Genetics of Monoamine Endophenotypes and Mental Health

单胺内表型遗传学与心理健康

• 批准号: 6769988
• 负责人: JEFFREY A. ROGERS
• 金额: $ 39.6万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769988
• 关键词: 3 methoxy 4 hydroxyphenylethyleneglycol; amines; anxiety disorders; baboons; behavior test; behavioral genetics; biomarker; biotechnology; cerebrospinal fluid; disease /disorder etiology; family genetics; gene environment interaction; gene expression; genetic disorder; genetic susceptibility; genotype; homovanillate; hydroxyindoleacetate; linkage mapping; mental disorder diagnosis; mental disorders; microarray technology; phenotype; polymerase chain reaction; prefrontal lobe /cortex; psychosis; quantitative trait loci

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.

描述（由申请人提供）：现有数据强烈表明 精神疾病的成因很复杂，患病的风险也很大 患有抑郁症、精神分裂症、焦虑症和其他精神疾病 受遗传、非遗传生物因素的影响 外部环境因素，例如社会压力。此外，还明确 单胺类神经递质（血清素、多巴胺和去甲肾上腺素） 与抑郁症、焦虑症和其他疾病的发病和治疗有关 精神病理学。尽管有证据表明遗传对精神疾病有影响 疾病、单胺神经递质水平以及正常变化 气质与疾病有关，影响这些性状的特定基因是 不为人所知。使用连锁分析进行全基因组扫描 多代谱系是定位功能基因的有力方法 影响诸如此类的复杂特征。不幸的是，对于几个 由于原因，这种方法不能用于人类家族来定位基因 影响脑脊液 (CSF) 中单胺的水平，或研究 行为的正常变化。在这个项目中，我们建议进行一个整体 非人类灵长类动物模型（狒狒、狒狒）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）并研究气质的个体差异 让每只狒狒接受涉及对小说的反应的行为挑战 对象。所有 650 只研究动物均已进行连锁图谱基因分型 由 350 个人类微卫星位点组成，分辨率为 7 cM。我们也会 使用基因表达阵列方法评估已识别的分子效应 前额皮质中的 QTL 位点。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 挑战具有很强的遗传性。最重要的是，可用 基因型允许进行初步基因组扫描，四个 LOD 分数大于 已获得 1.9，其中多巴胺的 LOD 分数为 2.4 代谢物 HVA，以及与焦虑相关的行为特征 2.6。我们的 初步数据证明了狒狒模型的价值，并表明 来自相同谱系的更大样本可能会提供重要的新信息 有关影响单胺神经递质水平的基因的信息 和行为反应（即气质）。这些基因的鉴定 对于未来的遗传危险因素研究具有重要意义 人类的精神疾病。