GENETICS OF MONOAMINE ENDOPHENOTYPES AND MENTAL HEALTH

单胺内表型遗传学与心理健康

• 批准号: 7349782
• 负责人: JEFFREY A. ROGERS
• 金额: $ 7.27万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349782
• 关键词: GENETICS; MONOAMINE; ENDOPHENOTYPES; MENTAL; HEALTH

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 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. 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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。现有数据有力地表明，精神疾病的病因复杂，患抑郁症、精神分裂症、焦虑症等精神疾病的风险受到遗传遗传、非遗传生物因素和社会压力等外部环境因素的影响。此外，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对精神疾病、单胺神经递质水平以及与疾病相关的气质的正常变化有影响，但影响这些特征的具体基因尚不清楚。在多代谱系中使用连锁分析进行全基因组扫描是定位影响此类复杂性状的功能基因的强大方法。不幸的是，由于多种原因，这种方法不能用于人类家族来定位影响脑脊液 (CSF) 单胺水平的基因，或研究行为的正常变异。在这个项目中，我们建议在非人类灵长类动物模型（狒狒、狒狒）中进行全基因组连锁扫描。我们将寻找影响脑脊液单胺代谢物（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 650 只研究动物均已完成连锁图谱的基因分型，该连锁图谱由 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前额皮质中已识别的 QTL 位点的分子效应。来自约 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。最重要的是，可用的基因型允许进行初步的基因组扫描，并且已经获得了四个大于 1.9 的 LOD 分数。我们的初步数据证明了狒狒模型的价值，并表明来自同一谱系的更大样本可能会提供有关影响单胺神经递质水平和行为反应性（即气质）的基因的重要新信息。这些基因的鉴定对于未来人类精神疾病遗传风险因素的研究非常重要。