Rare Penetrant Mutations Confer Severe Risk of Common Diseases

Authors

Petko P Fiziev
Jeremy McRae
Jacob C Ulirsch
Jacqueline S Dron
Tobias Hamp
Yanshen Yang
Pierrick Wainschtein
Zijian Ni
Joshua G Schraiber
Hong Gao
Dylan Cable
Yair Field
Francois Aguet
Marc Fasnacht
Ahmed Metwally
Jeffrey Rogers
Tomas Marques-Bonet
Heidi L Rehm
Anne O'Donnell-Luria
Amit V Khera
Kyle Kai-How Farh

Language

English

Publication Date

6-2-2023

Journal

Science

DOI

10.1126/science.abo1131

PMID

37262146

Abstract

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.

Keywords

Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, Multifactorial Inheritance, Mutation, Phenotype, Risk Factors, Penetrance

Published Open-Access

yes

Recommended Citation

Fiziev, Petko P; McRae, Jeremy; Ulirsch, Jacob C; et al., "Rare Penetrant Mutations Confer Severe Risk of Common Diseases" (2023). Faculty and Staff Publications. 5089.
https://digitalcommons.library.tmc.edu/baylor_docs/5089