Because multiple independent CHRNA5 risk variants were identified, a critical question is what proportion of phenotypic variance is explained by coding variation in this one gene. Genetic studies of complex traits have identified reproducible associations, but these findings often explain a modest proportion of phenotypic variance.31 For nicotine dependence, rs16969968, arguably the single strongest genetic risk factor in European ancestry populations, accounts for 1.0% of variance in European Americans in our study and others.32_ENREF_10 The addition of low frequency and rare coding variants increased the estimated phenotypic variance explained by this gene in European Americans to 2.4%. In African Americans, though rs16969968 is less common and therefore explains a smaller proportion of estimated phenotypic variance (R2=0.4%), adding low frequency and rare coding variants increased this estimate (R2=1.0%). Since self-reported smoking behaviors are crude measures of exposure to nicotine, the variance explained by these polymorphisms for biomarkers of smoking such as carbon monoxide and cotinine will likely be greater.33,34 For example rs16969968 explained four to five times more of the variance in carbon monoxide and cotinine levels compared to self-reported cigarette
