MOLECULAR EPIDEMIOLOGY OF ALCOHOLISM /COMORBID DISORDERS

这项新的MARC研究，旨在建立在基因发现的主题，这是为治疗确定的酗酒者和他们的亲属。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4项成熟的前瞻性纵向研究，涵盖从青春期早期到成年早期的年龄范围，并进行3-7波前瞻性评估。除了从目标样本中收集DNA外，本研究还将结合二级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，以在信息数据集中建立一致的表型定义（并非所有数据集都能提供所有感兴趣的表型信息）；（ii）使用现有的双胞胎数据集进行行为遗传分析，以确认在阶段(i)中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最适合理解遗传效应（如果遗传和环境影响的结构非常不同，情况可能并非如此）；（iii）对有限数量的候选基因进行基因分型；（四）遗传关联分析。当结合候选基因数据和丰富的纵向数据集时，这种谨慎的分阶段方法是必要的，以尽量减少多次测试的危险。出于同样的原因，我们将重点放在有限数量的候选表型上，这些表型的前瞻性数据有望为理解酒精中毒的病因提供信息，正如背景和初步研究中所证明的那样。候选表型和候选基因的选择以MARC为指导，关注行为欠控制、负面影响调节和药物易感性在酒精使用障碍（AUDs）病因学中的重叠机制的作用。

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).