ANTISOCIAL ALCOHOLISM AND SEROTONIN MARKERS IN FAMILIES

申请人摘要：越来越多的人认为酒精中毒(酒精) 滥用和依赖)通过复杂的交互作用随时间发展 在成熟的人和环境之间，风险的表现是 既取决于个人经验，也取决于个人素质。环境 设置将在整个生命周期内触发或抑制风险。然而， 如果没有清楚的知识，发展变化是很难论证的 初始脆弱性标记物和环境风险增强剂 专门针对酒精中毒。病因学的复杂性和不一致性 基因研究的结果挫伤了人们对基因研究的兴趣 酒精中毒的单基因效应。然而，权威的研究表明 同源亚型和真正相关的候选基因还没有 指挥。已经确定了反社会的生物标记物 酒精中毒亚型，特别是5-羟色胺(5-羟色胺)功能低下。这个 这项研究的一致性为测试提供了强有力的理由 与5-羟色胺代谢相关的候选基因的相关性。单人 同源亚型的基因效应可能是可以检测到的。建议数 这项研究采用了基于家庭的设计，即单倍型相对风险方法(a 防止因种族差异而混淆对照的研究设计 和受影响的群体)。这项提案要求有足够的资金用于 常染色体5-羟色胺标志物(色氨酸羟基酶， 5-羟色胺转运体和3种5-羟色胺受体类型[1a，1b，2a] 男性反社会酗酒者(n=50名前辈及其100名父母)和基金 进行两项可行性研究：(L)X连锁标记(单胺 氧化酶A、B和1种5-羟色胺受体[2C])在男性先证者中的分布 以及(2)常染色体和X连锁标记在10名 他们的20位父母。对于这项探索性/发展性研究，样本 同种的种族背景将被寻求。具体的目的是为了测试 反社会性酒精中毒与遗传多态的关系 色氨酸羟基酶，5-羟色胺转运体，单胺氧化酶A和B， 和四种5-羟色胺受体类型(1a、1b、2a和2c)。研究计划 还将允许保存DNA以供将来使用和评估 今后研究是否可能涉及同胞间的联系、招募 其他种族的足够样本，以及对遗传和 环境对疾病慢性化的影响。

APPLICANT'S ABSTRACT: There is a growing consensus that alcoholism (alcohol abuse and dependence) develops over time through a complex interaction between a maturing person and the environment, where expression of risk is dependent upon individual experience as well as diathesis. Environmental settings will trigger or suppress risk over the life span. However, developmental changes are difficult to demonstrate without clear knowledge of initial vulnerability markers and environmental risk enhancers that are specific to alcoholism. The complexity of etiology and the inconsistent results from genetic studies have discouraged interest in research on single-gene effects in alcoholism. However, definitive research with homogeneous subtypes and truly relevant candidate genes has not been conducted. Biological markers have been identified for the Antisocial Alcoholism subtype, specifically lower serotonin (5-HT) function. The consistency of this research provides a strong rationale for testing associations with candidate genes that relate to 5-HT metabolism. Single gene effects may be detectable with homogeneous subtypes. The proposed study uses a family-based design, the haplotype relative risk method (a study design that prevents confounding by ethnic differences between control and affected groups). This proposal requests sufficient funding for a definitive study of autosomal serotonin markers (tryptophan hydroxylase, the serotonin transporter, and three serotonin receptor types [lA, lB, 2A]) in male antisocial alcoholics (n=50 probands and their 100 parents), and funds for conducting two feasibility studies: (l) X-linked markers (monamine oxidase A and B and one serotonin receptor type [2C]) in 10 male probands and their 20 parents; and (2) autosomal and X-linked markers in 10 women and their 20 parents. For this exploratory/developmental study, a sample with homogeneous ethnic background will be sought. The specific aims are to test genetic associations between antisocial alcoholism and polymorphisms in tryptophan hydroxylase, the serotonin transporter, monamine oxidase A and B, and four serotonin receptor types (lA, lB, 2A, and 2C). The research plan will also allow preservation of DNA for future use and assessment of the feasibility of future studies involving sib-pair linkage, recruitment of adequate samples of other races, and longitudinal studies of genetic and environmental effects on chronicity of the disorder.