Genetics of Monoamine Endophenotypes and Mental Health

描述（由申请人提供）：现有数据强烈表明， 精神疾病的原因是复杂的， 抑郁症、精神分裂症、焦虑症和其他精神疾病 受遗传遗传、非遗传生物学因素和 社会压力等外部环境因素。此外，很明显， 单胺神经递质（血清素、多巴胺和去甲肾上腺素） 与抑郁症、焦虑症等的发病和治疗有关 精神病理学尽管有证据表明遗传因素对精神疾病有影响， 疾病、单胺神经递质水平以及神经递质的正常变化 与疾病有关的气质，影响这些特征的特定基因是 不太出名。利用连锁分析进行全基因组扫描 多代家系是定位功能基因的有效方法 影响着这些复杂的特征。不幸的是，对于一些 由于种种原因，这种方法不能用于人类家庭定位基因， 影响脑脊液（CSF）单胺水平，或研究 行为的正常变化。在这个项目中，我们建议进行一次全面的 在非人灵长类动物模型（狒狒，狒狒）中进行基因组连锁扫描。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），并研究气质的个体差异 通过让每只狒狒接受涉及对小说反应的行为挑战， 对象所有650只研究动物都已经进行了基因分型，以绘制连锁图 由350个人类微卫星位点组成，分辨率为7 cM。我们还将 使用基因表达阵列方法来评估鉴定的 前额皮质的QTL位点。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 都具有很强的遗传性。最重要的是，现有的 基因型允许初步基因组扫描，四个LOD得分大于 1.9包括多巴胺的LOD得分为2.4， 代谢物HVA，和2.6焦虑相关的行为特征。我们 初步数据证明了狒狒模型的价值，并表明， 来自同一家系的更大样本可能会提供重要的新信息。 关于影响单胺神经递质水平的基因的信息 和行为反应性（即，气质）。鉴定这些基因 对今后研究遗传风险因素具有重要意义。 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.