One locus, three phenotypes: LPA as the common genetic driver of early aortic valve calcification, coronary artery calcification and carotid plaque
D Freiholtz, A Wang, A Mahdi, B Gigante, T Fall, A Gummesson, M Ohro-Melander, C Gunnarsson, T Jernberg, S Soderberg, G Bergstrom, H M Bjorck, B ShahimAbstract
Background
Aortic valve calcification (AVC), coronary artery calcification (CAC), and carotid atherosclerotic plaque represent related yet distinct manifestations of cardiovascular mineralization. These conditions frequently co-occur and overlapping genetic loci have been reported, particularly with late clinical manifestations in elderly cohorts. However, the extent to which these phenotypes share a common causal genetic signal in middle-aged adults remains unclear.
Purpose
We aimed to determine whether AVC, CAC, and carotid plaque share a common underlying genetic architecture at major loci in a low disease-burden middle-aged population.
Methods
We performed a genome-wide association study (GWAS) of CT-derived AVC in 24,303 European-ancestry participants (48% men) of the Swedish CArdioPulmonary bioImage Study (SCAPIS), including 1,772 with AVC. Logistic regression was applied to imputed genotypes using an additive model with adjustment for age, sex, study site, and ancestry principal components. Publicly available GWAS summary statistics from previous SCAPIS reports on CAC and carotid plaque were acquired. Regional summary statistics were aligned across datasets and analyzed using Bayesian colocalization with for biologically and statistically prioritized loci.
Results
The AVC GWAS identified a strong association signal at the LPA locus (lead variant rs118039278, p-value = 3.6 x 10-31). Regional comparison revealed overlapping association patterns for AVC, CAC and carotid plaque within the same genomic interval. Bayesian colocalization analysis within 1 Mb supported a shared causal signal at the LPA locus between AVC and CAC (posterior probability for a shared signal (PP.H4) = 0.99) and between AVC and carotid plaque (PP.H4 = 0.99). Effect estimates were directionally consistent across traits following allele harmonization.
Conclusions
Genetic variation at the LPA locus contributes to calcific and atherosclerotic processes across multiple vascular territories. Colocalization analysis suggests a shared causal mechanism, linking aortic valve calcification with coronary and carotid artery calcification, emphasizing lipoprotein(a) as a key driver of early cardiovascular calcification.Abstract figure