Statistical power in association studies is in part a function of minor allele frequency and it is expected that individual tests of rare variants will lack sufficient statistical power. To address this, we implemented a series of burden tests that grouped nonsynonymous variants within a gene and test for an association between the grouping value and the phenotype(35, 36). Different burden tests perform more or less well depending on the true genetic effect(35). Accordingly, we selected two burden tests with different assumptions: a variable threshold collapsing and multivariate count method (VTCMC(37, 38)), and the sequence kernel association test (SKAT(39)).
