用，以预测在实验室中在青少年中引起的观察到的情绪反应。此外，对青少年抑郁症发展的研究尤其重要，因为青春期抑郁症与成年后复发的可能性增加2-7倍有关(Rutter，Kim-Cohen，&Maughan，2006)。因此，为了给预防工作提供信息，在反复发作之前预测青春期抑郁症是重要的。对抑郁症发展途径的研究与国家精神卫生研究所的使命是一致的，即了解精神疾病的轨迹，以帮助确定如何最好地进行干预。此外，拟议的项目将以NIMH发展转化研究部门的高度优先领域为目标，1)专注于识别反映情绪调节/负面情绪的行为表型，这将有助于发现潜在的遗传脆弱性，2)测试一个将遗传学、负面情绪和经验/环境因素纳入抑郁症发生发展的模型，以及3)采用纵向设计来检查抑郁症的路径和日益加重的抑郁症的轨迹。此外，这项建议旨在解决先前关于抑郁症的g x e研究的局限性，采用多方法、多信息者、多波设计，仔细评估环境变量(慢性应激)以及365名3年级、6年级和9年级学生的抑郁诊断和症状，共7波数据，每3个月进行一次定期跟踪，为期18个月。此外，这项拟议的研究将采用强有力的方法，通过观察情绪来评估负面情绪的潜在内在表型[在实验室中引发的冲突讨论]。最后，这项研究将检测三个精心挑选的、具有理论动机的候选基因：5-羟色胺转运体基因(5-HTTLPR)、多巴胺D2受体基因(DRD2)和单胺氧化酶A(MAOA)。这项研究将检验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。 公共卫生相关性：世界卫生组织指出，抑郁症占非致命性疾病造成的疾病负担的最大比例(Utun&Chatterji，2001)，许多人在青春期经历了第一次临床意义上的抑郁症(Hankin等人，1998年)。此外，对青春期抑郁症发展的研究尤其重要，因为青春期抑郁症与成年后复发的可能性增加2-7倍相关(Rutter，Kim-Cohen，&Maughan，2006)。因此，这项拟议的研究旨在研究青少年抑郁症的发展途径，以便在复发之前为预防工作提供信息。

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. PUBLIC HEALTH RELEVANCE: The World Health Organization states that depression accounts for the greatest proportion of disease burden attributed to non-fatal illnesses (Utsun & Chatterji, 2001), and many individuals experience their first clinically significant depression during adolescence (Hankin et al., 1998). Furthermore, the study of the development of depression during adolescence 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, the proposed research aims to study developmental pathways to depression among youth to inform prevention efforts before recurrent episodes occur.