Fig. 5: Disease applications of constraint.
From: The mutational constraint spectrum quantified from variation in 141,456 humans
a, The rate ratio is defined by the rate of de novo variants (number per patient) in 5,305 cases of intellectual disability/developmental delay (ID/DD) divided by the rate in 2,179 controls. pLoF variants in the most constrained decile of the genome are approximately 11-fold more likely to be found in cases compared to controls. Error bars represent 95% confidence intervals. b, Marginal enrichment in per-SNV heritability explained by common (minor allele frequency > 5%) variants within 100-kb of genes in each LOEUF decile, estimated by linkage disequilibrium (LD) score regression48. Enrichment is compared to the average SNV genome-wide. The results reported here are from random effects meta-analysis of 276 independent traits (subsetted from the 658 traits with UK Biobank or large-scale consortium GWAS results). Error bars represent 95% confidence intervals. c, Conditional enrichment in per-SNV common variant heritability tested using regression of linkage disequilibrium score in each of 658 common disease and trait GWAS results. P values evaluate whether per-SNV heritability is proportional to the LOEUF of the nearest gene, conditional on 75 existing functional, linkage disequilibrium, and minor-allele-frequency-related genomic annotations. Colours alternate by broad phenotype category.
