GENETICS OF MONOAMINE ENDOPHENOTYPES AND MENTAL HEALTH

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 现有数据有力地表明，精神疾病的原因是复杂的，患抑郁症、精神分裂症、焦虑症和其他精神疾病的风险受到遗传、非遗传生物因素和社会压力等外部环境因素的影响。此外，单胺神经递质（5-羟色胺、多巴胺和去甲肾上腺素）显然与抑郁症、焦虑症和其他精神病理学的发病和治疗有关。尽管有证据表明遗传因素会影响精神疾病、单胺神经递质水平以及与疾病相关的正常气质变化，但影响这些特征的特定基因并不为人所知。在多代系谱中使用连锁分析的全基因组扫描是定位影响诸如这些复杂性状的功能基因的有力方法。不幸的是，由于几个原因，这种方法不能用于人类家庭定位影响脑脊液（CSF）单胺水平的基因，或调查行为的正常变化。在这个项目中，我们正在非人类灵长类动物模型（狒狒，Papio hamadryas）中进行全基因组连锁扫描。我们正在寻找影响CSF单胺代谢物（5-HIAA，HVA和MHPG）水平的基因，并通过对每只狒狒进行涉及对新物体反应的行为挑战来研究个体气质差异。所有研究动物均已针对由350个人类微卫星基因座组成的连锁图谱进行基因分型，分辨率为7 cM。我们还将使用基因表达阵列方法来评估前额叶皮层中已鉴定的QTL位点的分子效应。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对挑战的行为反应都具有很强的遗传性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 are conducting a whole genome linkage scan in a nonhuman primate model (baboons, Papio hamadryas). We are searching for genes that influence CSF levels of monoamine metabolites (5-HIAA, HVA and MHPG) and also investigating individual variation in temperament by subjecting each baboon to a behavioral challenge involving response to novel objects. All study animals will 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.