Year: 2026
Type: article
Abstract: BACKGROUND AND AIMS: Coronary artery disease (CAD), peripheral arterial disease (PAD), and ischemic stroke (IS) are the principal manifestations of atherosclerotic cardiovascular diseases (ASCVDs). Here we systematically explored the shared and distinct genetic underpinnings of these ASCVDs. METHODS: SNP-based heritability estimates were calculated using GCTA-GREML in a subset of the UK Biobank, where 8000 controls and equally sized cases were randomly selected for the three ASCVDs separately. Genetic correlations and causal relations were analyzed among three ASCVDs, 13 risk factors and three comorbid conditions using summary data of respective genome-wide association studies (GWASs). Cross-trait meta-analyses and pathway analyses were conducted to investigate shared and distinct risk loci, as well as pathway activities. RESULTS: = 0.48). Of 233 significant risk loci, 71 (30.5%) were shared by three, and 159 (68.2%) by at least two ASCVDs. Analyses of genetic correlations, Mendelian randomization, and pathway enrichment revealed significant differences between respective ASCVDs. Specially, lipid traits were more strongly associated with CAD and PAD than IS; diabetes mellitus and lifestyle factors affected predominantly PAD, while blood coagulation/clotting pathways and atrial fibrillation were predominantly associated with IS. Interestingly, pathways related to vascular remodeling and inflammation were significantly enriched by genes affecting all ASCVD. CONCLUSIONS: The genetic foundation of the three ASCVDs varies substantially, including genetically-mediated effects of associated risk factors and pathways, suggesting commonalities but also differences in the pathogenesis of atherosclerosis in respective arterial beds. Shared genetic features of ASCVDs may be particularly informative for drug target identification.
Source: Atherosclerosis
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,020
Funders: Foundation for Cardiovascular Research, Deutsches Zentrum für Herz-Kreislaufforschung, British Heart Foundation, European Commission, Deutsche Forschungsgemeinschaft, Fondation Leducq, Bundesministerium für Bildung und Forschung, Sydäntutkimussäätiö, Bayerisches Staatsministerium für Gesundheit, Pflege und Prävention
Awards: G1257221297, G1587635158, G1635499681, G1753257508, G1901460537, G2116070757, G2824680073, G3182220650, AbCD-Net - Analyse des genetischen Risikos für häufige Erkrankungen basierend auf Aberration des Transkriptoms - Genetische Faktoren bei aberrantem Splicing in koronaren Herzerkrankungen (TP 3), Defining the Roles of Smooth Muscle Cells and Other Extracellular Matrix Producing Cells in Late Stage Atherosclerotic Plaque Pathogenesis, G4086240853, COMMITMENT - Modellierung von Komorbiditäts-Prozessen durch integratives, maschinelles Transfer-Lernen für psychiatrische Erkrankungen - TP1: Entwicklung einer Informationstechnologie - Lösung zur Anwendung von verteiltem maschinellen Lernen, G4287685855, G4288477973, Erforschung des Zusammenhangs zwischen genetisch dysreguliertem Fettgewebe und dem Risiko der koronaren Herzkrankheit, TRR 267: Nichtkodierende RNA im kardiovaskulären System, G5944543424, G6257202014, G6655092555, G6810932530, G7198714827, G7357404214, G7768179268, G828942294
OpenAlex ID: W7155159007