Neurogenetic influences linking impulsive personality traits and alcohol use disorder progression across development

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) is a prevalent global health problem with substantial social, economic, and public health costs. Progression from initial alcohol exposure to AUD often begins in adolescence and emerging adulthood with impulsive personality traits (IPTs) being critical developmental risk factors. However, there is

limited understanding of the dynamic longitudinal interplay between IPTs and alcohol involvement from childhood to adulthood and the role neurobiological and genetic vulnerability play in this etiology in part because: 1) longitudinal studies of IPT-AUD associations to date typically characterize specific developmental epochs (e.g.,

late adolescence), rarely comprehensively examining these associations across the full developmental span; 2) studies of neuroanatomical variation associated with IPT-AUD pathways are primarily based on small, cross- sectional datasets and restricted subsets of brain regions, despite accumulating evidence that large samples

sizes are necessary to reliably characterize brain-phenotype associations and the importance of neurodevelopmental trajectories on complex behavior; and 3) large-scale genome-wide association studies of IPTs have been primarily conducted in older adults of European ancestry, despite the clear developmental

context underlying IPT-AUD pathways and need for further incorporation of diverse ancestral populations into genomics research. This K01 proposal addresses these gaps by: 1) Aim 1: characterizing developmental associations (childhood to middle adulthood) between distinct IPTs, heavy alcohol use, and AUD progression

through data harmonization and longitudinal integrative data analysis of 16 extant primarily longitudinal study samples (N=85,862); 2) Aim 2: examining whether IPTs represent plausible mechanisms through which brain structure is linked to alcohol involvement using a subset of 9 neuroimaging studies (N=17,297) spanning

childhood to young adulthood; and 3) Aim 3: identifying developmentally specific genetic influences on IPTs, alcohol involvement, and the links between them to assess genetic stability and/or uniqueness across development using trans-ancestral genetic data. This K01 would provide the applicant with training to facilitate

transition to career independence by enabling him to: 1) acquire expertise in longitudinal data harmonization and integrative data analytic approaches; 2) build a foundational neuroimaging data analysis skill set and developmental addiction neuroscience knowledge base; 3) expand genomic analytic expertise to encompass

trans-ancestral and longitudinal genome-wide association study approaches; and 4) cultivate professional and career development toward an independent research career. Collectively, this proposal would prepare the applicant to lead an innovative research program into the genetic and biological etiology of AUD development

as an independent investigator and would provide novel insights into the developmental etiology and neurogenetic sources of variation underlying IPT-AUD pathways.