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).
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