Human genetic studies on alcohol-related phenotypes have used family-based linkage and population-based association analyses to identify quantitative trait loci (QTLs). Linkage studies are based on co-segregation between genetic markers and alcohol dependence in families with several affected members. By contrast, association studies evaluate the strength of association between genetic variants and alcohol phenotypes in samples of unrelated individuals; these can be attributable to a causal effect of the variant or linkage disequilibrium (LD) between the molecular variant and the true causal allele. Association analyses give more precise localization of QTLs than linkage studies; however, false-positive associations can arise from population stratification of cases and controls, and by chance in small samples. In both designs, large numbers of individuals are required to detect QTLs with small effects. Early efforts to dissect the genetic basis of alcohol consumption and addiction in humans were based on candidate genes. The main pathway of ethanol metabolism involves its conversion to acetaldehyde by alcohol dehydrogenase (ADH; Figure 1). Acetaldehyde is oxidized to acetate by aldehyde dehydrogenase (ALDH). The activated form of acetate, acetyl-CoA, can be metabolized
