Relations between alcohol use, aggression, executive function, and ADHD: a genetic analysis

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PROJECT SUMMARY/ABSTRACT Long Term Objectives: The overarching goals of this application are to (1) utilize advanced multivariate genome-wide association study (GWAS) approaches to improve current models of the relationship between aggression, alcohol use, executive function, and attention deficit hyperactivity disorder (ADHD), and (2) apply improved genetic liability modeling techniques to the prediction of the changing genetic relationships among these phenotypes in a developmentally relevant longitudinal sample. The applicant’s main career objective is to develop a program of research integrating sophisticated statistical genetics modeling approaches with theoretically and empirically informed models of personality, neurocognition and addiction to investigate genetic influences on the developmental etiology of problematic drinking and related externalizing disorders. Specific Aims: The proposed project aims to (1) Identify biological contributions and individual genomic regions impacting multiple traits and their covariation, (2) Test causal, directional relations between aggression, executive function, ADHD, and alcohol use, and (3) Examine longitudinal changes in genetic covariation between phenotypes. In order to complete the proposed project, the applicant will receive extensive training in advanced statistical methods to model genetic and phenotypic data from experts in the fields of quantitative and molecular genetics and alcohol use, executive function, and externalizing disorder etiology. Training will be obtained via (1) coursework, (2) conference and workshop attendance, and (3) meetings with expert consultants. Method: To complete the abovementioned aims, the applicant will acquire relevant aggression, executive function, ADHD and alcohol use GWAS summary statistics (discovery samples; see Table 1 in Research Strategy section) along with genome-wide genetic and phenotypic data from a longitudinal sample of adolescents and young adults (target sample) provided by Dr. Slutske (Consultant). Following discovery sample data acquisitions, stratified-linkage disequilibrium score regression and GNOVA will be employed to identify biological contributions to the heritability of each trait and their covariation. Next, these samples will be meta-analyzed to identify the variants they share followed by downstream analyses to identify shared biological contributions. Next, Mendelian randomization and joint association methods will be utilized to identify causal relationships among the phenotypes. Finally, mxGREML in OpenMx will be employed to model genetic covariation between each of the phenotypes across adolescence and young adulthood. Significance: Results from this project will increase understanding of genetic factors contributing to the alcohol- aggression relationship and related risk factors, and importantly will increase understanding about changes in these relationships across a critical developmental period. Findings will also represent novel applications of state-of-the-art genetic modeling techniques.