The focus of this study on pair-wise analyses is one of its limitations. The reasons for this choice include limiting the large number of statistical tests performed, the theoretical results suggesting that factors not detectible with pair-wise analyses are unlikely to display large effects (Culverhouse et al. 2002), and the fact that our hypothesis-generating sample was of modest size for examining joint effects. We recognize that higher-order joint effects with three or more variants may play important roles in the etiology of complex disease, but larger datasets are needed to evaluate such complex multi-SNP effects. A second limitation of the study is that we were not able to test all of the identified signals in independent data.
