Polygenic risk scores for coronary artery disease and subsequent event risk amongst established cases.

Chris Finan,Riyaz S Patel,Frank Dudbridge,Aroon D Hingorani,Spiros Denaxas,Laurence J Howe,Folkert W Asselbergs,Amand F Schmidt

doi:10.1093/hmg/ddaa052

Abstract

BackgroundThere is growing evidence that polygenic risk scores (PRSs) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify the risk of subsequent events among those surviving a first CAD event remain uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias.MethodsUsing two baseline subsamples of UK Biobank: prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes.ResultsA 1 SD higher PRS was associated with an increased risk of incident myocardial infarction (MI) in participants without CAD (OR 1.33; 95% CI 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% CI 1.06, 1.25) and heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found an evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% CI 0.85, 0.98) compared with those without CAD (OR 1.01; 95% CI 0.99, 1.03) and heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke [prevalent CAD (OR 0.78; 95% CI 0.67, 0.90); without CAD (OR 1.09; 95% CI 1.04, 1.15), heterogeneity P < 0.001].ConclusionsBias induced by case stratification and survival into UK Biobank may distort the associations of PRS derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research.

Highlights

Coronary artery disease (CAD) is heritable, with over 300 independent genetic loci with additive effects known to influence disease risk having been identified in Genome-Wide Association Studies (GWAS) [1,2,3,4]
In the coronary artery disease (CAD) free sample, we found strong evidence of positive associations between the CAD polygenic risk scores (PRS) and incident cardiovascular and fatal outcomes such as MI, CAD death and ischemic stroke
We found some evidence that the CAD PRS is associated with increased systolic blood pressure (SBP) in those without CAD, but this association was largely attenuated in the prevalent CAD sample (Int P=0.020)

Summary

Introduction

Coronary artery disease (CAD) is heritable, with over 300 independent genetic loci with additive effects known to influence disease risk having been identified in Genome-Wide Association Studies (GWAS) [1,2,3,4]. There is growing evidence that polygenic risk scores (PRS) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can be used to stratify risk of subsequent events among those surviving a first CAD event remains uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias. Conclusions: Bias induced by case stratification and survival into UK Biobank may distort associations of polygenic risk scores derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research

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