Rare penetrant mutations confer severe risk of common diseases

We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer similar to 10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared with common-variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.

Automated summary

We discovered that rare, penetrant mutations in genes associated with complex traits and common diseases have about 10-fold larger effects than common variants in the same genes. By identifying individuals at the phenotypic extreme and at risk for severe, early-onset disease through rare penetrant variants, rather than relying on many weak common variants, we greatly improve the clinical utility of genetic-based risk prediction. Our unified genetic risk model, combining rare variants across phenotype-associated genes, shows superior portability across diverse global populations compared to common-variant polygenic risk scores.