The enrichment of de novo damaging (LGD + Mis3) variants in TD, as well as the observation of 5 genes with multiple de novo damaging variants raises the possibility that this class of variant targets a set of genes that mediates TD risk. We tested this hypothesis with the transmitted and de novo association (TADA) test, a Bayesian model that can effectively combine data from de novo variants, inherited variants in families, and standing variants in the population (via case-control cohorts) to assess the association of specific genes with TD risk. In this study, we elected not to include rare inherited exome variants because we have not yet associated this class of variant with TD risk, as expected given their small effect size. Instead, we used a specialized version of TADA that analyzes only the de novo variants from exome sequencing data, called TADA-Denovo (He et al., 2013).
