Genetics of Monoamine Endophenotypes and Mental Health

描述(由申请人提供)：现有数据有力地表明 精神疾病的原因是复杂的，而痛苦的风险 抑郁症、精神分裂症、焦虑症和其他精神疾病 受遗传遗传、非遗传生物因素和 社会压力等外部环境因素。此外，很明显， 单胺类神经递质(5-羟色胺、多巴胺和去甲肾上腺素) 与抑郁症、焦虑症和其他疾病的发病和治疗有关 精神变态。尽管有证据表明基因对精神疾病的影响 疾病，对单胺类神经递质水平的影响，以及对 与疾病相关的气质，影响这些特征的特定基因是 不太为人所知。利用连锁分析进行全基因组扫描 多世代家系是定位功能基因的有效方法 会影响到这些复杂的特征。不幸的是，对于几个人来说 原因是，这种方法不能用于人类家族来定位 影响脑脊液(CSF)中单胺类物质水平的研究 行为上的正常变化。在这个项目中，我们建议进行一个整体 非人灵长类动物模型的基因组连锁扫描。我们 将寻找影响脑脊液单胺代谢物水平的基因 (5-HIAA、HVA和MHPG)，并调查气质的个体差异 通过让每只狒狒接受一个行为挑战，包括对小说的反应 物体。所有650只研究动物都已经为连锁图谱进行了基因分型 由350个人类微卫星组成，分辨率为7厘米。我们还将 使用基因表达阵列方法评估鉴定的分子效应 前额叶皮质的QTL基因座。来自大约300只狒狒的初步结果 表明所有三种单胺代谢物和几种行为反应 挑战是具有很强的遗传性的。最重要的是，可用的 基因类型允许进行初步基因组扫描，并且有四个LOD得分大于 已获得1.9，包括多巴胺的LOD分数2.4 代谢物HVA，以及与焦虑相关的行为特征的2.6。我们的 初步数据证明了狒狒模型的价值，并表明 来自相同家系的更大样本可能会提供重要的新的 影响两种单胺类神经递质水平的基因信息 和行为反应性(即，气质)。这些基因的鉴定 将对今后的遗传风险因素的研究具有重要意义。 人类的精神疾病。

DESCRIPTION (provided by applicant): The available data strongly suggest that the causes of psychiatric illnesses are complex, and that the risk of suffering from depression, schizophrenia, anxiety disorder and other psychiatric diseases is influenced by genetic inheritance, nongenetic biological factors and external environmental factors such as social stress. In addition, it is clear that monoamine neurotransmitters (serotonin, dopamine and norepinephrine) are related to the onset and treatment of depression, anxiety disorders and other psychopathologies. Despite the evidence for genetic influences on psychiatric disorders, on levels of monoamine neurotransmitters, and on normal variation in temperament related to disease, the specific genes that affect these traits are not well known. Whole genome scanning using linkage analysis in multi-generation pedigrees is a powerful method for locating functional genes that influence complex traits such as these. Unfortunately, for several reasons, this approach cannot be used with human families to locate genes that influence cerebrospinal fluid (CSF) levels of monoamines, or to investigate normal variation in behavior. In this project, we propose to conduct a whole genome linkage scan in a nonhuman primate model (baboons, Papio hamadryas). We will search for genes that influence CSF levels of monoamine metabolites (5-HIAA, HVA and MHPG) and also investigate individual variation in temperament by subjecting each baboon to a behavioral challenge involving response to novel objects. All 650 study animals have already been genotyped for a linkage map consisting of 350 human microsatellite loci, with 7 cM resolution. We will also use gene expression array methods to assess the molecular effects of identified QTL loci in prefrontal cortex. Preliminary results from about 300 baboons indicate that all three monoamine metabolites and several behavioral responses to challenge are strongly heritable. Most significantly, the available genotypes permit a preliminary genome scan, and four LOD scores greater than 1.9 have been obtained, including a LOD score of 2.4 for the dopamine metabolite HVA, and 2.6 for an anxiety-related behavioral trait. Our preliminary data demonstrate the value of the baboon model and indicate that a larger sample from the same pedigrees would likely provide important new information about genes that influence both monoamine neurotransmitter levels and behavioral reactivity (i.e., temperament). Identification of these genes will be very significant for future studies of genetic risk factors for psychiatric illness in humans.