The AGRS approach has limitations in that it is not necessarily a candidate system approach (although in this case all of the included candidate polymorphisms are related to the dopamine system). Additionally, the AGRS score in this study assumed equal weights as sufficient data on pharmacogenetic predictors of bupropion response to assign relative weights were not available. Furthermore the AGRS approach used in this study assumes additive effects and does not allow for epistasis. Nevertheless, the approach has strengths in allowing for the complex genetics of smoking cessation to be modeled in a more statistically and logically tractable fashion. This study has limitations, such as a limited sample size, and a reliance on existing genetic markers related to bupropion response. The DRD2 TaqIA marker, for example is unlikely to be a causal variant but may be in linkage disequilibrium with other putatively functional variants nearby (e.g.,26). Similarly, variation in the DRD4 gene may be more complex than the traditional binning methods and merit alternative coding strategies.21 Moreover population stratification of individual variants may artificially inflate or reduce the AGRS with
