Family History of Alcohol and Other Substance Use Disorders Integrated With Associated Phenotypic Characteristics Reveal Brain Structural Differences in Non-Abusing Young Adults

ABSTRACT Early adulthood is a critical developmental period for the emergence of alcohol and substance use disorders (A/SUD). Young adults with family histories of A/SUD (FH+) have a higher risk for developing A/SUD themselves compared to individuals without such family histories (FH−). FH+ individuals often exhibit behavioral and cognitive alterations similar to those observed in A/SUD populations; however, A/SUD-related structural brain alterations have not been consistently observed in FH+ neuroimaging studies, which may reflect underlying heterogeneity in FH+ individuals. We compared n=79 FH+ and 128 FH− young adults (ages 18-25) on brain volume differences in five regions of interest identified from prior A/SUD neuroimaging mega-analyses. Additionally, we compared study participants who scored low and high on a novel family history integrated phenotype (FHIP) score that combined family history with key phenotypic variables related to FH+ status. FH+ participants displayed trend-level reductions in corpus callosum volumes compared to FH− participants. However, participants with high FHIP scores had significantly decreased whole corpus callosum and increased amygdala volumes compared to participants with low FHIP scores. Post hoc testing of corpus callosum subregions found that participants with high FHIP scores had significantly reduced mid-anterior corpus callosum volume. There were no differences in hippocampus, thalamus, or putamen volumes between FH or FHIP score-based groupings. FHIP scores were more sensitive than family history status alone in identifying structural brain differences in non-abusing healthy young adults. These findings suggest that corpus callosum and amygdala volumes differences could be related to a possible overarching A/SUD-relevant endophenotype rather than simply be consequences of problem alcohol and other substance use.