study-wide significance levels for individual categories). The SNPratio test compares the proportion of nominally significant (p < .05) SNPs within genes to all SNPs within genes that relate to a specific biological pathway (from 220 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes (KEGG)). The NCBI definition of gene boundaries (including the 5 kb upstream and 2 kb downstream flanking region), was used to define a gene. An empirical p-value is estimated from the comparisons to ratios in datasets where the trait score has been randomised (1000 permutations). Because PLINK output was used for this analysis, the Brisbane cohort was re-run using PLINK on a randomly selected single member from each family. It should be noted that pathway categories differ between GO and KEGG databases. The GO categories are descriptors of gene products that fall into three broadly defined groups: biological process, cellular component and molecular function, whereas the KEGG database contain pathways that have been constructed through knowledge of molecular interaction and reaction networks.
