Ian R. Gizer

Sensation seeking is bidirectionally associated with levels of alcohol consumption in both adult and adolescent samples, and shared neurobiological and genetic influences may in part explain these associations. Links between sensation seeking and alcohol use disorder (AUD) may primarily manifest via increased alcohol consumption rather than through direct effects on increasing problems and consequences. Here the overlap among sensation seeking, alcohol consumption, and AUD was examined using multivariate modelling approaches for genome‐wide association study (GWAS) summary statistics in conjunction with neurobiologically informed analyses at multiple levels of investigation. Meta‐analytic and genomic structural equation modelling (GenomicSEM) approaches were used to conduct GWAS of sensation seeking, alcohol consumption, and AUD. Resulting summary statistics were used in downstream analyses to examine shared brain tissue enrichment of heritability and genome‐wide evidence of overlap (e.g., stratified GenomicSEM, RRHO, genetic correlations with neuroimaging phenotypes), and to identify genomic regions likely contributing to observed genetic overlap across traits (e.g., H‐MAGMA and LAVA). Across approaches, results supported shared neurogenetic architecture between sensation seeking and alcohol consumption characterised by overlapping enrichment of genes expressed in midbrain and striatal tissues and variants associated with increased cortical surface area. Alcohol consumption and AUD evidenced overlap in relation to variants associated with decreased frontocortical thickness. Finally, genetic mediation models provided evidence of alcohol consumption mediating associations between sensation seeking and AUD. This study extends previous research by examining critical sources of neurogenetic and multi‐omic overlap among sensation seeking, alcohol consumption, and AUD which may underlie observed phenotypic associations.

Background and Aims Previous studies have demonstrated associations between substance use and reduced educational attainment; however, many were unable to account for potential confounding factors like genetics and the rearing environment. In the few studies that controlled for these factors, the substances assessed were limited to alcohol, cannabis, and tobacco. To address these limitations, we examined the relationship between adolescent use of seven kinds of substances, the number of additional substances used, and high school noncompletion within a large sample of Australian twins. Design A series of two‐level generalized mixed effects logistic regressions were conducted to examine associations between adolescent substance use and high school noncompletion. Setting Australia. Participants A total of 9579 adult Australian twins from two cohorts of the Australian Twin Registry. Measurements Assessments of high school completion, childhood major depression, conduct disorder symptoms, substance use initiation, demographics, and parental educational attainment using the Australian version of the Semi‐Structured Assessment for the Genetics of Alcoholism. Findings There were unique within‐twin‐pair effects of use of sedatives (odds ratio [OR] = 22.39 [95% confidence interval (CI) = 1.18–423.48]) and inhalants/solvents (OR = 10.46 [95% CI = 1.30–84.16]) on high school noncompletion. The number of substances used in adolescence was strongly associated with high school noncompletion across all discordant twin models (ORs from 1.50–2.32, Ps < 0.03). Conclusions In Australia, adolescent substance use appears to be associated with early school dropout, with the effects of any given substance largely because of the confounding factors of parental education, childhood conduct disorder symptoms, and use of other substances. Sedatives and inhalants/solvents have effects on high school noncompletion that cannot be explained by polysubstance use or familial factors.