Extended Data Fig. 4. Impact of the number of controls on loss-of-function intolerance enrichment.

a, Enrichment of case (red, n = 64) under-expression outliers in LoF sensitive genes as we increase the number of controls (7,600 random subsets for each sample size indicated in legend). This enrichment was not observed for rare disease family member controls (gray, n = 34). b, Benjamini & Hochberg adjusted −log₁₀ P value associated with the enrichment at different number of controls (two-sided t-test, n = 64 cases). Horizontal line indicates 0.05 significance cutoff. The P values are decreasing as we increase the number of controls. When switching cases for controls (gray) we observed significant negative log odds when using the a smaller number of controls, but this trend disappeared when using the full set of 900 controls. For a and b, Boxplots represent median value, with lower and upper hinges corresponding to the 25th and 75th percentiles, and lower and upper whiskers extend from the hinge to the smallest and largest value at most 1.5× interquartile range of the hinge, respectively.