Alcohol Dependence (AD) is a major public health problem. Prior research demonstrates that genetic factors play a critical etiologic role in AD. The goal of this project is to identify specific loci (SL) which impact on risk for AD. This application builds on the achievements of the first two funding periods during which we completed collections of a large affected sibling pair and control sample for AD in Ireland. We have completed and analyzed a genome scan for AD, AD symptoms and other AD-related traits and have begun to test physiological and positional candidate genes. We have screened 122 genes using the NIAAA developed """"""""addictions array,"""""""" completed 439 markers under our chromosome 4 linkage peak and completed a pooled genome wide association (GWA) for AD. We have produced strong evidence for association between AD and ZNF699 a human homolog of the Drosophila gene hangover. This application for a second competitive renewal has six specific aims: i) to continue fine mapping SL under our linkage peak in our affected sibpair sample;ii) to collect, in Ireland, a new sample of 1,000 AD cases and 1,000 controls to increase our power to detect, by association analysis, modest effect SL for AD;iii) to establish a bioinformatic prioritzation system to select genes to be tested in our new sample that will utilize eight different sources of data including prior results from our first sample (fine mapping, addictions array and pooled GWA), as well as, careful analyses of the linkage studies for alcohol related traits in model organisms and genes whose level changes in mouse brain in response to ethanol;iv) to genotype, using a two-stage design and a false-discovery rate format, 150-200 prioritized genes for AD in sample sizes sufficient to detect 80 percent of true effects with odds ratios greater than or equal to 1.3;v) to study the molecular biology of selected positive SL and AD starting with ZHF699;vi) for all suggestive SL, to examine gene x gene, gene x sex and gene x environment interactions, explore whether these SL impact on patterns of and reactions to ethanol consumption in our control sample, define the boundaries of the phenotypic spectrum of these SL and determine whether the impact of these SL on AD is mediated through other traits.
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