Advances and Applications of Polygenic Scores for Coronary Artery Disease

Abstract

Polygenic scores quantify inherited risk by integrating information from many common sites of DNA variation into a single number. Rapid increases in the scale of genetic association studies and new statistical algorithms have enabled development of polygenic scores that meaningfully measure—as early as birth—risk of coronary artery disease. These newer-generation polygenic scores identify up to 8% of the population with triple the normal risk based on genetic variation alone, and these individuals cannot be identified on the basis of family history or clinical risk factors alone. For those identified with increased genetic risk, evidence supports risk reduction with least two interventions, adherence to a healthy lifestyle and cholesterol-lowering therapies, that can substantially reduce risk. Alongside considerable enthusiasm for the potential of polygenic risk estimation to enable a new era of preventive clinical medicine is recognition of a need for ongoing research into how best to ensure equitable performance across diverse ancestries, how and in whom to assess the scores in clinical practice, as well as randomized trials to confirm clinical utility. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Genomic Innovation in Early Life Cardiovascular Disease Prevention and Treatment

“…Leveraging PRS for Early Life Primordial CVD Prevention PRS have been shown to separate individuals into markedly different lifetime trajectories of CVD risk. 19,20,85,[125][126][127][128] As an invariable risk factor present at birth, PRS may be especially relevant to early life disease preventioncapturing information that might not yet be measurable clinically at a time when lifestyle and behaviors are most malleable. Indeed, early work from studies that have longitudinally followed participants from childhood through midlife, including data from the Young Finns Study and BHS (Bogalusa Heart Study), have already provided compelling evidence for the relevance of PRS in identifying children at increased risk of developing obesity, 19,126 diabetes, 22,125 and hypertension.…”

Pragmatic Approach to Applying Polygenic Risk Scores to Diverse Populations

“…While several tutorials and methods have been published to inform PRS development and optimization, they often require strict dataset requirements which are rarely available for most populations (Choi et al., 2020; Hao et al., 2022; Page et al., 2022; Patel and Khera, 2022). In this pragmatic multistep approach, we will present a framework that is flexible in accommodating variable data availability across populations.…”

Polygenic score informed by genome-wide association studies of multiple ancestries and related traits improves risk prediction for coronary artery disease

“…18,19 The past decade has seen numerous advances in score development, however, there still remains room for improvement in their performance, particularly among individuals of non-European ancestry. 20 Simulation studies suggest that larger sample sizes of GWAS have the potential to more accurately estimate the effect size associated with each SNP to improve scores for CAD. 21 Polygenic scores integrating GWAS data from individuals of diverse ancestries in addition to that of the target population show relative improvement in predictive accuracy compared with methods only utilizing GWAS data from a single ancestry source.…”