Alcoholism is a common, complex (non-Mendelian) disorder with contributions from both genetic and environmental influences and their interactions [41]. As psychiatric diagnosis is dichotomous (either affected or unaffected), it is difficult to use diagnosis as the sole phenotype when studying the genetics of complex disorders, such as alcoholism. It has been suggested that, ideally, molecular genetic studies should not be performed on psychiatric diagnoses alone, which reflect distal and variable effects of genes, but on quantitative neurobiological measures or markers that reflect more proximal effects of genes involved in the genetic predisposition for developing psychiatric disorders [174]. These quantitative biological markers (endophenotypes or intermediate phenotypes) serve as covariates that correlate with the main trait of interest (diagnosis) and serve to better define that trait or its underlying genetic mechanism [43,175,176]. The advantages of using quantitative neurobiological measures of risk as endophenotypes in the search for genes involved in complex disorders are that they are closer to gene action involved in the predisposition for the disorder, they are genetically simpler than clinical endpoints, and quantitative traits provide more power to localize and characterize disease susceptibility genes [177].
