Pathway analyses of the ‘age at first tooth’ and ‘number of teeth’ GWASs were performed using the ALIGATOR method (13). The implementation of ALIGATOR described in Holmans et al. (13) maps genes to gene ontology categories; however, the method is equally applicable to other gene to pathway mappings and we used ALIGATOR to test for the enrichment of significant genes within biological pathways; significant genes are defined by the method as those with one or more SNPs with an association P-value less than a predefined threshold within the gene. We considered 2276 pathways curated by the Broad Institute (http://www.broadinstitute.org/gsea/), as well as pathways from ‘Pathway Commons’ (http://www.pathwaycommons.org/pc/home.do) and additional inflammatory pathways (58,59). All genotyped and imputed SNPs with minor allele frequencies of >0.05 were included in the analyses. The method corrects for variable gene size, and multiple testing of non-independent pathways using permutation. All ALIGATOR analyses used 10 000 simulated replicate gene lists and 2000 simulated replicate studies. We compared results using P-value thresholds for association at 0.005, 0.001 and 0.0005 and 0.0001, and as suggested Holmans et al. (13) report results from the analysis showing the most significant enrichment of pathways.
