|Title||Rare penetrant mutations confer severe risk of common diseases.|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||Fiziev, PP, McRae, J, Ulirsch, JC, Dron, JS, Hamp, T, Yang, Y, Wainschtein, P, Ni, Z, Schraiber, JG, Gao, H, Cable, D, Field, Y, Aguet, F, Fasnacht, M, Metwally, A, Rogers, J, Marques-Bonet, T, Rehm, HL, O'Donnell-Luria, A, Khera, AV, Farh, KKai-How|
|Date Published||2023 Jun 02|
|Keywords||Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Mutation, Penetrance, Phenotype, Risk Factors|
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.