B. A likely underlying genetic architecture for addiction (and other common heritable brain-based phenotypes for which linkage data fails to provide evidence for “genes of major effect”) We approach analyses of the molecular genetic bases of addiction and related disorders from perspectives that are based on sets of working hypotheses concerning the underlying genetic architectures of these disorders and phenotypes. In general, the best experimental design and analytic approaches are likely to arise from the best possible working hypotheses concerning: 1) the genetic architectures of the disorders or phenotypes being evaluated 2) the population genetics of the samples being tested 3) the anticipated association signals. It is also desirable to consider and provide controls for alternative hypotheses that might provide alternative explanations for systematic differences between disease and control samples. Alternative hypotheses include: 1) unintended stratification based on eg racial/ethnic differences between “disease” and “control” samples, as noted above, 2) uneven distribution of noise in some assays, so that SNPs with the largest variance might be identified rather than the SNPs whose allelic frequencies truly differ between disease and control
