Journal Article

DZNE-2026-00533

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Common and distinct genetic features of three atherosclerotic cardiovascular diseases.

Li, L. ; Malik, R. ; Abrahamian, C. ; von Scheidt, M. ; Chen, Z. ; Kessler, T. ; Dichgans, M.DZNE* ; Schunkert, H.

2026
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.atherosclerosis.2026.120733

Abstract: 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.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.Overall, CAD showed the highest SNP-based heritability estimate (23.7 ± 3.3%), which was significantly higher than that of PAD (15.1 ± 2.3%) and IS (9.1 ± 2.8%). Genetic correlations were modest, being largest for CAD-PAD (rg = 0.65), and similar for CAD-IS (rg = 0.47) and PAD-IS (rg = 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.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.

Keyword(s): Humans (MeSH) ; Genome-Wide Association Study (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Coronary Artery Disease: genetics (MeSH) ; Coronary Artery Disease: epidemiology (MeSH) ; Coronary Artery Disease: diagnosis (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Peripheral Arterial Disease: genetics (MeSH) ; Peripheral Arterial Disease: epidemiology (MeSH) ; Peripheral Arterial Disease: diagnosis (MeSH) ; Atherosclerosis: genetics (MeSH) ; Atherosclerosis: epidemiology (MeSH) ; Risk Factors (MeSH) ; Male (MeSH) ; Ischemic Stroke: genetics (MeSH) ; Ischemic Stroke: epidemiology (MeSH) ; Ischemic Stroke: diagnosis (MeSH) ; Female (MeSH) ; Middle Aged (MeSH) ; Phenotype (MeSH) ; Aged (MeSH)

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Contributing Institute(s):

1. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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