Addressing Issues in the Detection of Gene-Environment Interaction Through the Study of Conduct Disorder

This work addresses issues in the study of gene-environment interaction (GxE) through research of conduct disorder (CD) among adolescents and extends the recent report of significant GxE and subsequent replication studies. A sub-sample of 1,299 individual participants/649 twin pairs and their parents from the Virginia Twin Study of Adolescent and Behavioral Development was used for whom Monoamine Oxidase A (MAOA) genotype, diagnosis of CD, maternal antisocial personality symptoms, and household neglect were obtained. This dissertation (1) tested for GxE by gender using MAOA and childhood adversity using multiple approaches to CD measurement and model assessment, (2) determined whether other mechanisms would explain differences in GxE by gender and (3) identified and assessed other genes and environments related to the interaction MAOA and childhood adversity. Using a multiple regression approach, a main effect of the low/low MAOA genotype remained after controlling other risk factors in females. However, the effects of GxE were modest and were removed by transforming the environmental measures. In contrast, there was no significant effect of the low activity MAOA allele in males although significant GxE was detected and remained after transformation. The sign of the interaction for males was opposite from females, indicating genetic sensitivity to childhood adversity may differ by gender. Upon further investigation, gender differences in GxE were due to genotype-sex interaction and may involve MAOA. A Markov Chain Monte Carlo approach including a genetic Item Response Theory modeled CD as a trait with continuous liability, since false detection of GxE may result from measurement. In males and females, the inclusion of GxE while controlling for the other covariates was appropriate, but was little improvement in model fit and effect sizes of GxE were small. Other candidate genes functioning in the serotonin and dopamine neurotransmitter systems were tested for interaction with MAOA to affect risk for CD. Main genetic effects of dopamine transporter genotype and MAOA in the presence of comorbidity were detected. No epistatic effects were detected. The use of random forests systematically assessed the environment and produced several interesting environments that will require more thoughtful consideration before incorporation into a model testing GxE