key: cord-0969934-rut8z8i8
authors: Rotter, Jerome I.; Lin, Henry J.
title: An Outbreak of Polygenic Scores for Coronary Artery Disease
date: 2020-06-09
journal: J Am Coll Cardiol
DOI: 10.1016/j.jacc.2020.04.054
sha: 20311fed09fb11f386ae61618af0775caa4e4cb3
doc_id: 969934
cord_uid: rut8z8i8

[Figure: see text]

R eaders may have noticed a proliferation of articles on polygenic scores and risks for various medical conditions. More than likely, the deadly COVID-19 pandemic-for which a diagnosis and DNA can be had with 1 swab-will soon yield polygenic scores for susceptibility to the infection and its sequelae. Polygenic scores for coronary artery disease (CAD) have also attracted wide interest.

CAD can occur as a single-gene disorder or as a polygenic condition. In this issue of the Journal, Aragam et al. (1) show that polygenic scores based on >6 million common single nucleotide polymorphisms (SNPs) throughout the genome "robustly prognosticate coronary artery disease risk in the general population" and may be useful for prevention of CAD. This is not an insignificant addition to the target population for prevention of CAD.

The science of polygenic inheritance is more than 100 years old (2). Wigan (3) gave the following explana- Rotter has received support from National Institutes of Health grants HL151855, UL1TR001881, and DK063491. Dr. Lin has reported that he has no relationships relevant to the contents of this paper to disclose.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.

heterozygous for the polygenes, recombination may give rise to new combinations of polygenes, which, on coming together in a new zygote, will

give a phenotype departing more widely from the optimum and hence not as well balanced to the prevailing conditions.

In early statistical models, the number of polygenes for a trait could be as few as 3, or there could be an "infinite series" (6). One article chose 100 polygenes, for the sake of discussion, when conjecturing about genes that influence "fecundity in a sexually reproducing organism" (7).

Polygenes were "invisible" entities (8) for nearly a century. They were grasped only through complex statistical analyses-"too small in their individual effects to be separated and counted" (9) . Then the genome-wide association study (GWAS) era made polygenes real-countable and identifiable-with measurable effects (called beta values). The first CAD GWAS was in 2007, involving 23,000 participants (10).

By 2017, large international consortia and biobanks led to discovery of 95 CAD genes (or loci) (11) . The current number may be more than 150 (12) . Some of the genes play a role in lipid regulation, insulin resistance, clotting, inflammation, or vascular tone, but the mechanisms of action for most CAD polygenes are unknown (13) .

Polygenic scores (also called polygenic risk scores or 

Although we acknowledge all of the comments stated here, we believe that the cumulative data favor the view that polygenic scoring is a low-cost test that can be done once in a lifetime at any age and for a growing list of important conditions. This study extends the evidence that polygenic scores do appear to provide an added axis of risk for prevention of CAD, 

Limitations of contemporary guidelines for managing patients at high genetic risk of coronary artery disease

The polygene concept

A common allele on chromosome 9 associated with coronary heart disease

Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease

Genetics of common, complex coronary artery disease

Genetics of coronary artery disease: discovery, biology and clinical translation

Generating genetic risk scores from intermediate phenotypes for use in association studies of clinically significant endpoints

Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities study

Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials