Molecular epidemiology of alcoholism and comorbid disorders

This new MARC research project, project 5, seeks to build upon gene-discovery projects such as COGA (Collaborative Study on the Genetics of Alcoholism: PIs Begleiter and Reich) and similar projects (e.g. PIs Hill, Kendler) which are studying treatment-ascertained alcoholics and their relatives, and the MARC-affiliated Alcohol-QTL IRPG consortium (PIs Heath, Martin, Madden, Todd), which is studying community-ascertained alcoholics and heavy smokers and their adult relatives, by incorporating a molecular genetic component into 4 mature, prospective longitudinal studies (PIs Chassin, Cooper, Heath, Sher) 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 (years 1-3), this research project 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) (years 1-3); (ii) behavioral genetic analyses using existing twin data sets (MOAFTS, the former MARC Project 1, or other U.S. and Australian data-sets to which we have access through the MARC) 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) (years 1-3); (iii) genotyping for a limited number of candidate genes (years 3-5); and (iv) genetic association analysis (years 4-5). 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 under control, 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).