This is a 5-year proposal to extend current methodologies and develop optimal strategies for investigating the genetics of susceptibility to alcoholism. Long term objectives are to develop realistic genetic and nongenetic transmission models which accurately represent the complexities of the familial distribution patterns of alcoholism, to identify optimal techniques to detect genetic effects in the etiology of alcoholism, and ultimately, to find the chromosomal location of those genes, both of small and large effect, responsible for the disease. The collaboration with others in the genetic study of alcoholism and its complications will result in a better understanding of the pathogenesis of alcoholism and will lead to a significant improvement in the treatment accorded to those affected with this illness and its medical consequences. The specific goals are to: (1) investigate the properties of oligogenic models of disease by, among other things, deriving analytically the recurrence risk to various classes of relatives of an affected individual and determining sample size needed to do effectively linkage analysis under such models; (2) determine sampling strategies for pedigrees in which alcoholism is segregating in order to optimize opportunities to identify linkage between genetic markers and trait genes; (3) determine the most effective linkage methods for detecting genes involved in the etiology of traits determined by a variety of oligogenic models; (4) determine the extent to which maximization of lod scores over genetic parameters predict the underlying mode of inheritance; (5) assess the techniques developed on existing sets of data for compatibility with the theoretical results obtained on various genetic models. This proposal consists of theoretical exploration, computer simulation, and data analysis. First, solutions of theoretical questions relating to models of inheritance, sampling strategies, and linkage analysis, will be pursued; second, adaptation of computer programs to implement simulation of data, evaluation of existing linkage analytic methods, and investigations into alternative research strategies will be accomplished. After these goals are met, the new strategies will be applied to simulated data, and finally, to existing data sets of pedigrees in which alcoholism has been diagnosed. This research will significantly contribute to the ability to locate susceptibility loci in complex traits and to the clarification of those etiological mechanisms responsible for susceptibility to alcoholism.
