MOLECULAR EPIDEMIOLOGY OF ALCOHOLISM /COMORBID DISORDERS

这项新的MARC研究试图建立在基因发现主题的基础上，这些主题是用于治疗的--确定的酗酒者及其亲属。此外，社区确定的酗酒者和重度吸烟者及其成年亲属将通过将分子遗传成分纳入从青春期早期到年轻成年期的4项成熟的前瞻性纵向研究来进行研究，并进行3-7波前瞻性评估。除了从目标样本中收集DNA，这项研究还将结合二次数据分析和基因分型，分4个阶段进行：(I)纵向和其他表型分析，以在信息性数据集上建立一致的表型定义(并非所有数据集对所有感兴趣的表型都具有信息性)；(Ii)使用现有的双胞胎数据集进行行为遗传学分析，以确认在(I)阶段定义的表型的遗传性，并在可能的情况下确定表型操作是否对了解遗传效应是最佳的(如果遗传和环境影响的结构非常不同，则可能不是这样)；(Iii)对有限数量的候选基因进行基因分型；(4)遗传关联分析。当组合候选基因数据和丰富的纵向数据集时，这种谨慎的阶段性方法是必要的，以最大限度地减少多次测试的危险。出于同样的原因，我们将重点放在少数候选表型上，在这些表型中，预期的数据有望为了解酒精中毒的病因提供信息，正如背景和初步研究所证明的那样。候选表型和候选基因的选择是在MARC的指导下进行的，重点是行为控制不足、负面情绪调节和药物脆弱性的重叠机制在酒精使用障碍(AUD)的病因中的作用， 强调AUD表型与(A)外化症状、(B)耐受性和定量消费指数、(C)酒精使用的认知方面(预期)、(D)与烟草依赖共存以及(E)消极情绪(抑郁、自杀)有关。

This new MARC research, seeks to build upon gene-discovery subjects which are for treatment-ascertained alcoholics and their relatives. Also, community-ascertained alcoholics and heavy smokers and their adult relatives will be studied by incorporating a molecular genetic component into 4 mature, prospective longitudinal studies spanning the age-range from early adolescence into young adulthood, with 3-7 waves of prospective assessment. In addition to collecting DNA from the target samples, this research will combine secondary data-analysis and genotyping, proceeding in 4 stages: (i) longitudinal and other phenotypic analyses to establish consistent phenotype definition across informative data-sets (not all data-sets will be informative for all phenotypes of interest); (ii) behavioral genetic analyses using existing twin data sets to confirm heritability of phenotypes defined at stage (i), and where possible determine whether that phenotypic operationalization is optimal for understanding genetic effects (which may not be the case if the structures of genetic and environmental influences are very different); (iii) genotyping for a limited number of candidate genes; and (iv) genetic association analysis. This carefully staged approach is necessary to minimize the dangers of multiple testing when combining candidate gene data and rich longitudinal data-sets. For the same reason, we focus on a limited number of candidate phenotypes where prospective data are expected to be informative for understanding the etiology of alcoholism, as justified under Background and Preliminary studies. Selection of candidate phenotypes and candidate genes is guided by the MARC focus on the roles of overlapping mechanisms of behavioral undercontrol, negative affect regulation and pharmacologic vulnerability in the etiology of alcohol use disorders (AUDs), emphasizing AUD phenotypes associated with (a) externalizing symptoms, (b) tolerance and quantitative consumption indices, (c) cognitive aspects of alcohol use (expectancies), (d) co-occurrence with tobacco dependence, and (e) negative affect (depression, suicidality).