Multivariate analyses of polygenic risk for impulsivity and alcohol use: A study of longitudinal trajectories of binge drinking in emerging adulthood

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(7) 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 genetic risk for impulsivity, and (2) apply improved genetic liability models and polygenic risk scoring techniques to the prediction of changing binge drinking behaviors in developmentally relevant longitudinal samples. The applicant’s main career objective is to develop a program of research integrating sophisticated statistical genetics modeling approaches with empirically informed personality, neurocognitive and addictions science to investigate genetic influences on the developmental etiology of problematic drinking and related disorders. Specific Aims: The proposed project aims to (1a) calculate single nucleotide polymorphism-based heritability estimates and genetic correlations for impulsivity and alcohol use phenotypes, (1b) conduct exploratory and confirmatory multivariate GWAS analyses of impulsivity and alcohol use phenotypes, and (2) utilize summary statistics obtained from multivariate GWAS approaches to calculate polygenic risk scores to predict binge drinking across late adolescence and early adulthood. In order to complete the proposed project, the applicant will receive extensive training in advanced statistical approaches to model genetic and phenotypic data from experts in the fields of quantitative and molecular genetics and alcohol use and externalizing disorder etiology. Training will be obtained via (1) coursework, (2) conference and workshop attendance, and (3) meetings with expert consultants in impulsivity and binge drinking as well as statistical genetics and longitudinal modeling. Method: Towards the abovementioned aims, the applicant will request and acquire relevant impulsivity and alcohol use GWAS summary statistics (discovery samples; see Table 1 in Research Strategy section). Genome-wide genetic and phenotypic binge drinking data from three independent longitudinal samples of emerging adults (target samples) provided by Dr. Slutske (Co-Sponsor) and Dr. Fromme (consultant). Following discovery sample data acquisitions, linkage disequilibrium score regression will be employed to generate within-trait estimates of single nucleotide polymorphism-based heritability and between-trait estimates of genetic correlations. Next, summary statistics will be analyzed using two advanced multivariate GWAS approaches that incorporate genetic correlations to generate optimized trait-specific and latent dual-systems impulsivity summary statistics. Finally, these statistics will be used in polygenic models to predict longitudinal changes in binge drinking across late adolescence and early adulthood in each target sample. Significance: Results from this project will increase understanding of genetic factors contributing to changes in binge drinking across a critical developmental period, and more broadly, the genetic etiology of alcohol use disorder development. Findings will also represent novel applications of state-of-the-art genetic modeling.