Contextualizing genetic risk score for disease screening and rare variant discovery

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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.

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Zhou, D., Yu, D., Scharf, J. M., Mathews, C. A., McGrath, L., Cook, E., … Gamazon, E. R. (2021). Contextualizing genetic risk score for disease screening and rare variant discovery. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-24387-z

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