In the analyses presented in this review, we focus on addiction-associated allelic variants that lie in genes. Evolutionarily-old common haplotypes (eg groups of nearby variants that travel together through generations) that lie within genes are among the most likely to be tagged by SNP markers that are represented on current microarrays. Haplotypes that involve genes are thus among the most likely variants to exist in currently-reported datasets. It seems reasonable to postulate that many of these allelic variants that lie within genes provide regulatory variants that alter expression or regulation. Other variants are likely to alter mRNA halflives or mRNA splicing. Variants that alter mRNA splicing could occur at the locus of the affected gene (cis) or at genes at different loci that alter generic mRNA splicing processes (trans). Reproducible association of A2BP1 gene variants with addiction vulnerability, for example [12], provide a good candidate for trans effects on mRNA splicing, since this gene’s product regulates splicing and thus are likely to modify the functions of a number of other genes expressed in brain. It also seems likely that a minority of the addiction-associated variants will involve missense effects on expressed proteins.
