More Than Just Bad Lifestyles: A De novo Genetic Approach Identifies Links Between Coronary Artery Disease and its Comorbidities

Abstract

Comorbidities greatly influence the mortality of patients with coronary artery disease (CAD), but their shared genetic basis remind largely unknown. Despite coronary artery disease (CAD) being the leading cause of death in the past decade, identified CAD associated genetic variants collectively can only explain ~36% of the estimated heritability. Recent studies have made progress in understanding the role(s) of CAD associated genetic variants in gene regulation, but most have focused on a cross tissue level and without considering spatial constraints on regulation in spite of increasing evidence supporting its importance. For CAD comorbidities, previous studies have only been based on statistical associations using medical records, giving the power to identify but no helps in the understanding of the comorbidities’ co-occurrence. Integrating data on genomic spatial and protein-protein interactions with expression quantitative trait loci (eQTL) analysis and a network diffusion comorbidity analysis, we investigated the tissue-specific regulatory impacts of 1286 single nucleotide polymorphisms (SNPs) associated with CAD (P ≤ 1 x 10-6). We observed eight CAD-associated gene regulations unique to the coronary artery, including PTGER3, RASSF5, TTBK2, BRE, and CHEK1. The network diffusion comorbidity analysis identified both recognised (i.e., chronic pulmonary disease, asthma, cholesterol levels, hypertension, myocardial infarction) and novel (i.e., IgA vasculitis, hepatitis B, gut microbiota abundance) comorbid conditions of CAD, and the potential shared disease mechanisms between them. We observed distinct clusters of comorbid traits in the aorta and coronary, characterised by similar biological relevancy and shared gene enrichment patterns. Our results explored tissue-specific and spatially regulated interactions affected in CAD and its comorbidities, improving our understanding of their genetic pathologies and highlighting the significance of tissue-specific and spatial regulatory effects. Notably, these alterations were observed in the coronary artery tissue even though this tissue (low number of tissue samples in GTEx) had a relatively lower power to detect eQTLs, making these findings more significant. The perspective of tissue-specificity and spatial regulation in the comorbidity study of CAD-associated gene/gene interactions provided novel targets that may represent high-value targets for the development of therapeutic interventions for CAD and the comorbidities of CAD.