A unified framework for estimating country-specific cumulative incidence for 18 diseases stratified by polygenic risk

Abstract

Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant to clinical and public health decision-making, it is important to account for varying effects due to age and sex. Here, we develop a novel framework to estimate country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases. We integrate PGS associations from seven studies in four countries (N = 1,197,129) with disease incidences from the Global Burden of Disease. PGS has a significant sex-specific effect for asthma, hip osteoarthritis, gout, coronary heart disease and type 2 diabetes (T2D), with all but T2D exhibiting a larger effect in men. PGS has a larger effect in younger individuals for 13 diseases, with effects decreasing linearly with age. We show for breast cancer that, relative to individuals in the bottom 20% of polygenic risk, the top 5% attain an absolute risk for screening eligibility 16.3 years earlier. Our framework increases the generalizability of results from biobank studies and the accuracy of absolute risk estimates by appropriately accounting for age- and sex-specific PGS effects. Our results highlight the potential of PGS as a screening tool which may assist in the early prevention of common diseases.

Population Performance and Individual Agreement of Coronary Artery Disease Polygenic Risk Scores

“…3 These applications include combining PRSs with clinical variables into a comprehensive risk models, considering a PRS as a "risk enhancer" to be applied to individuals at borderline risk, or considering a PRS risk estimate as a stand-alone test. 4 Although use of CAD PRSs in any form is not currently the standard of care, 1 it is nevertheless a growing reality, increasingly trialed by academic medical centers and major consortia, [5][6][7] and offered clinically via physician-based and direct-to-consumer genetic testing companies. 4,8 Advances in statistical techniques and the size and diversity of the genetic datasets used to construct PRSs continue to fuel the development of novel scores.…”