We conducted gene-based burden tests of rare nonsynonymous variants identified in the whole genome sequences. Non-synonymous variants were annotated using EPACTS (Kang et al. 2010) against GENCODE v11. Two types of gene-based tests were conducted, a variable threshold burden test (VT), and the sequence kernel association test (SKAT; Price et al. 2010; Wu et al. 2011). In the VT approach, each participant is assigned a burden score for each gene. The burden score is simply the sum of the number of non-synonymous minor alleles under a certain minor allele frequency (MAF). The MAF is allowed to vary until the sum score shows the strongest association with the trait, and the resulting p value is corrected for the number of MAF thresholds considered. The SKAT approach is more complex, but the basic intuition is that it conducts a test of the variance of variant effects within a gene, and whether that variance is larger than expected by chance. That is, do the variant effects differ from zero more than expected by chance? In SKAT we tested both MAF = 0.01 and
