Intermediate Phenotypes for Alcoholism and Anxi

酒精中毒和安希的中间表型

• 批准号: 6983120
• 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/6983120
• 关键词: Native Americans; alcoholism /alcohol abuse; anxiety disorders; behavioral /social science research tag; behavioral genetics; bioimaging /biomedical imaging; biomarker; brain electrical activity; catechol methyltransferase; caucasian American; clinical research; electroencephalography; evoked potentials; family genetics; gene environment interaction; genetic mapping; genetic polymorphism; genetic susceptibility; human genetic material tag; human population genetics; human subject; neurogenetics; psychometrics; substance abuse epidemiology; Native Americans; alcoholism /alcohol abuse; anxiety disorders; behavioral /social science research tag; behavioral genetics; bioimaging /biomedical imaging; biomarker; brain electrical activity; catechol methyltransferase; caucasian American; clinical research; electroencephalography; evoked potentials; family genetics; gene environment interaction; genetic mapping; genetic polymorphism; genetic susceptibility; human genetic material tag; human population genetics; human subject; neurogenetics; psychometrics; substance abuse epidemiology

The heritability of alcoholism is 40-60% in both men and women, but, as in other complex psychiatric diseases, it has proved difficult to identify causative 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. 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. 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. 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 are undertaking 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. We have found that in this tribe the COMT Met/Met genotype is protective against alcoholism. In addition, the Met158 allele is protective against smoking in women. We have also found that LVA is associated with the DRD2 functional promoter polymorphism, -141CIns/Del. Haplotype analyses are currently underway in other key candidate genes for alcoholism, anxiety and EEG phenotype. We have completed the collection of another large dataset including EEG and ERP phenotypes, HRV, blind-rated DSM-IV psychiatric diagnoses, personality tests, demographics and DNA on 198 members of a Southeastern American Indian tribe with a low rate of alcoholism and other psychiatric disorders. We have almost finished the processing of EEG, ERP and HRV data. We plan on comparing the low and high alcoholism prevalence tribes for gene x environment interactions. Formerly titled "Genetic studies of the electroencephalogram and event-related potentials" and "Genetic studies of EEG and ERP traits related to alcoholism".

酗酒的遗传力在男性和女性中均为40-60％，但是，与其他复杂的精神疾病一样，事实证明，很难识别病因基因。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，尤其是伴有焦虑症。此外，我们发现LVA个体无论临床状态如何，都减少了听觉和视觉p300 ERP振幅，从而进一步加强了我们对LVA与酒精中毒脆弱性的关联的论点。 不出所料，酗酒者的p300幅度降低了，在患有焦虑症的酗酒者中，仅在焦虑症患者中最低。 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。我们正在进行候选基因分析，并发现在贝塞斯达和平原印度妇女中，降低的活动符合catechol-o-o-甲基转移酶（COMT）功能多态性多态性val158met的等位基因（尤其是Met/MET纯合子）与LVA和危害相关联，并与焦虑量相关。 我们发现，在这个部落中，COMT MET/MET基因型具有保护性的酗酒。此外，Met158等位基因可保护女性吸烟。我们还发现，LVA与DRD2功能启动子多态性-141CINS/DEL有关。目前在其他关键候选基因的酒精中毒，焦虑和脑电图表型中正在进行单倍型分析。 我们已经完成了另一个大型数据集的收集，包括脑电图和ERP表型，HRV，盲率的DSM-IV精神病诊断，人格测试，人口统计学和DNA，对东南美洲印第安人部落的198名成员，其酒精中毒率低和其他精神疾病的率低。我们几乎完成了EEG，ERP和HRV数据的处理。我们计划比较基因X环境相互作用的低酒精中毒流行部落。 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”。