Contextualizing genetic risk score for disease screening and rare variant discovery

Nat Commun. 2021 Jul 20;12(1):4418. doi: 10.1038/s41467-021-24387-z.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clinical Decision-Making / methods
  • Datasets as Topic
  • Genetic Predisposition to Disease*
  • Genetic Testing / methods*
  • Genome-Wide Association Study
  • Humans
  • Models, Genetic*
  • Multifactorial Inheritance / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Software
  • Whole Genome Sequencing