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Genetics of Subclinical Coronary Atherosclerosis Imaging

Summary

Coronary atherosclerosis is silent for decades before it causes events, and its accumulated burden can be measured directly by CT as coronary artery calcium (CAC) or, on CT coronary angiography (CCTA), as plaque burden. Both are heritable quantitative endophenotypes with well-powered GWAS, and — importantly for subtyping — the genetics of calcification is partly distinct from that of clinical coronary artery disease (CAD). These imaging GWAS provide fixed, mechanistically-interpretable endophenotypes against which pathway-partitioned polygenic scores can be anchored, rather than relying on noisy clinical event endpoints.

Coronary Artery Calcium: Kavousi et al. 2023

A multi-ancestry GWAS meta-analysis of CAC combined 26,909 European-ancestry and 8,867 African-ancestry individuals (total N=35,776); CAC heritability from family data is 30–40%.[1] It identified 11 independent risk loci, of which 8 are novel for CAC, and 5 of those 8 have not been associated with clinical CAD.[1] The novel loci implicate calcification-specific biology — phosphate catabolism/homeostasis (ENPP1, ENPP3, FGF23), bone mineralization, and hormone metabolism — and several candidate genes are regulators of smooth-muscle-cell-mediated calcification validated ex vivo/in vitro.[1]

Crucially, colocalization with cardiometabolic-tissue eQTLs separated shared from calcification-specific signals: the known CAD loci PHACTR1 and ADAMTS7 colocalized with both CAC and CAD, whereas other genes colocalized strongly with CAC but not CAD (posterior probability >0.8 for CAC, <0.5 for CAD).[1] This is direct genetic evidence that coronary calcification is not simply a readout of CAD liability — consistent with the clinical view that dense calcium is partly a stabilizing/healing response rather than a monotonic severity marker.

CCTA Plaque Burden: Gummesson et al. 2025 (SCAPIS)

Because CAC captures only calcified plaque, a GWAS of directly-measured plaque burden is complementary. Gummesson et al. performed a GWAS of the CCTA segment involvement score (SIS, the number of coronary segments containing any plaque) in 24,811 European participants of the Swedish CArdioPulmonary bioImage Study (SCAPIS) — the largest population-based cohort with CCTA.[2] They found 20 independent SNPs at 18 loci, 3 of them not previously implicated in atherosclerotic cardiovascular disease (LEPR; MYLK4/LINC01600; MRPL15 region).[2] A GWAS of CAC in the same cohort gave similar results to SIS, whereas a GWAS of ultrasound-assessed carotid plaque shared some but not all loci with SIS — i.e. coronary and carotid subclinical atherosclerosis are genetically related but not identical.[2] Two-sample Mendelian randomization linked the imaging trait to events: one additional diseased coronary segment corresponded to OR 1.83 (95% CI 1.59–2.10) for myocardial infarction.[2]

Relevance to Polygenic Subtyping of CVD

Lab interpretation: these are the endophenotypes to anchor pathway-partitioned polygenic scores against — quantitative, closer to the silent biology than a clinical event, and (for CAC) demonstrably carrying calcification-specific genetic signal distinct from CAD. A partitioned score that drives calcified versus non-calcified/low-attenuation plaque differently would be the kind of opposite-direction, hard-to-fake signal the field needs. See Polygenic Subtyping of Cardiovascular Disease.

See Also

Citations

[1] Kavousi, M., et al. (2023). Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. Nature Genetics, 55(10), 1651–1664. DOI: 10.1038/s41588-023-01518-4. Source: s41588-023-01518-4.pdf. Supports: sample sizes, heritability, 11 loci / 8 novel / 5-not-CAD, calcification-specific pathways, and CAC-vs-CAD colocalization above. Location: Full text — Results; Figs. 1–2 and Supplementary Tables 9–10. Verified 2026-07-21.

[2] Gummesson, A., et al. (2025). A genome-wide association study of imaging-defined atherosclerosis. Nature Communications, 16, article 57457 (s41467-025-57457-7). DOI: 10.1038/s41467-025-57457-7. Source: 41467_2025_Article_57457.pdf. Supports: SCAPIS N=24,811, SIS phenotype, 20 SNPs/18 loci, 3 novel loci, CAC-vs-carotid comparison, and the MR OR 1.83 for MI above. Location: Full text — Abstract and Results. Verified 2026-07-21.