We also analyzed high-order interactions between SNPs using the multifactor dimensionality reduction (MDR) constructive induction algorithm. A detailed explanation on the MDR method has been described elsewhere [42, 43] . SNPs in LD (cut-off of r 2 ,0.8) were excluded from the MDR analysis. Cross-validation and permutation testing were used to identify the best models. All possible two-, three-and four-way SNP interactions were tested using 100-fold cross-validation and the exhaustive search. The model with the highest testing balanced accuracy (TA) and cross validation consistency (CVC) was selected as ''best model''. Statistical significance was evaluated using a 1.000-fold permutation test to compare observed testing balanced accuracies with those expected under the null hypothesis of no association (using the MDR permutation testing module 0.4.9 alpha). MDR results were considered statistically significant at the 0.05 level. Finally, interactions were visualized by constructing an interaction dendrogram according to the method described by Moore et al [43] . MDR software and MDR permutation testing module are open-source and freely available from http://www.epistasis.org.