Case/control status was assigned randomly and a T5 test for burden of rare variants was executed on all genes (T5 is a variant of the CMC test58 that considers only non-synonymous variants with minor allele frequencies below 5%, uses the total count of alternative minor alleles in cases as the test statistic, and assigns significance by permuting phenotype labels). The overall deflation in significant p-values (i.e., there are fewer genes associated at any significance level than expected by chance, is due to low counts of variants in genes. Results were similar for T1 version of CMC, as well as for WSS59, and VT tests61. This pattern is expected in studies with small sample sizes (below around 1000 individuals). Whole-exome permutations can be used to establish exome-wide significance in such cases.
