The most highly constrained missense (top 25% missense Z scores) and PTV (pLI ≥0.9) genes show higher expression levels and broader tissue expression than the least constrained genes20 (Figure 3c). These most highly constrained genes are also depleted for eQTLs (p < 10−9 for missense and PTV; Figure 3d), yet are enriched within genome-wide significant trait-associated loci (χ2 p < 10−14, Figure 3e). Intuitively, genes intolerant of PTV variation are dosage sensitive: natural selection does not tolerate a 50% deficit in expression due to the loss of single allele. Unsurprisingly, these genes are also depleted of common genetic variants that have a large enough effect on expression to be detected as eQTLs with current limited sample sizes. However, smaller changes in the expression of these genes, through weaker eQTLs or functional variants, are more likely to contribute to medically relevant phenotypes.
