The original P-values were more significant than the empirical P-values (compare Table II and Supplemental Table I) because the permutation tests took into account the multiple SNPs tested across the genes. Most of the genes that yielded empirical P <0.05 had multiple independent significant SNPs in the gene, a criteria which COGA has routinely used to bolster confidence in significantly associated genes. However, we note that none of the SNPs would have passed a stringent Bonferroni correction for all SNPs tested across the chromosome, which would have required a P-value of 6 × 10−7. Because our study was not completely atheoretical, but rather, we targeted this region of the genome and this particular phenotype based on evidence of linkage in the region, we believe that a gene-based permutation strategy represents a more appropriate means of evaluating significance than the overly conservative Bonferroni correction. However, follow-up in independent samples will ultimately be necessary to evaluate the role of the genes implicated in this study.
