chromosomes 4 and 7. Follow-up association studies of candidate genes in the linkage regions have identified association with several genes in each region, including GABRA2,48 NFKB1,51 ADH4, ADH1A, ADH1B,49 CHRM2,52 and TAS2R16.53 Although these studies illustrate the potential of genome-wide linkage approaches (followed by targeted association tests in the linked regions) to identify novel genetic variants, linkage studies are largely underpowered to detect genes of small effect, such as those hypothesized to be involved in addiction. Although linkage was successful in the identification of genes involved in monogenic diseases, mapping polygenic disease genes requires a large number of family members to ensure sufficient power to detect genetic variants.54 In addition, linkage mapping lacks the precision other methods provide, because the linkage peaks resulting from this strategy do not precisely localize the associated genes, and imprecise linkage peaks make it difficult to know the exact region to target for follow-up with association studies.
