Extended Data Fig. 6: Calibration of gene-level association analyses.

For both the burden and SKAT tests, we tested for gene-level association within seven different allelic masks. As this produced seven P values for each test, we developed two means to consolidate these results (Methods). a, b, The quantile–quantile plots of associations are shown for the minimum P-value burden test (a) and the weighted burden test (b). Each test is two-sided and consists of n = 43,071 unrelated individuals. Only genes with combined minor allele count of 20 or greater are shown in the quantile–quantile plots, to avoid deflation from genes with too few variants to produce P values asymptotically uniform under the null distribution. The λ values indicate genomic control, as measured by the ratio in observed median χ² statistic to that expected under the null hypothesis. The three genes with exome-wide significant associations are labelled. Red line, expectation of P values under the null distribution. Blue lines (and grey region), 95% confidence interval of expectations under the null distribution.