Intermediate Phenotypes for Alcoholism and Anxiety

酗酒和焦虑的中间表型

• 批准号: 6684833
• 负责人: MARY ANNE ENOCH
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6684833
• 关键词: American; Native Americans; alcoholism /alcohol abuse; anxiety disorders; behavioral /social science research tag; behavioral genetics; brain electrical activity; disease /disorder proneness /risk; electroencephalography; evoked potentials; family genetics; genetic markers; genetic polymorphism; human genetic material tag; human population genetics; human subject; interview; linkage mapping; patient oriented research; phenotype; psychometrics

The heritability of alcoholism is 40-60% in both men and women, but, as like other complex psychiatric diseases, it has proved difficult to map genes. Intermediate phenotypes are associated biological traits that may be influenced by variation at fewer genes and may mediate different aspects of the disease. The intermediate phenotypes we are studying include resting EEG phenotypes, event-related potentials (ERPs) and heart rate variability (HRV). We have identified an intermediate phenotype for alcoholism vulnerability, the low voltage alpha (LVA) EEG, a normal, traitlike heritable variant of the resting EEG, present in 7-14% of the population, in which the alpha rhythm is virtually absent. We have a complete data set, including EEG and ERP phenotypes, blind-rated DSM-III-R psychiatric diagnoses, psychometric tests and DNA on 247 predominantly Caucasian individuals from Bethesda, MD. We have shown that LVA is associated with alcoholism, particularly when accompanied by anxiety disorders (Enoch et al 1995,1999). Moreover, we found that LVA individuals, irrespective of clinical state, had reduced auditory and visual P300 ERP amplitudes, further strengthening our argument for the association of LVA with alcoholism vulnerability (Enoch et al 2002). As expected, P300 amplitude was reduced in alcoholics, however, it was lowest in alcoholics with comorbid anxiety disorders and highest in individuals with anxiety disorders alone (Enoch et al 2001). In order to obtain sufficient power to map genes for alcoholism we have also studied a Plains American Indian tribe that has a high prevalence of alcoholism. We now have a complete dataset on 365 tribal members including EEGs and ERPs, blind-rated DSM-III-R psychiatric diagnoses and DNA. Preliminary studies confirm the relationship of LVA with alcoholism and anxiety disorders. We have started candidate gene analyses and have found that in both Bethesda and Plains Indian women, the low activity Met allele (and particularly the Met/Met homozygote) of the catechol-O-methyltransferase (COMT) functional polymorphism Val158Met is associated both with LVA and harm avoidance, a dimensional measure of anxiety (Enoch et al, in press). Preliminary analyses show that LVA is also associated with the DRD2 functional promoter polymorphism, -141CIns/Del in both populations. The Plains Indian pedigree has now been completed and we have formed a collaboration with a group in Germany to perform a whole genome linkage scan. We will soon be in a position to commence analyses for mapping genes for alcoholism. HRV is a potential intermediate phenotype for alcoholism and major depression. We have collected EKG recordings from both the Bethesda and Plains Indian populations. The data has been processed and is currently being analyzed. Formerly titled "Genetic studies of the electroencephalogram and event-related potentials" and "Genetic studies of EEG and ERP traits related to alcoholism".

酒精中毒的遗传力在男性和女人中均为40-60％，但是就像其他复杂的精神病疾病一样，映射基因也很难。中间表型是相关的生物学特征，可能受到较少基因变异的影响，并且可能介导该疾病的不同方面。我们正在研究的中间表型包括静止的脑电图表型，与事件相关电位（ERP）和心率变异性（HRV）。 我们已经确定了酒精中毒脆弱性的中间表型，低压α（LVA）脑电图是一种正常的，特质的遗传性脑电图，占7-14％的人口，其中α节奏实际上是不存在的。我们有一个完整的数据集，包括脑电图和ERP表型，盲率的DSM-III-R精神诊断，心理测试和DNA，以及247个主要是来自医学博士贝塞斯达的高加索人。我们已经表明，LVA与酒精中毒有关，尤其是在患有焦虑症时（Enoch等，1995年，1999年）。此外，我们发现LVA个体无论临床状态如何，都降低了听觉和视觉p300 ERP振幅，从而进一步加强了我们对LVA与酒精中毒脆弱性关联的论点（Enoch等，2002）。不出所料，酒精中毒的p300幅度降低了，在患有合并焦虑症的酒精中毒中，仅在焦虑症的患者中最低（Enoch等，2001）。 为了获得足够的能力来绘制酗酒的基因，我们还研究了一个普通的美洲印第安人部落，该部落的酗酒率很高。现在，我们对365个部落成员（包括脑电图和ERP，盲率的DSM-III-R精神诊断和DNA）拥有完整的数据集。初步研究证实了LVA与酒精中毒和焦虑症的关系。我们已经开始候选基因分析，发现在贝塞斯达和平原的印度妇女中，低活性遇到了catechol-o-o-甲基转移酶（COMT）功能多态性val158ment的等位基因（尤其是Met/MET纯合子），与LVA和伤害相关联，与焦虑量相关联（EN）。初步分析表明，LVA也与两个人群中的DRD2功能启动子多态性，-141CINS/DEL相关。平原印度的血统现在已经完成，我们与德国的一个团体进行了合作，以进行整个基因组链接扫描。我们很快就可以开始分析用于酗酒的基因。 HRV是酒精中毒和严重抑郁症的潜在中间表型。我们已经收集了来自贝塞斯达和平原印度人口的心电图记录。数据已经处理过，目前正在分析。 以前的标题为“脑电图和事件相关电位的遗传研究”和“与酒精中毒有关的脑电图和ERP特征的遗传研究”。