Rare penetrant mutations confer severe risk of common diseases.

TitleRare penetrant mutations confer severe risk of common diseases.
Publication TypeJournal Article
Year of Publication2023
AuthorsFiziev, P, 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 Published2023 May 08

UNLABELLED: 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 to common variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.

ONE SENTENCE SUMMARY: Rare variant polygenic risk scores identify individuals with outlier phenotypes in common human diseases and complex traits.

Alternate JournalmedRxiv
PubMed ID37205493
PubMed Central IDPMC10187340
Grant ListR01 HG010898 / HG / NHGRI NIH HHS / United States