Impact of an integrated monogenic and polygenic risk assessment on Tier-1 conditions in a real-world cohort

Tier-1 conditions, including breast, colorectal, and prostate cancers and coronary artery disease, have been characterized primarily in patients with hereditary phenotypes but are also common in the general population, partly due to polygenic contributions. We evaluated pathogenic variants (PVs) in nine Tier-1 genes, externally developed polygenic risk scores (PRS), and GenProb, an integrated model combining PVs and PRS, in the Genomic Health Initiative (GHI), a U.S. community-based healthcare biobank. Population attributable risk percentage (PAR%), C-index, and net reclassification index (NRI) were estimated using Cox regression models. Among 20,477 participants, the median age was 64 years, 65% were female, and 36% were of non-European ancestry. Tier-1 conditions were common, affecting 5381 participants (26%). Across conditions, PRS explained substantially higher PAR% (3.44–13.96%) than PVs (0.17–2.65%). A monogenic-only testing strategy limited to individuals with family history identified 166 PV carriers, accounting for only 1.5% of all cases. In contrast, GenProb identified 6563 high-risk individuals, including 1259 cases, accounting for 23.4% of all cases. GenProb outperformed PV-only testing for risk assessment of Tier-1 conditions and may improve identification of high-risk individuals in the general population.