Demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention and treatment of these conditions. Unequivocal proof of such an association, however, requires adherence to established methodological guidelines, which include independent replication of initial positive findings. Recently, single nucleotide polymorphisms (SNPs) within GAD2 were found to be associated with class III obesity (BMI > 40 kg/m2) in 188 families (612 individuals) segregating the condition and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (-243A>G) were also presented. In the present study, we attempted to replicate this association in larger groups of subjects, and to extend the functional studies of the -243A>G SNP. In 2,327 subjects comprising 692 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the -243A>G SNP and obesity (odds ratio (OR) = 0.99, 95 percent CI 0.83 - 1.18, in the pooled sample). These negative findings were reinforced by a meta-analysis for the association between the 243G allele and class III obesity, which yielded an OR of 1.11 (95 percent CI 0.90 - 1.36) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Finally, we were unable to confirm or extend the functional data pertaining to th e -243A>G variant. Potential confounding variables in association studies invo lving common variants and complex diseases (low power to detect modest genetic effects, over-interpretation of marginal data, population stratification and biological plausibility) are also discussed in the context of GAD2 and severe obesity.