MOLECULAR GENETICS OF EARLY-ONSET RECURRENT DEPRESSION

主要的情感疾病是一组使人衰弱的疾病，这些疾病可能 每五个人中就有一个人在一生中受到影响。这个 家庭、双胞胎和收养研究的结果表明， 明确两种主要亚型疾病背后的遗传成分- 躁郁症和单相病。然而，确切的继承模式 以及与此相关的基因(S)的染色体位置(S 这些疾病的病理生理学尚不清楚。的长期目标是 本研究旨在从分子水平上刻画该基因(S) 与早发性、复发性、非精神病性、 单相抑郁。通过将注意力集中在一个严重的临床上 严重抑郁的表现，是我们最大限度地发挥潜力的意图 遗传负荷，同时减少表型和遗传异质性。这个 将采用的实验策略旨在补充 由NIMH赞助的正在进行的遗传研究的国家联盟 双相情感障碍和精神分裂症(RFA MH-89-05)。的具体目标 调查有四个方面：(L)招募样本一百人 通过早发性(小于或等于25)确定的核心家庭 年)，反复发作(3次)抑郁先证者。招募家庭参加 这项研究将包括两个在世的父母和至少一个额外的兄弟姐妹。 这一临床样本将提供(A)进行联系的手段 同时使用受影响的同胞对和Lod Score方法进行分析，(B) 作为资源，识别信息量大、信息量大的 既适合连锁又适合分离的多世代家系 分析，以及(C)促进对遗传异质性的潮汐评估 一旦建立了假定的联系；(2)调查遗传 复发性抑郁症的遗传参数和遗传方式 分离分析；(3)对基因进行系统的基因组搜索 使用高度多态的电池的潜在疾病易感性 DNA标记。最初，标记位于可能发挥作用的基因附近 在抑郁症的病理生理学中，一个重要的作用将是 评估；及(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 遗传分析中的表型不稳定性。圆满完成 这项研究可能(A)验证复发的遗传性质 抑郁症，(B)阐明疾病的遗传模式(S)，(C) 产生关于早发的遗传成分的新信息 复发性抑郁症，(D)为隔离和 增加疾病易感性的基因的特征，以及(E) 为未来的基因分析提供国家资源，使 社区快速评估新建立的共性联系 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。

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.