Exome sequencing on tens of thousands of parent-proband trios has
identified numerous deleterious de novo mutations (DNMs) and implicated
risk genes for many disorders. Recent studies have suggested shared genes
and pathways are enriched for DNMs across multiple disorders. However,
existing analytic strategies only focus on genes that reach statistical
significance for multiple disorders and require large trio samples in each
study. As a result, these methods are not able to characterize the full
landscape of genetic sharing due to polygenicity and incomplete penetrance.
In this work, we introduce EncoreDNM, a novel statistical framework to
quantify shared genetic effects between two disorders characterized by
concordant enrichment of DNMs in the exome. EncoreDNM makes use of
exome-wide, summary-level DNM data, including genes that do not reach
statistical significance in single-disorder analysis, to evaluate the
overall and annotation-partitioned genetic sharing between two disorders.
Applying EncoreDNM to DNM data of nine disorders, we identified abundant
pairwise enrichment correlations, especially in genes intolerant to
pathogenic mutations and genes highly expressed in fetal tissues. These
results suggest that EncoreDNM improves current analytic approaches and may
have broad applications in DNM studies.