RT Journal Article SR Electronic T1 Quantifying concordant genetic effects of de novo mutations on multiple disorders JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.06.13.448234 DO 10.1101/2021.06.13.448234 A1 Hanmin Guo A1 Lin Hou A1 Yu Shi A1 Sheng Chih Jin A1 Xue Zeng A1 Boyang Li A1 Richard P. Lifton A1 Martina Brueckner A1 Hongyu Zhao A1 Qiongshi Lu YR 2021 UL http://biorxiv.org/content/early/2021/11/13/2021.06.13.448234.abstract AB 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.Competing Interest StatementThe authors have declared no competing interest.