Use of polygenic risk scores and other molecular markers to enhance cardiovascular risk prediction: prospective cohort study and modelling analysis

Sun, Luanluan; Pennells, Lisa; Kaptoge, Stephen; Nelson, Christopher P.; Abraham, Gad; Arnold, Matthew; Bell, Steven; Bolton, Thomas; Burgess, Stephen; Dudbridge, Frank; Guo, Qi; Ritchie, Scott C.; Sofianopoulou, Eleni; Stevens, David P.; Thompson, John R.; Butterworth, Adam S.; Wood, Angela; Danesh, John; Samani, Nilesh J.; Inouye, Michael; Angelantonio, Emanuele Di

doi:10.1101/744565

Cited by 9 publications

(11 citation statements)

References 40 publications

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“…Using the integrated PRS+ CHA 2 DS 2 -VASc tool, around 11,000 of these people will be reclassified and not be recommended anticoagulation, and thus not suffer from these bleeding complications. Similar to previous research (38), this shows that even modest improvements in risk prediction have implications for a large number of people.…”

Section: Discussionsupporting

confidence: 88%

Combining clinical and polygenic risk improves stroke prediction among individuals with atrial fibrillation

O’Sullivan¹,

Shcherbina

Justesen

et al. 2020

Preprint

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Background Atrial fibrillation (AF) is associated with a five fold increased risk of ischemic stroke. A portion of this risk is heritable, however current risk stratification tools (CHA2DS2VASc) do not include family history or genetic risk. Objectives To construct and test a PRS to predict ischemic stroke in patients with AF, both independently and integrated with clinical risk factors. Methods Using data from the largest available GWAS in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank (UK Biobank), both independently and integrated with clinical risk factors. Results The integrated PRS and clinical risk factors risk tool had the greatest predictive ability. Compared with the currently recommended risk tool (CHA2DS2VASc), the integrated tool significantly improved net reclassification (NRI: 2.3% (95%CI: 1.3% to 3.0%)), and fit (χ2 P =0.002). Using this improved tool, >115,000 people with AF would have improved risk classification in the US. Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (Hazard Ratio: 1.13 per 1 SD (95%CI: 1.06 to 1.23))). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearsons correlation coefficient: -0.018). Conclusions In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors, however the prediction of stroke remains challenging.

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Section: Discussionsupporting

confidence: 88%

Combining clinical and polygenic risk improves stroke prediction among individuals with atrial fibrillation

O’Sullivan¹,

Shcherbina

Justesen

et al. 2020

Preprint

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“…Cardiometabolic diseases have a major polygenic component, which is due to the combination of many thousands of variants across the genome, each exerting small lifelong effects 9–13 . Risk stratification using cardiometabolic PGSs have shown potential clinical utility for disease prevention 14 ; however, molecular mediators of polygenic risk and their potential to be modulated to reduce disease risk remains unknown. Variants associated with polygenic traits are spread across many different pathways, exerting their effects through multiple levels of regulation, including gene expression, proteins and their interactions, cell morphology, and higher order physiological processes 15 .…”

Section: Main Textmentioning

confidence: 99%

Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases

Ritchie

Liu

Teo

et al. 2019

Preprint

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Polygenic risk scores (PRSs) capture the polygenic architecture of common diseases by aggregating genome-wide genetic variation into a single score that reflects individual's disease risk, affording a new opportunity to identify downstream molecular pathways involved in disease pathogenesis. We performed an integrative analysis to characterise associations of PRSs of five cardiometabolic diseases with 3,442 plasma proteins in 3,175 healthy individuals. Through polygenic association scans we identified 48 plasma proteins whose levels were associated with PRSs for coronary artery disease (CAD), chronic kidney disease (CKD), or type 2 diabetes (T2D). This approach identified both well-known disease-associated proteins as well as those with previously no known link to these diseases. We found that PRSs to protein associations were largely truly polygenic; independent of single loci and genomic regions expected to have strong effects on protein levels. Our integrative analysis and laboratory experiments revealed a role for polygenic effects on several well-known disease proteins and identified several promising novel targets for follow-up studies, including genes which through Mendelian randomization analysis displayed causal evidence for effects on disease risk. Mouse studies highlighted specific tissues and phenotypes for PRSassociated human proteins. We found that implicated genes were responsive to dietary intervention in mice and showed strong evidence of druggability in humans, consistent with PRS-associated proteins having therapeutic potential. Overall, our study provides a framework for polygenic association studies, and demonstrates the power of polygenic scores to unravel novel disease biology. Research (NIHR), the NIHR BioResource

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“…PRSs were empirically shown to explain a substantial proportion of the variance in disease liability, and individuals at the highest PRS percentiles were shown to have risk that can be even ≈3x higher compared to the population mean 2-4 . This suggests the feasibility personalized prevention and/or intervention in these individuals, whose high risk may not always manifest as traditional risk factors 5 .…”

Section: Introductionmentioning

confidence: 99%

Cascade screening following a polygenic risk score test: what is the risk of a relative conditional on a high score of a proband?

Carmi

2021

Preprint

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Polygenic risk scores (PRSs) for predicting disease risk have become increasingly accurate, leading to increasing popularity of PRS tests. Consider an individual whose PRS test has placed him/her at the top q-quantile of genetic risk. Recently, Reid et al. (Circ Genom Precis Med. 2021;14:e003262) have investigated whether such a finding should motivate cascade screening in the proband's siblings. Specifically, using data from the UK biobank, Reid et al. computed the empirical probability of a sibling of the proband to also have a PRS at the top q-quantile. In this short note, I use the liability threshold model to compute this probability analytically, showing excellent agreement with the empirical results of Reid et al., including that this probability is disease-independent. Further, I compute the probability of a sibling of the proband to be affected, as a function of the quantile threshold q, the proportion of variance explained by the score, and the disease prevalence.

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Use of polygenic risk scores and other molecular markers to enhance cardiovascular risk prediction: prospective cohort study and modelling analysis

Abstract: 300/300 words)Background There is debate about the value of adding information on genetic and other

Cited by 9 publications

References 40 publications

Combining clinical and polygenic risk improves stroke prediction among individuals with atrial fibrillation

Combining clinical and polygenic risk improves stroke prediction among individuals with atrial fibrillation

Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases

Cascade screening following a polygenic risk score test: what is the risk of a relative conditional on a high score of a proband?

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