LAUSR

Background Genetic influences on alcohol dependence (AD) have been well established, with the heritability of AD as estimated in behavioral genetic studies ranging from 50-60%. However, robust genetic association signals in human studies of AD have been limited. As part of the VCU Alcohol Research Center, we use multiple model organism systems (C. Elegans, Drosophila, mouse, and rat) and human studies to advance our understanding of the genetic basis of alcohol related outcomes. Molecular responses to ethanol are likely to be shared across species because signaling mechanisms are evolutionarily conserved. As individual genes and gene networks are associated with ethanol response in model organisms, it is critical to understand their association with human alcohol related phenotypes. In this study we tested the effect of several gene sets identified through model organism research with a range of phenotypes hypothesized to be involved in alcohol-related outcomes in human studies. Methods All the sets and genes were tested using one of the two related software depending if the sample contains independent individuals (Plink set based analysis) or the sample has dependent individuals (Gskat). In all human samples we used imputed data if available. Plink uses algorithm based on significant pruned SNPs (r^2=0.5) at the threshold (p=0.05) keeping LD structure and permuting phenotype randomly between individuals. Gskat performs Family based association test for sets via GEE Kernel Machine score test. We used covariates same as in previous GWAS and other analyses for each of the samples. Results We find evidence that there is some evidence of association in human samples in all three considered gene sets and genes separately for some considered phenotypes. Max number of drinks was strongly associated with several genes in human samples. Externalizing phenotype also showed association with several genes across most human samples. Considering several human samples allows us more preciously determine gene structure affecting alcohol related phenotypes. Discussion In these analyses we tested gene sets with known association in mouse and invertebrate models for the association in human samples using alcohol related phenotypes in an effort to characterize similarities between human phenotypes and animal analogues. It is important to take into account the multiple pathways by which genes may exert an effect on alcohol problems in humans. Analogues between human and animal models will help with explaining the biological and functional reasons creating behavioral problems.