Despite growing sample sizes and our ability to capture over 2.5 million SNPs across the genome, SNPs reaching formal significance levels in association studies typically explain <2% of the variance in addiction-related phenotypes. For instance, the effect associated with rs1051730 and liability for smoking was a β of 1.03. Thus, it was first thought, as has been suggested for other complex multifactorial traits, that most of the heritability of addiction is ‘missing'.93, 94 However, Visscher and colleagues95 point out that the emphasis on SNPs reaching only formal significance at 5 × 10−8 overlooks the evidence for polygenic association in the remainder of the GWAS data. For instance, studies of smoking and substance-related phenotypes have identified cell-adhesion genes as contributors although no signal has attained genomewide significance (for example, Bierut et al.81 and Johnson et al.96). In addition, recent studies have found that sets of SNPs of nominal significance might be used to identify genomic regions that are over-represented across independent GWAS97, 98—here as well, cell-adhesion genes, such as cadherins, are prominent, although only nominally significant in the individual studies. Although
