As Goldman (2014, this issue) notes, epistasis, which is key to the type of emergenic traits and network interactions that Miller et al. (Miller, Clayson, & Yee, 2014, this issue) and Schumann (2014, this issue) discussed, is another possible contributing factor we did not evaluate. In our experience, epistasis is only evaluated once a number of known genetic loci have been identified, and then pairwise tests of epistasis are conducted on those known loci. This is due to the overwhelming multiple testing burden incurred by naively testing all pairwise SNP combinations. For instance, if we confined ourselves to examine just pairwise interactions for the SNPs we evaluated in our GWAS analyses, we would need to adopt a p-value cutoff of 5 × 10−16. If we included the 27 million variants from the sequencing study, we would need to calculate hundreds of trillions of statistical tests! Methods are being developed to prioritize SNPs for exploring interaction effects using statistical learning algorithms (Lubke et al., 2013). Nevertheless, the computational burden is significant, and accommodating the family structure of our sample may not
