|Title||Rare penetrant mutations confer severe risk of common diseases.|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||Fiziev, 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 Published||2023 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.
|PubMed Central ID||PMC10187340|
|Grant List||R01 HG010898 / HG / NHGRI NIH HHS / United States|