Rare penetrant mutations confer severe risk of common diseases

• 成果类型: Article
• 署名作者: 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
• 署名单位: Illumina; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Queensland; University of Wisconsin System; University of Wisconsin Madison; Baylor College of Medicine; Baylor College of Medicine; University of Wisconsin System; University of Wisconsin Madison; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC-UPF - Institut de Biologia Evolutiva (IBE); Pompeu Fabra University; ICREA; Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Institut Catala de Paleontologia Miquel Crusafont (ICP); Autonomous University of Barcelona; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10846
• DOI: 10.1126/science.abo1131
• 发表日期: 2023-06-02
• 页码: 930-+
• 关键词: familial hypercholesterolemia; genetic-variation; breast-cancer; prediction; variants; biobank; identification; cholesterol; PREVALENCE; DISCOVERY

摘要

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.