Zhongxiang Chen, Diqi Zhu, Kaa Seng Lai, Yiwei Chen, Yuqing Hu, Yabo Fang, Zihang Yan, Beibei Hu, Zhen Zhang, Min Zhang, Fen Li
{"title":"VEGFA Stop-Gained Variant Deteriorates Cardiac Remodeling in Myocardial Infarction.","authors":"Zhongxiang Chen, Diqi Zhu, Kaa Seng Lai, Yiwei Chen, Yuqing Hu, Yabo Fang, Zihang Yan, Beibei Hu, Zhen Zhang, Min Zhang, Fen Li","doi":"10.1161/CIRCGEN.124.004879","DOIUrl":"10.1161/CIRCGEN.124.004879","url":null,"abstract":"<p><strong>Background: </strong>A sustained dosage of VEGFA (vascular endothelial growth factor A) is crucial for angiogenesis in both homeostasis and cardiovascular diseases. Start codon CUG-initiated alternative translation is a conserved mechanism for producing mature VEGFA. Genetic surveys have identified stop-gained variants predicted to prematurely terminate CUG-initiated translation without affecting start codon ATG-initiated translation. However, the impacts of these variants on the vasculature in steady-state and disease conditions remain unknown.</p><p><strong>Methods: </strong>Using CRISPR/Cas9 genome editing, we established the <i>Vegfa</i><sup><i>Q150X/Q150</i></sup> allele (Q150X), a mouse genetic model that mimics the human VEGFA stop-gained variant. The effects of this variant were tested in both adult homeostatic conditions and the acute myocardial infarction (MI) model. We analyzed and quantified cardiac vasculature structure using immunofluorescence and light-sheet imaging. Furthermore, we characterized cellular heterogeneity, cell-cell interactions, and gene regulation using single-nucleus RNA sequencing, as well as cell type-specific transcriptomics and epigenomics.</p><p><strong>Results: </strong>Homozygous mice carrying the stop-gained variant were viable. VEGFA dosage was reduced to 70% in the Q150X homeostatic heart, with no significant alteration in cardiac function or vasculature. In the MI model, VEGFA dosage in Q150X was reduced to about 40% within the first week post-infarction, leading to functional deterioration in the post-MI hearts. Significant changes in cellular composition were observed 3 days post-MI. In particular, endothelial cells in Q150X diverged into a state that showed a higher level of hypoxia stress, an elevated inflammatory response, and increased extracellular matrix secretion. In addition, we observed an increase in Nppb<sup>+</sup> stressed cardiomyocytes in both 3 days post-MI and homeostasis. Finally, proinflammatory macrophages, neutrophils, and Cd8<sup>+</sup>T cells were enriched in the ischemic zone of Q150X hearts.</p><p><strong>Conclusions: </strong>CUG-initiated translation contributes significantly to the production of mature VEGFA in ischemic hearts. VEGFA dosage is critical in determining the cellular microenvironment during ischemic injury.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004879"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elizabeth Jordan, Hanyu Ni, Patricia Parker, Daniel D Kinnamon, Anjali Owens, Brian Lowes, Chetan Shenoy, Cindy M Martin, Daniel P Judge, Daniel P Fishbein, Douglas Stoller, Elina Minami, Evan P Kransdorf, Frank Smart, Garrie J Haas, Gordon S Huggins, Gregory A Ewald, Jamie Diamond, Jane E Wilcox, Javier Jimenez, Jessica Wang, Jose Tallaj, Mark H Drazner, Mark Hofmeyer, Matthew T Wheeler, Omar Wever Pinzon, Palak Shah, Stephen S Gottlieb, Stuart D Katz, Supriya Shore, W H Wilson Tang, Ray E Hershberger
{"title":"Implementing Precision Medicine for Dilated Cardiomyopathy: Insights From the DCM Consortium.","authors":"Elizabeth Jordan, Hanyu Ni, Patricia Parker, Daniel D Kinnamon, Anjali Owens, Brian Lowes, Chetan Shenoy, Cindy M Martin, Daniel P Judge, Daniel P Fishbein, Douglas Stoller, Elina Minami, Evan P Kransdorf, Frank Smart, Garrie J Haas, Gordon S Huggins, Gregory A Ewald, Jamie Diamond, Jane E Wilcox, Javier Jimenez, Jessica Wang, Jose Tallaj, Mark H Drazner, Mark Hofmeyer, Matthew T Wheeler, Omar Wever Pinzon, Palak Shah, Stephen S Gottlieb, Stuart D Katz, Supriya Shore, W H Wilson Tang, Ray E Hershberger","doi":"10.1161/CIRCGEN.125.005078","DOIUrl":"10.1161/CIRCGEN.125.005078","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005078"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chai-Ann Ng, Matthew J O'Neill, Samskruthi R Padigepati, Yi-Lee Ting, Flavia M Facio, Matteo Vatta, Sarah R Poll, Jason A Reuter, Jamie I Vandenberg, Brett M Kroncke
{"title":"Calibrated Functional Data Decrease Clinical Uncertainty for <i>KCNH2</i>-Related Long-QT Syndrome.","authors":"Chai-Ann Ng, Matthew J O'Neill, Samskruthi R Padigepati, Yi-Lee Ting, Flavia M Facio, Matteo Vatta, Sarah R Poll, Jason A Reuter, Jamie I Vandenberg, Brett M Kroncke","doi":"10.1161/CIRCGEN.125.005204","DOIUrl":"10.1161/CIRCGEN.125.005204","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005204"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C Anwar A Chahal, Fares Alahdab, Babken Asatryan, Daniel Addison, Nay Aung, Mina K Chung, Spiros Denaxas, Jessilyn Dunn, Jennifer L Hall, Nathalie Pamir, David J Slotwiner, Jose D Vargas, Antonis A Armoundas
{"title":"Data Interoperability and Harmonization in Cardiovascular Genomic and Precision Medicine.","authors":"C Anwar A Chahal, Fares Alahdab, Babken Asatryan, Daniel Addison, Nay Aung, Mina K Chung, Spiros Denaxas, Jessilyn Dunn, Jennifer L Hall, Nathalie Pamir, David J Slotwiner, Jose D Vargas, Antonis A Armoundas","doi":"10.1161/CIRCGEN.124.004624","DOIUrl":"10.1161/CIRCGEN.124.004624","url":null,"abstract":"<p><p>Despite advances in cardiovascular care and improved outcomes, fragmented healthcare systems, nonequitable access to health care, and nonuniform and unbiased collection and access to healthcare data have exacerbated disparities in healthcare provision and further delayed the technological-enabled implementation of precision medicine. Precision medicine relies on a foundation of accurate and valid omics and phenomics that can be harnessed at scale from electronic health records. Big data approaches in noncardiovascular healthcare domains have helped improve efficiency and expedite the development of novel therapeutics; therefore, applying such an approach to cardiovascular precision medicine is an opportunity to further advance the field. Several endeavors, including the American Heart Association Precision Medicine platform and public-private partnerships (such as BigData@Heart in Europe), as well as cloud-based platforms, such as Terra used for the National Institutes of Health All of Us, are attempting to temporally and ontologically harmonize data. This state-of-the-art review summarizes best practices used in cardiovascular genomic and precision medicine and provides recommendations for systems' requirements that could enhance and accelerate the integration of these platforms.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004624"},"PeriodicalIF":6.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Robin M Perelli, Madeleine J Sitton, Joel D Bohning, Adrian Pickar-Oliver, K Tyler McCullough, Mary E Moya-Mendez, Scott Zheng, Heather Daniels, Garth Devlin, Aravind Asokan, Charles A Gersbach, Andrew P Landstrom
{"title":"Deletion of Exon 51 in a Humanized Duchenne Muscular Dystrophy Mouse Model Abolishes Ventricular Arrhythmia Predisposition.","authors":"Robin M Perelli, Madeleine J Sitton, Joel D Bohning, Adrian Pickar-Oliver, K Tyler McCullough, Mary E Moya-Mendez, Scott Zheng, Heather Daniels, Garth Devlin, Aravind Asokan, Charles A Gersbach, Andrew P Landstrom","doi":"10.1161/CIRCGEN.124.004867","DOIUrl":"10.1161/CIRCGEN.124.004867","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004867"},"PeriodicalIF":6.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Identification and Functional Assessment of Candidate Causal <i>Cis</i>-Regulatory Variants Underlying Electrocardiographic QT Interval GWAS Loci.","authors":"Supraja Kadagandla, Lavanya Gunamalai, Dongwon Lee, Ashish Kapoor","doi":"10.1161/CIRCGEN.124.005032","DOIUrl":"10.1161/CIRCGEN.124.005032","url":null,"abstract":"<p><strong>Background: </strong>Identifying causal variants among tens or hundreds of associated variants at each locus in genome-wide association studies is challenging. As the vast majority of genome-wide association studies variants are noncoding, sequence variation at <i>cis</i>-regulatory elements (CREs) affecting transcriptional expression of specific genes is a widely accepted molecular hypothesis. Following this hypothesis, combined with the observation that open chromatin is a universal hallmark of all types of CREs, we aimed to identify candidate causal <i>cis</i>-regulatory variants underlying QT interval genome-wide association studies loci.</p><p><strong>Methods: </strong>Common variants in high linkage disequilibrium with genome-wide significant variants were identified using variant call format tools. Genome-wide maps of cardiac putative CREs were generated by MACS2-based peak calling in human cardiac left ventricular DNase I sequencing and Assay for Transposase-Accessible Chromatin using sequencing data sets (<i>n</i>=13). Variant-CRE overlap was performed using custom tracks in the Table Browser tool at the UCSC Genome Browser. Luciferase reporter-based enhancer assays for variant-centered test elements were performed in mouse HL1 cardiomyocyte cells. Reporter activities of allelic pairs were compared using the Wilcoxon rank-sum test.</p><p><strong>Results: </strong>At a dozen genome-wide association studies loci, selected for higher effect sizes and better understanding of the likely causal genes, we identified all genome-wide significant variants (<i>n</i>=1401) and included all common variants (minor allele frequency >1%) in high linkage disequilibrium (<i>r</i><sup>2</sup>>0.9) with them as candidate variants (<i>n</i>=3482). Candidate variants were filtered for overlap with cardiac left ventricular putative CREs to identify candidate causal <i>cis</i>-regulatory variants (<i>n</i>=476), which were further assessed for being a known cardiac expression quantitative trait locus variant as additional functional evidence (<i>n</i>=243). Functional evaluation of a subset of seven candidate variants by luciferase reporter-based enhancer assays in HL1 cells using variant-centered test elements led to the identification of 6 enhancer variants with significant allelic differences.</p><p><strong>Conclusions: </strong>These efforts have generated a comprehensive set of candidate causal variants expected to be enriched for <i>cis</i>-regulatory potential and thereby, explaining the observed genetic associations.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005032"},"PeriodicalIF":6.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parag R Gajendragadkar, Adam Von Ende, Federico Murgia, Alison Offer, C Fielder Camm, Rohan S Wijesurendra, Barbara Casadei, Jemma C Hopewell
{"title":"Mechanistic Pathways Underlying Genetic Predisposition to Atrial Fibrillation Are Associated With Different Cardiac Phenotypes and Cardioembolic Stroke Risk.","authors":"Parag R Gajendragadkar, Adam Von Ende, Federico Murgia, Alison Offer, C Fielder Camm, Rohan S Wijesurendra, Barbara Casadei, Jemma C Hopewell","doi":"10.1161/CIRCGEN.124.004932","DOIUrl":"10.1161/CIRCGEN.124.004932","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide association studies have clustered candidate genes associated with atrial fibrillation (AF) into biological pathways reflecting different pathophysiological mechanisms. We investigated whether these pathways associate with distinct intermediate phenotypes and confer differing risks of cardioembolic stroke.</p><p><strong>Methods: </strong>Three distinct subsets of AF-associated genetic variants, each representing a different mechanistic pathway, that is, the cardiac muscle function and integrity pathway (15 variants), the cardiac developmental pathway (25 variants), and the cardiac ion channels pathway (12 variants), were identified from previous AF genome-wide association studies. Using genetic epidemiological methods and large-scale datasets such as UK Biobank, deCODE, and GIGASTROKE, we investigated the associations of these pathways with AF-related cardiac intermediate phenotypes, which included electrocardiogram parameters (≈16 500 electrocardiograms), left atrial and ventricular size and function (≈36 000 cardiac magnetic resonance imaging scans), and relevant plasma biomarkers (N-terminal pro-B-type natriuretic peptide, ≈70 000 samples; high-sensitivity troponin I and T, ≈87 000 samples), as well as with subtypes of ischemic stroke (≈11 000 cases).</p><p><strong>Results: </strong>Genetic variants representing distinct AF-related mechanistic pathways had significantly different effects on several AF-related phenotypes. In particular, the muscle pathway was associated with a longer PR interval (<i>P</i> for heterogeneity between pathways [<i>P</i><sub>het</sub>]=1×10<sup>-10</sup>), lower left atrial emptying fraction (<i>P</i><sub>het</sub>=5×10<sup>-5</sup>), and higher N-terminal pro-B-type natriuretic peptide (<i>P</i><sub>het</sub>=2×10<sup>-3</sup>) per log-odds higher risk of AF compared with the developmental and ion-channel pathways. In contrast, the ion-channel pathway was associated with a lower risk of cardioembolic stroke (<i>P</i><sub>het</sub>=0.04 in European, and 7×10<sup>-</sup><sup>3</sup> in multiancestry populations) compared with the other pathways.</p><p><strong>Conclusions: </strong>Genetic variants representing specific mechanistic pathways for AF are associated with distinct intermediate cardiac phenotypes and a different risk of cardioembolic stroke. These findings provide a better understanding of the etiological heterogeneity underlying the development of AF and its downstream impact on disease and may offer a route to more targeted treatment strategies.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":"18 3","pages":"e004932"},"PeriodicalIF":6.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Till Joscha Demal, Marco Sachse, Celia Metzlaff, Helke Schüler, Katalin Szöcs, Jakob Olfe, Veronika Stark, Peter Frommolt, Yskert von Kodolitsch, Thomas S Mir, Meike Rybczynski, Hermann Reichenspurner, Kerstin Kutsche, Christian Kubisch, Christian Detter, Georg Rosenberger
{"title":"Thoracic Aortic Disease in Patients With Heterozygous Variants Outside the Central Region of <i>FBN2</i>.","authors":"Till Joscha Demal, Marco Sachse, Celia Metzlaff, Helke Schüler, Katalin Szöcs, Jakob Olfe, Veronika Stark, Peter Frommolt, Yskert von Kodolitsch, Thomas S Mir, Meike Rybczynski, Hermann Reichenspurner, Kerstin Kutsche, Christian Kubisch, Christian Detter, Georg Rosenberger","doi":"10.1161/CIRCGEN.124.004672","DOIUrl":"10.1161/CIRCGEN.124.004672","url":null,"abstract":"<p><strong>Background: </strong>Heterozygous pathogenic variants in the central region (exon 23-34) of <i>FBN2</i> cause a hereditary connective tissue disorder named congenital contractural arachnodactyly, which presents with obligatory skeletal features but rarely with vascular manifestations. Scarce data exist on the association between <i>FBN2</i> variants and aortic disease. This study aimed to investigate whether the location of <i>FBN2</i> variants correlates with distinct clinical features, including aortic disease.</p><p><strong>Methods: </strong>In this case-controlled cohort study, we ascertained clinical features, sequenced 62 (candidate) disease genes, and classified variants according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines in 392 patients with suspected connective tissue or thoracic aortic diseases. We summarized our results and published data and compared clinical manifestations between patients with variants outside and within the central region of <i>FBN2</i>.</p><p><strong>Results: </strong>Heterozygous <i>FBN2</i> variants outside the central region were identified in 10 patients from 5 families. Two variants were of uncertain significance, 1 was likely pathogenic, and 2 were pathogenic. A total of 60% of these patients had thoracic aortic disease, but only 20% were diagnosed with congenital contractural arachnodactyly according to an established clinical scoring system. Combined data from the literature and this study revealed that patients with <i>FBN2</i> variants outside the central region presented with aortic dilatation (55.0% versus 9.9%; <i>P</i><0.001) more often and had less pronounced musculoskeletal manifestations (congenital contractural arachnodactyly score, 5.6±5.1 versus 9.8±3.6; <i>P</i>=0.011) compared with those with central region variants.</p><p><strong>Conclusions: </strong>Our results suggest that heterozygous <i>FBN2</i> variants outside the central region predispose individuals to thoracic aortic disease and are less associated with the typical clinical presentation of congenital contractural arachnodactyly than pathogenic variants in the <i>FBN2</i> central region.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004672"},"PeriodicalIF":6.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ebuka Onyenobi, Michael Zhong, Opeyemi Soremekun, Abram Kamiza, Romuald Boua, Tinashe Chikowore, Segun Fatumo, Ananyo Choudhury, Scott Hazelhurst, Clement Adebamowo, Michèle Ramsay, Bamidele Tayo, Jennifer S Albrecht, Timothy D O'Connor, Yuji Zhang, Braxton D Mitchell, Sally N Adebamowo
{"title":"Development and Validation of Polygenic Risk Scores for Blood Pressure Traits in Continental African Populations.","authors":"Ebuka Onyenobi, Michael Zhong, Opeyemi Soremekun, Abram Kamiza, Romuald Boua, Tinashe Chikowore, Segun Fatumo, Ananyo Choudhury, Scott Hazelhurst, Clement Adebamowo, Michèle Ramsay, Bamidele Tayo, Jennifer S Albrecht, Timothy D O'Connor, Yuji Zhang, Braxton D Mitchell, Sally N Adebamowo","doi":"10.1161/CIRCGEN.124.005048","DOIUrl":"10.1161/CIRCGEN.124.005048","url":null,"abstract":"<p><strong>Background: </strong>Most polygenic risk scores (PRS) have been developed in European populations, frequently leading to limited transferability across diverse ancestry populations. This study aimed to develop and evaluate PRS for blood pressure (BP) traits in continental African populations and investigate how African genetic diversity influences PRS performance.</p><p><strong>Methods: </strong>We generated PRS for systolic BP, diastolic BP, pulse pressure, and hypertension. We used a pan-African cohort as the target population and compared single-ancestry and multi-ancestry PRS methods. We compared the performance of African ancestry-derived PRS against multi-ancestry PRS on the entire data set and within South, East, and West African subpopulations.</p><p><strong>Results: </strong>Multi-ancestry PRS demonstrated significantly higher predictive accuracy compared with single-ancestry PRS models. PRS predictive accuracy varied across different African regions, with the highest performance observed in East Africa. In the combined population, the difference in mean BP values between the first multi-ancestry PRS quartile and the top quartile was 6.53 (95% CI, 5.3-7.74), 3.81 (95% CI, 3.9-4.52), and 3.59 (95% CI, 2.4-4.32) mm Hg for systolic BP, diastolic BP, and pulse pressure, respectively. Individuals in the highest PRS risk quartile had odds of hypertension that were 1.47 (95% CI, 1.7-1.69) times greater than those in the lowest risk quartile.</p><p><strong>Conclusions: </strong>These findings highlight the importance of integrating diverse ancestries in PRS development and accounting for subpopulation genetic variation to improve the predictive accuracy of BP PRS in African populations.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005048"},"PeriodicalIF":5.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}