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- Title
Contextualizing genetic risk score for disease screening and rare variant discovery.
- Authors
Zhou, Dan; Yu, Dongmei; Scharf, Jeremiah M.; Mathews, Carol A.; McGrath, Lauren; Cook, Edwin; Lee, S. Hong; Davis, Lea K.; Gamazon, Eric R.
- Abstract
Studies of the genetic basis of complex traits have demonstrated a substantial role for common, small-effect variant polygenic burden (PB) as well as large-effect variants (LEV, primarily rare). We identify sufficient conditions in which GWAS-derived PB may be used for well-powered rare pathogenic variant discovery or as a sample prioritization tool for whole-genome or exome sequencing. Through extensive simulations of genetic architectures and generative models of disease liability with parameters informed by empirical data, we quantify the power to detect, among cases, a lower PB in LEV carriers than in non-carriers. Furthermore, we uncover clinically useful conditions wherein the risk derived from the PB is comparable to the LEV-derived risk. The resulting summary-statistics-based methodology (with publicly available software, PB-LEV-SCAN) makes predictions on PB-based LEV screening for 36 complex traits, which we confirm in several disease datasets with available LEV information in the UK Biobank, with important implications on clinical decision-making. Genetic studies on complex traits have revealed a substantial role for common, small-effect polygenic burden and large-effect variants. Here, the authors investigate how these types of variation can inform disease risk stratification and prediction.
- Subjects
UNITED Kingdom; RARE diseases; DECISION making
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-24387-z