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: 2430938
• 负责人: GEORGE S ZUBENKO
• 金额: $ 42.01万
• 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 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2430938
• 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， 影响多达五分之一的人的一生。的 家庭、双胞胎和收养研究的结果表明， 两种主要亚型疾病背后的明确遗传成分 躁郁症和单极症。然而，确切的遗传方式 以及有助于产生细胞凋亡的基因的染色体位置。 这些疾病的病理生理学是未知的。的长期目标 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 严重抑郁症的表现，是我们的意图，以最大限度地发挥潜力， 遗传负荷，同时减少表型和遗传异质性。 的 将采用的实验策略旨在补充 正在进行的NIMH赞助的国家联盟的遗传调查， 双相情感障碍和精神分裂症（RFA MH-89-05）。的具体目标 调查分为四个方面：（l）招募100名样本 通过早发性（小于或等于25）确定的核心家庭 年），复发性（3次发作）抑郁先证者。被招募的家庭 研究将包括两个活着的父母和至少一个额外的兄弟姐妹。 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） 作为一种资源， 适合连锁和分离的多代系谱 分析，以及（c）促进遗传异质性的潮汐评估 一旦假定的联系建立;（2）调查遗传 复杂的复发性抑郁症的遗传参数和模式 分离分析;（3）进行系统的基因组搜索， 使用一组高度多态性的 DNA标记。最初，位于基因附近的标记， 在重性抑郁症的病理生理学中， （4）开展纵向家庭研究， 精神病诊断的稳定性，并评估 遗传分析的表型不稳定性。圆满完成 这项研究可以（a）提供复发性乳腺癌的遗传本质的验证， 抑郁症，（B）阐明疾病的遗传模式，（c） 产生关于早发性糖尿病遗传成分的新信息， 复发性抑郁症，（d）奠定隔离的基础， 表征增强疾病易感性的基因，和（e） 为未来的基因分析提供国家资源， 社区迅速评估新建立的联系，以实现共同点 和/或主要精神疾病的遗传病因学差异 精神障碍和情感障碍亚型。