MOLECULAR GENETICS OF EARLY-ONSET RECURRENT DEPRESSION

早发性复发性抑郁症的分子遗传学

• 批准号: 2248523
• 负责人: GEORGE S ZUBENKO
• 金额: $ 35.01万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2248523
• 关键词: cell line; clinical depression; early diagnosis; family genetics; genetic markers; human subject; interview; linkage mapping; longitudinal human study; major depression; medical records; mental disorder diagnosis; molecular genetics; relapse /recurrence; restriction fragment length polymorphism

The major affective illnesses are a set of debilitating diseases which may affect as many as one individual in five in the course of a lifetime. The results of family, twin, and adoption studies indicate that there are clear genetic components underlying both major subtypes of the disease - bipolar and unipolar disorders. However, the exact modes of inheritance and the chromosomal location(s) of the gene(s) contributing to the pathophysiology of these disorders is unknown. The long-term objective of this research effort is to characterize at the molecular level the gene(s) involved in the etiology of early-onset, recurrent, non-psychotic, unipolar depression. By focusing attention on a severe clinical manifestation of major depression, is our intent to maximize the potential genetic load, while diminishing phenotypic and genetic heterogeneity. The experimental Strategies to be employed are designed to complement the ongoing NIMH-sponsored national consortium for genetic investigation of bipolar disorder a and schizophrenia (RFA MH-89-05). The specific aims of the investigation are four fold: (l) To recruit a sample of one hundred nuclear families ascertained through early-onset (less than or equal to 25 years), recurrent (3 episodes) depressive probands. Families recruited for study will contain two living parents and at least one additional sibling. This clinical sample will provide the means (a) to conduct linkage analyses using both affected sib-pair and lod score methodologies, (b) serve as a resource to identify large, highly informative multigenerational pedigrees suitable for both linkage and segregation analyses, and (c) to facilitate tide assessment of genetic heterogeneity once putative linkages are established; (2) To investigate the genetic parameters and mode of inheritance of recurrent depression by complex segregation analysis; (3) To conduct a systematic genome search for genes underlying disease susceptibility using a battery of highly polymorphic DNA markers. Initially, markers located adjacent to genes that could play a significant role in the pathophysiology of major depression will be evaluated; and (4) To initiate longitudinal family studies to assess the stability of psychiatric diagnoses over time, and evaluate the effects of phenotypic instability on genetic analyses. The successful completion of this study may (a) provide verification of the genetic nature of recurrent depression, (b) clarify the inheritance pattern(s) of the disease, (c) generate new information on the genetic components underlying early-onset recurrent depression, (d) lay the foundation for the isolation and characterization of the genes augmenting disease susceptibility, and (e) provide a national resource for future genetic analysis, enabling the community to rapidly evaluate newly established linkages for commonalities and/or differences in the genetic etiology of the major psychiatric disorders and within affective disorder subtypes.

主要的情感疾病是一系列使人衰弱的疾病，可能会导致 在一生中影响多达五分之一的人。这 家庭、双胞胎和收养研究的结果表明， 该疾病的两种主要亚型背后都有明确的遗传成分 - 双相情感障碍和单相情感障碍。然而，具体的遗传方式 以及贡献基因的染色体位置 这些疾病的病理生理学尚不清楚。长期目标 这项研究工作是在分子水平上表征基因 涉及早发性、复发性、非精神病性、 单相抑郁症。 通过将注意力集中在严重的临床上 重度抑郁症的表现，是我们最大化潜力的意图 遗传负荷，同时减少表型和遗传异质性。 这 所采用的实验策略旨在补充 NIMH 资助的正在进行的国家基因调查联盟 双相情感障碍 a 和精神分裂症 (RFA MH-89-05)。具体目标 调查分为四部分： (l) 招募 100 名样本 通过早期发病确定的核心家庭（少于或等于 25 年），复发（3 集）抑郁先证者。招募家庭是为了 研究将包含两名在世父母和至少一名额外的兄弟姐妹。 该临床样本将提供 (a) 进行关联的方法 使用受影响的同胞对和 Lod 评分方法进行分析，(b) 作为识别大型、信息丰富的资源 适合连锁和分离的多代谱系 分析，以及（c）促进遗传异质性的潮汐评估 一旦建立了假定的联系； (2) 遗传研究 复杂的复发性抑郁症的参数和遗传模式 分离分析； (3) 对基因进行系统的基因组搜索 使用一组高度多态性的潜在疾病易感性 DNA 标记。最初，标记位于可以发挥作用的基因附近 在重度抑郁症的病理生理学中起着重要作用 评估； (4) 启动纵向家庭研究以评估 精神病学诊断随时间的稳定性，并评估其效果 遗传分析的表型不稳定性。顺利完成 这项研究可能 (a) 验证复发性 抑郁症，(b) 阐明该疾病的遗传模式，(c) 生成有关早发型遗传成分的新信息 反复出现的抑郁症，（d）为隔离和隔离奠定了基础 增强疾病易感性的基因的特征，以及（e） 为未来的遗传分析提供国家资源，使 社区快速评估新建立的联系的共性 和/或主要精神疾病的遗传病因学差异 疾病和情感障碍亚型。