Rare penetrant mutations confer severe risk of common diseases-Reference-Cited by-同舟云学术

Rare penetrant mutations confer severe risk of common diseases

Published:2023-06-02 Issue:6648 Volume:380 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Fiziev Petko P.¹^ORCID,McRae Jeremy¹^ORCID,Ulirsch Jacob C.¹^ORCID,Dron Jacqueline S.²³^ORCID,Hamp Tobias¹,Yang Yanshen¹,Wainschtein Pierrick¹⁴^ORCID,Ni Zijian⁵^ORCID,Schraiber Joshua G.¹,Gao Hong¹^ORCID,Cable Dylan⁶,Field Yair¹^ORCID,Aguet Francois¹^ORCID,Fasnacht Marc¹,Metwally Ahmed¹^ORCID,Rogers Jeffrey⁷⁸^ORCID,Marques-Bonet Tomas⁹¹⁰¹¹¹²^ORCID,Rehm Heidi L.²³¹³^ORCID,O'Donnell-Luria Anne³¹³¹⁴^ORCID,Khera Amit V.²³¹⁵^ORCID,Farh Kyle Kai-How¹^ORCID

Affiliation:

1. Artificial Intelligence Laboratory, Illumina, Inc., San Diego, CA 92122, USA.

2. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

3. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

4. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

5. Department of Statistics, University of Wisconsin–Madison, Madison, WI 53706, USA.

6. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA.

7. Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

8. Wisconsin National Primate Research Center, University of Wisconsin–Madison, Madison, WI 53715, USA.

9. Institute of Evolutionary Biology (UPF-CSIC), 08003 Barcelona, Spain.

10. Catalan Institution of Research and Advanced Studies (ICREA), 08010 Barcelona, Spain.

11. CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain.

12. Institut Català de Paleontologia Miquel Crusafont, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain.

13. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

14. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, USA.

15. Verve Therapeutics, Cambridge, MA 02215, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.abo1131

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