Translational genetic analysis in human and mouse GWAS to identify the genomic architecture of alcohol sensitivity and tolerance

ABSTRACT Alcohol use disorder (AUD) is a major U.S. health problem with 12-month and lifetime prevalence being 13.9% and 29.1%, respectively. AUD is partly caused by genetic factors with the estimated heritability being about 50%. Therefore, identification of genes related AUD can help us elucidate the genetic mechanisms of AUD and develop novel prevention and treatment strategies. While recent large-scale genome wide association studies (GWAS) have identified multiple AUD-associated genes, these genes only explain a small portion of heritability, indicating that many additional genes with small effects remain to be discovered. AUD is a heterogeneous disorder with multiple interacting genetic and environmental influences. Therefore, two individuals could receive the same AUD diagnosis, but have multiple different symptoms. One strategy to interrogate heterogeneous disorders is the inclusion of more homogenous endophenotypes, which deconstruct diagnostic categories into component features that may be more amenable to genetic research and provide a cost-effective way to increase statistical power without dramatically increasing the sample size. Alcohol sensitivity and tolerance are two important contributing features to the development and maintenance of AUD in humans, can be effectively measured in mice, and are known to be at least partly genetically mediated in both species. In this study, we propose a systematic and translational strategy to identify and validate variants and genes related to alcohol sensitivity and tolerance using both human and Diversity Outbred (DO) mice. In Aim 1, we will perform GWAS of alcohol sensitivity and tolerance in both European and African ancestry populations after adjusting for the effects of alcohol metabolism genes. Next, we will use high throughput reporter assays in multiple cell lines representing four major brain cells to identify functional variants with sub-threshold P values. We will then use a Mendelian randomization framework to identify target genes of those functional variants. In Aim 2, we will perform QTL, eQTL, and gene expression-trait correlation analyses to identify genetic variants associated with ethanol sensitivity and tolerance in DO mice. DO mice are genetically heterogeneous with large amounts of recombination that provide high mapping resolution approximating that of a human GWAS, but with a much smaller sample size. In Aim 3, we will employ our newly developed VariantGraph database to identify variants and genes with shared regulatory effects across mouse and human. The findings will advance our knowledge of the genetic architecture of alcohol sensitivity and tolerance and will shed light on AUD etiologies.