A unified framework for estimating country-specific cumulative incidence for 18 diseases stratified by polygenic risk

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 12, 2024

Abstract Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across life course; a key benefit over short-term prediction models. To produce estimates relevant clinical and public health decision-making, it is important account varying effects due age sex. Here, we develop novel framework estimate country-, age-, sex-specific of cumulative incidence stratified by PGS 18 high-burden diseases. We integrate associations from seven studies in four countries ( N = 1,197,129) with disease incidences Global Burden Disease. has significant effect asthma, hip osteoarthritis, gout, coronary heart type 2 diabetes (T2D), all but T2D exhibiting larger men. younger individuals 13 diseases, decreasing linearly age. show breast cancer that, relative bottom 20% polygenic risk, top 5% attain an absolute screening eligibility 16.3 years earlier. Our increases generalizability results biobank accuracy appropriately accounting age- effects. highlight potential as tool which may assist early prevention common

Language: Английский

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A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry

Hepatology Communications, Journal Year: 2024, Volume and Issue: 8(6)

Published: May 10, 2024

Background: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with (ALC) versus drinkers who did not have evidence liver fibrosis/cirrhosis. Methods: Using data-driven approach, ALC was generated using meta-genome-wide study (N=4305) an independent cohort heavy without significant disease (N=3037). It validated in 2 additional cohorts UK Biobank diagnosed (N=467) high-risk drinking controls (N=8981) participants Indiana Liver (N=121) (N=3239). Results: A 20-single-nucleotide (PRSALC) that stratified top bottom deciles validation (ORs: 2.83 [95% CI: 1.82 -4.39] Biobank; 4.40 [1.56 -12.44] cohort). Furthermore, PRSALC improved prediction when added to models clinically known predictors risk. also metabolic dysfunction -associated steatotic -cirrhosis (3.94 [2.23 -6.95]) -based exploratory analysis. Conclusions: incorporates 20 polymorphisms, predicts increased ALC, improves compared only include clinical factors. This new score has potential early detection are at high ALC.

Language: Английский

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Evaluating Performance and Agreement of Coronary Heart Disease Polygenic Risk Scores

JAMA, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 16, 2024

Importance Polygenic risk scores (PRSs) for coronary heart disease (CHD) are a growing clinical and commercial reality. Whether existing provide similar individual-level assessments of susceptibility remains incompletely characterized. Objective To characterize the agreement CHD PRSs that perform similarly at population level. Design, Setting, Participants Cross-sectional study participants from diverse backgrounds enrolled in All Us Research Program (AOU), Penn Medicine BioBank (PMBB), University California, Los Angeles (UCLA) ATLAS Precision Health Biobank with electronic health record genotyping data. Exposures published new developed separately testing samples. Main Outcomes Measures performed population-level prediction were identified by comparing calibration discrimination models prevalent CHD. Individual-level was tested intraclass correlation coefficient (ICC) Light κ. Results A total 48 calculated 171 095 AOU participants. The mean (SD) age 56.4 (16.8) years. 104 947 (61.3%) female. 35 590 (20.8%) most genetically to an African reference population, 29 801 (17.4%) admixed American 100 493 (58.7%) European remaining Central/South Asian, East Middle Eastern populations. There 17 589 (10.3%) 153 506 without (89.7%) When included model CHD, 46 had practically equivalent Brier area under receiver operator curves (region practical equivalence ±0.02). Twenty percent least 1 score both top bottom 5% risk. Continuous individual predictions poor (ICC, 0.373 [95% CI, 0.372-0.375]). κ, used evaluate consistency assignment, did not exceed 0.56. Analysis among 41 193 PMBB 53 092 yielded different sets scores, which also lacked agreement. Conclusions Relevance level demonstrated highly variable estimates Recognizing may generate incongruent estimates, effective implementation will require refined statistical methods quantify uncertainty strategies communicate this patients clinicians.

Language: Английский

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A scalable variational inference approach for increased mixed-model association power

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Abstract The rapid growth of modern biobanks is creating new opportunities for large-scale genome-wide association studies (GWASs) and the analysis complex traits. However, performing GWASs on millions samples often leads to trade-offs between computational efficiency statistical power, reducing benefits data collection efforts. We developed Quickdraws, a method that increases power in quantitative binary traits without sacrificing efficiency, leveraging spike-and-slab prior variant effects, stochastic variational inference graphics processing unit acceleration. applied Quickdraws 79 50 405,088 UK Biobank samples, identifying 4.97% 3.25% more associations than REGENIE 22.71% 7.07% FastGWA. had costs comparable REGENIE, FastGWA SAIGE Research Analysis Platform service, while being substantially faster BOLT-LMM. These results highlight promise machine learning techniques scalable or robustness.

Language: Английский

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Translation of genomics into routine cardiological practice: insights from a European Society of Cardiology Cardiovascular Round Table

European Heart Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Cardiovascular diseases (CVD) remain the leading cause of death globally and there is an urgent need for innovative approaches to treatment. One emerging avenue genetic therapies, which hold particular promise with a monogenic basis. Gene silencing techniques using antisense oligonucleotides or ribonucleic acid interference strategies are currently at forefront therapies in CVD, several acid-targeted already approved treatment conditions such as familial hypercholesterolaemia transthyretin amyloidosis. For caused by loss-of-function variants, growing interest gene therapy, applying either replacement adeno-associated virus vectors editing tools clustered regularly interspaced short palindromic repeats repeats-associated protein-9 system. Preclinical studies have highlighted potential this technology CVD promising data beginning emerge from early-phase clinical trials. During European Society Cardiology Round Table workshop, challenges translating these novel therapeutic routine cardiology clinic were discussed. Several key priorities identified, including disease-specific preclinical models, precision diagnostics, adequately powered trials meaningful endpoints, enhanced education healthcare professionals patients. The also considered role polygenic risk scores stratification how can potentially be implemented practice.

Language: Английский

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Impact of polygenic risk communication: an observational mobile application-based coronary artery disease study

npj Digital Medicine, Journal Year: 2022, Volume and Issue: 5(1)

Published: March 11, 2022

We developed a smartphone application, MyGeneRank, to conduct prospective observational cohort study (NCT03277365) involving the automated generation, communication, and electronic capture of response polygenic risk score (PRS) for coronary artery disease (CAD). Adults with an existing 23andMe genetic profiling self-referred study. evaluated self-reported actions taken in personal CAD PRS information, special interest initiation lipid-lowering therapy. 19% (721/3,800) participants provided complete responses baseline follow-up use 20% (n = 19/95) high vs 7.9% 8/101) low initiated therapy at (p-value 0.002). Both statin non-statin was associated degree PRS: 15.2% 14/92) 6.0% 6/100) statins 0.018) 6.8% 8/118) 1.6% 2/123) non-statins 0.022) PRS, respectively. High also earlier lipid lowering (average age 52 65 years respectively, p-value 0.007). Overall, any follow-up: 42.4% 56/132) 28.5% 37/130) 0.009). find that digital communication information is increased individuals PRS. Loss primary limitation this Alternative routes, long-term studies EHR-based outcomes are needed understand generalizability durability finding.

Language: Английский

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Cardiovascular Disease Risk Assessment Using Traditional Risk Factors and Polygenic Risk Scores in the Million Veteran Program

JAMA Cardiology, Journal Year: 2023, Volume and Issue: 8(6), P. 564 - 564

Published: May 3, 2023

Importance Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic scores (PRSs) are proposed to improve ASCVD estimation. Objective To determine whether genome-wide PRSs for coronary artery (CAD) and acute ischemic stroke estimation with traditional clinical factors in an ancestrally diverse midlife population. Design, Setting, Participants This was a prognostic analysis incident events retrospectively defined longitudinal cohort conducted from January 1, 2011, December 31, 2018. Included the study were adults free statin naive at baseline Million Veteran Program (MVP), mega biobank genetic, survey, electronic health record data large US care system. Data analyzed March 15, 2021, 5, 2023. Exposures CAD derived cohorts largely European descent factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) smoking, diabetes status. Main Outcomes Measures Incident nonfatal myocardial infarction (MI), stroke, death, composite events. Results A 79 151 participants (mean [SD] 57.8 [13.7] years; 68 503 male [86.5%]) included study. The following harmonized genetic ancestry race ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), 53 861 White (68.0%) median (5th-95th percentile) follow-up 4.3 (0.7-6.9) years. From 2011 2018, 3186 MIs (4.0%), 1933 strokes (2.4%), 867 deaths (1.1%), 5485 (6.9%) observed. PRS associated MI (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), (HR, 1.26; 1.09-1.46), 1.23; 1.18-1.29) participants. Stroke 1.15; 1.08-1.21). combined plus among 1.19; 1.03-1.17) 1.11; 1.03-1.21) also across all groups but greater 1.20; 1.16-1.24) than 1.05-1.17) 1.12; 1.00-1.25) Net reclassification improvement adding model modest intermediate group CVD men (5-year >3.75%, 0.38%; 0.07%-0.68%), women, (6.79%; 3.01%-10.58%), age older 55 years (0.25%; 0.03%-0.47%), ages 40 (1.61%; −0.07% 3.30%). Conclusions Relevance Study results suggest that predominantly samples statistically significantly multiancestry older-age MVP cohort. Overall, discrimination metrics observed addition magnitude women younger groups.

Language: Английский

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Taking the risk. A systematic review of ethical reasons and moral arguments in the clinical use of polygenic risk scores

American Journal of Medical Genetics Part A, Journal Year: 2024, Volume and Issue: 194(7)

Published: March 7, 2024

Debates about the prospective clinical use of polygenic risk scores (PRS) have grown considerably in last years. The potential benefits PRS to improve patient care at individual and population levels been extensively underlined. Nonetheless, contexts presents a number unresolved ethical challenges consequent normative gaps that hinder their optimal implementation. Here, we conducted systematic review reasons literature discussing issues moral arguments related for prevention treatment common complex diseases. In total, included analyzed 34 records, spanning from 2013 2023. findings organized three major themes: first theme, consider harms individuals kin. theme "Threats health equity," concerns social relevance, with focus on justice issues. Finally, "Towards best practices" collects series research priorities provisional recommendations be considered an translation PRS. We conclude reinvigorates old debates matters justice; however, open questions, regarding practices counseling, suggest considerations applicable monogenic settings will not sufficient face emerging challenges.

Language: Английский

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Measured Blood Pressure, Genetically Predicted Blood Pressure, and Cardiovascular Disease Risk in the UK Biobank

JAMA Cardiology, Journal Year: 2022, Volume and Issue: 7(11), P. 1129 - 1129

Published: Sept. 28, 2022

Hypertension remains the major cardiovascular disease risk factor globally, but variability in measured blood pressure may result suboptimal management. Whether genetic contributors to elevated complementarily inform assessment is unknown.

Language: Английский

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Incremental Value of Polygenic Risk Scores in Primary Prevention of Coronary Heart Disease

JAMA Internal Medicine, Journal Year: 2022, Volume and Issue: 182(10), P. 1082 - 1082

Published: Aug. 22, 2022

Risk prediction for coronary heart disease (CHD) is a cornerstone of primary prevention strategies. Polygenic risk scores (PRSs) have emerged as new approach to predict in asymptomatic people. CHD been studied several populations, but there lack agreement about the incremental value PRS beyond traditional factor CHD.This narrative review critically appraised 5 most highly cited studies published through 2021 that also included large number (>45 000) single-nucleotide variations (formerly polymorphisms) and evaluated according reporting standards. The cohorts Atherosclerosis Communities Study, FINRISK, Framingham Heart Multi-Ethnic Study Atherosclerosis, UK Biobank. All focused predominantly on populations European ancestry. hazard ratio per standard deviation ranged from 1.24 (95% CI, 1.15-1.34) 1.74 1.61-1.86). C statistic alone 0.549 0.623. change when was added model between -0.001 +0.021. Net reclassification index reported 4 varied 0.001 0.097. At sensitivity (true-positive rate) 90%, positive predictive values 1.8% 16.6%, false-positive rates 77.1% 85.7%.In this review, significantly associated with all studies. degree improvement net indexes negligible modest. Based established metrics assess scores, addition does not appear provide meaningful improvements clinical decision-making populations.

Language: Английский

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