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Common and distinct genetic features of three atherosclerotic cardiovascular diseases
Ling Li1, Rainer Malik2, Carla Abrahamian1
1Department of Cardiology, German Heart Center, TUM University Hospital, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
Insights
Atherosclerotic cardiovascular diseases (ASCVDs) like coronary artery disease (CAD), peripheral arterial disease (PAD), and ischemic stroke (IS) share genetic underpinnings but also have distinct genetic factors. Understanding these genetic differences is key for targeted drug development.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Epidemiology
Background:
- Coronary artery disease (CAD), peripheral arterial disease (PAD), and ischemic stroke (IS) are major manifestations of atherosclerotic cardiovascular diseases (ASCVDs).
- The shared and distinct genetic factors influencing these conditions remain incompletely understood.
Purpose of the Study:
- To systematically investigate the common and unique genetic architectures of CAD, PAD, and IS.
- To identify shared and distinct genetic risk loci and associated pathways across these ASCVDs.
Main Methods:
- Calculated SNP-based heritability using GCTA-GREML in UK Biobank data.
- Analyzed genetic correlations and causal relationships using GWAS summary data for ASCVDs, risk factors, and comorbidities.
- Performed cross-trait meta-analyses and pathway analyses to pinpoint shared and distinct genetic risk loci and pathway activities.
Main Results:
- CAD exhibited the highest heritability (23.7%), followed by PAD (15.1%) and IS (9.1%).
- Significant genetic correlations were observed between CAD and PAD (rg=0.65), and between CAD/PAD and IS (rg=0.47-0.48).
- Of 233 significant risk loci, 71 were shared across all three ASCVDs, and 159 were shared by at least two. Lipid traits were strongly linked to CAD/PAD, while diabetes and lifestyle factors predominantly affected PAD. Blood coagulation pathways and atrial fibrillation were mainly associated with IS. Vascular remodeling and inflammation pathways were enriched across all ASCVDs.
Conclusions:
- The genetic basis of CAD, PAD, and IS shows substantial variation, with both shared and distinct genetic influences on risk factors and pathways.
- These findings highlight differences in atherosclerosis pathogenesis across arterial beds and suggest that shared genetic features are valuable for identifying drug targets.
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:
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.
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.
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