Speaker Abstracts

Background:The P300 component of the event-related potential (ERP) shows a lower amplitude in offspring with parental history of alcohol use disorder in comparison to controls and is a known predictor of AUD in those with a family history of AUD suggesting a genetic basis for ERP.Genetic variants have been extensively investigated but much less is known about epigenetic pathways.The availability of whole genome methods for interrogating transcript changes presents a new opportunity for better understanding of gene expression and identification of RNA transcripts such as long non-coding variants with potentially significant impact.Methods: Probands (Generation 2) with AUD or controls, their parents (Generation 1) and their children (Generation 3) were studied.Longitudinal follow up across childhood, adolescence and young adulthood of Generation 3 provided developmental ERP data and age of onset to develop AUD/SUD.From the larger cohort, 217 adolescent/ young adult participants from high and low risk for AUD families had a 3 T MRI scan with FreeSurfer analysis.Lymphocytes obtained in childhood were stored cryogenically.Recent RNAseq analysis of 73 Gen 3 participants contrasted those without a parent or grandparent with AUD (Group 1), parent only (Group 2) and both parent and grandparent (Group 3).Results: Regional cortical thickness and visual ERP components differed by familial risk group.Visual P300 amplitude at Pz and cortical thickness of the left lateral orbitofrontal region (lhOFC) were significantly correlated, a region significantly related to risk group status (F = 7.31, df 1, 215, p = 0.007).Comparison of Groups based on the number of generations affected, we find 250 differentially expressed genes (DEGs) and RNA transcripts (p < 0.05, FDR) for Group 2 versus 1.Five Group 3 versus 1, reached FDR 2.8 ×10 -5 .CHRNa6 previously reported to be associated with nicotine, cocaine, and alcohol use disorders differed in a Group 2 versus 1 expression comparison (DEG = 1.96 ×10 -5 ) and associated with a novel LNC RNA (r = 0.346, p = 0.003).Childhood N2 latency showed a trend for association with CHRNA6 expression (p = 0.09).Conclusions: These results suggest that transcriptomic changes occur in those with family history of AUD that have implications for previously identified markers of risk including P300 amplitude and orbitofrontal cortical-thickness.