(1) A comprehensive set of rare variant association tests were implemented for both autosomal and X-linked variants. These tests range from the simple burden test, which assumes rare variants in the gene region have similar effect sizes (Li and Leal, 2008), to sequence-kernel association tests that can handle scenarios where variants in the same gene region affect the phenotype in opposite directions (Wu et al., 2011), e.g. when both hypermorphic and hypomorphic alleles are present. For a comprehensive description of rare variant association analysis methods, the readers may refer to a recent review (Lee et al., 2014).
