Genetic determinants of risk behavior in relation to alcohol use and alcohol use disorder: a developmental perspective

Evidence from genetic and prospective studies suggests that a large part of the risk for substance use and substance use disorder (SUD) is mediated through a common factor (Zucker 2006). This common factor has been identified as reflecting risk for externalizing disorders (e.g. Kendler et al. 2003) and is characterized by dysregulation, aggression and impulsivity as well as personality traits reflecting sensation or novelty seeking (Cloninger et al. 1988; Koopmans 1997). These traits, in childhood and in adolescence and beyond, are substantially heritable and predict future substance use and SUD. The extent to which genetic influences on substance use and SUD reflect the genetics of these traits is unknown. In addition, onset of substance use and transitions from use to abuse also depend on environmental factors, including the social environment. As is the case with genetic influences, the extent to which environmental influences reflect influences shared with psychiatric and personality risk factors is unknown. Finally, the causal pathways whereby psychiatric and personality risk factors interact with environmental risk factors over developmental time are poorly understood. To resolve these questions longitudinal, genetically informative data are required. These can be collected in twin and family samples, in which the covariance structure among phenotypes (on e.g. substance use and abuse, psychiatric and personality traits and environmental risk and protective factors) in family members is informative for genetic epidemiology, or in samples in which genetic information comes from DNA polymorphisms. In the past 20 years we have collected two large prospective genetically informative cohorts that have substantial power to clarify the developmental and genetic relationships among the following three clusters of traits: 1) sensation seeking, externalizing and internalizing disorders, 2) alcohol, and other drug onset use and abuse and 3) lifestyle and social environment. The first dataset (young twins, YNTR) includes twins recruited at birth and followed into adolescence and young adulthood. The second dataset (adults, ANTR) consists of adolescent and adult twins and family members (parents, siblings, spouses), who have participated since 1991 in up to 7 surveys. Subsamples from both cohorts have been genotyped with microsatellite markers for genome-wide linkage studies, with genome-wide SNP/CNV sets for association studies and with SNPs (and other polymorphisms) in candidate genes. We seek to collect an additional survey in the young and adult participants to follow them into their period of risk. These surveys will specifically focus on alcohol, nicotine and other drug use and abuse, on early and later risk factors and on characterization of the environment. All longitudinal genetic data will be used to address the etiology of predictive associations between substance use and substance use disorder, externalizing and internalizing problems and personality using genetic epidemiology as well linkage and association studies.