In this section, we review recent advances in molecular genetic studies of nicotine dependence and alcohol dependence as representative of the kind of results and problems confronted in isolating genetic variants in human populations than contribute to risk for SUDs. Two paradigms dominate the field. Candidate gene association studies examine allelic variation in specific genes, selected on the basis of prior evidence, in SUD cases versus controls. Genome-wide association studies (GWAS) examine up to a million genetic polymorphisms across the genome for association with the phenotype of interest. The latter approach has the advantage of allowing an unbiased assessment of risk variants and the disadvantage of needing very stringent significance levels because of the large number of tests performed: nominal P-values must be less than 5 × 10−8 to remain significant after Bonferroni correction for the very large number of genetic markers tested. To detect genetic effects of modest size that are typical for complex traits like SUD, GWAS studies require very large samples. Efforts are under way to reduce the number of tests performed on GWAS data—for example, by looking at individual genes or networks of genes—and thereby increase statistical power.
