Rare penetrant mutations confer severe risk of common diseases

• Published in: Science (American Association for the Advancement of Science) Vol. 380; no. 6648; p. eabo1131
• Main Authors: Fiziev, Petko P, McRae, Jeremy, Ulirsch, Jacob C, Dron, Jacqueline S, Hamp, Tobias, Yang, Yanshen, Wainschtein, Pierrick, Ni, Zijian, Schraiber, Joshua G, Gao, Hong, Cable, Dylan, Field, Yair, Aguet, Francois, Fasnacht, Marc, Metwally, Ahmed, Rogers, Jeffrey, Marques-Bonet, Tomas, Rehm, Heidi L, O'Donnell-Luria, Anne, Khera, Amit V, Farh, Kyle Kai-How
• Format: Journal Article
• Language: English
• Published: United States 02.06.2023
• Subjects: Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Mutation; Penetrance; Phenotype; Risk Factors
• ISSN: 1095-9203
• DOI: 10.1126/science.abo1131

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 ~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.