Humans have almost identical DNA sequences throughout their 6-billion-letter genome, with minor differences between individuals making each person unique. These differences, called genomic variants, occur at specific DNA sites. There are about 4 to 5 million such genomic variants. The majority of the heritability of many common adult-onset diseases is mediated by numerous common (MAF >5%) and rare (MAF >0.5% and <5%) genetic variants, usually contributing to minor effects, most of which can be captured through whole-genome genotyping (e.g., Genome-Wide Association Studies, GWAS). These variants may be unique or shared among individuals. Some variants increase disease risk, others decrease it, while some have no impact.
Disease risk components are usually divided into genetic predisposition, environmental exposure, and lifestyle factors. The relative contribution of genetic susceptibility to disease in a population can be quantitatively determined based on the disease’s heritability. While heritability is related to the theoretical limit of genetic risk stratification at the population level, it does not directly correlate with the utility of genetic information for individuals.
Coronary heart disease (CHD) is a genetically complex disease with heritability estimated at 40-60%. In the last decade, GWAS has revealed numerous genetic susceptibility loci for CHD, sparking interest in using polygenic risk assessments.
Polygenic risk score (PRS) estimates an individual’s genetic risk for a particular trait. PRS is typically constructed as the sum of a set of genetic variants, usually single nucleotide polymorphisms (SNPs), and the resulting score typically has a normal distribution in the general population, with higher scores indicating higher risk. The utility of PRS can be divided into three main classes of interventions: therapeutic intervention based on PRS, screening for diseases based on PRS information, and planning preventive actions based on PRS. PRS can provide personal utility even without preventive actions, aiding in decision-making and interpretation of screening tests and disease prevention.
Based on: MarstonNA,PatelPN,KamanuFK,etal.Clinical application of a novel genetic risk score for ischemic stroke in patients with cardiometabolic disease. Circulation. 2021;143(5):470-478. Based on: AragamKG,JiangT,GoelA,etal.Discoveryand systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet. Published online December 6, 2022.