Our VEGAS-based analysis of 165 candidate genes for behavioral disinhibition also failed to yield any clear significant effects. Previous GWAS of phenotypes related to behavioral disinhibition have also failed to find support for candidate-gene associations (K. S. Kendler et al., 2011), and GWAS of other behavioral phenotypes including schizophrenia (Collins et al., 2012) and depression (Bosker et al., 2011) have similarly failed to find evidence of association with what had previously been identified as strong candidate genes for these disorders. This may reflect the now well-known limitations of candidate-gene research (Sullivan, 2007). Nonetheless, our failure to find associations between our nicotine phenotype and variants in the cholinergic nicotinic receptor subunit gene clusters on 15q25.1 (CHRNA5-CHRNA3-CHRNB4) (N. L. Saccone et al., 2010) and 8p11 (CHRNB3-CHRNA6) (Thorgeirsson et al., 2010) as well as nicotine-metabolizing enzyme genes on 19q13 (CYP2A6-CYP2B6) (Thorgeirsson et al., 2010) may seem a bit surprising since these variants have been identified in earlier GWAS of smoking.
