The biological link between CHRNA4 and nicotine addiction phenotypes in animal models (Ross et al., 2000; Labarca et al., 2001) and humans (Breese et al., 1997; Fenster et al., 1999; Buisson et al., 2001) has made this gene a notable candidate in genetic association studies of smoking behavior. However, prior association studies in small samples have shown inconsistent results, and recent GWAS studies as reflected by three meta-analyses of GWAS studies on smoking behavior, also did not identify CHRNA4 as a susceptibility gene for nicotine dependence. There are many possible explanations for this lack of association, including genetic heterogeneity, phenotypic heterogeneity, and the limited power of GWAS studies arising from the necessity to correct for multiple comparisons.
