Analysis of contribution of cellular composition and cell type specific gene expression to age-related and genetic variation in aortic distensibility

Background The capacity of the aorta to expand under pressure, known as aortic distensibility, declines with age, and reduced aortic distensibility is associated with negative cardiovascular outcomes. Genome-wide association studies have identified genetic variants associated with distensibility; however, the mechanisms leading to changes in distensibility remain unclear. In this study, we examined aortic distensibility through the lens of genomics, considering the contributions of inferred cellular composition and cell type-specific gene expression to the observed changes in distensibility associated with age and genotype. Methods We applied a deep learning model to segment 62,497 UK Biobank CMRI and identified genomic loci associated with aortic distensibility. Distensibility-associated SNPs were tested for association both with cellular proportions and cell type-specific gene expression, inferred using gene expression deconvolution in GTEx aortic samples. We also tested for SNP-by-age interactions to identify loci associated with age-related differences in distensibility. Results We found age-related decreases in the proportions of Pericytes and Fibroblast I cells, while the proportion of VSMC II increased. Notably, most of the gene expression changes associated with age were identified in VSMC I, VSMC II and Fibroblast I cells. Furthermore, when we mapped distensibility-associated loci to nearby genes, we found that the expression of the majority of these genes was significantly correlated with age in VSMC I, VSMC II, Pericytes and Fibroblast I cells. There were no significant SNP-by-age interactions for distensibility in the UKB cohort, suggesting that the association between genotype and distensibility did not differ substantially across the age range examined. None of the identified distensibility-associated SNPs was significantly associated with the inferred cellular proportions. Interestingly, we found that two independent SNPs that had a genome-wide significant association with distensibility were also associated with cell type-specific expression of nearby genes (SRR in VSMC I, VSMC II, Fibroblast I, as well as CDH13 in VSMC I) that have previously been implicated in aortic distensibility Conclusion This study identifies cell type-specific changes in gene expression that may help to explain genetic and age-related variation in aortic distensibility, a clinically important physiological phenotype.