Identification and Investigation of Coronary Artery Disease Loci with Discordant Associations with Rarer Cardiovascular Conditions

Genome wide association studies (GWAS) consistently identify genomic loci associated with coronary artery disease (CAD) and dissective vascular conditions such as spontaneous coronary artery dissection (SCAD). CAD and SCAD are both conditions which affect the coronary arteries and are characterised by their effect on arterial blood vessel walls, with CAD increasing and stiffening the vascular wall and SCAD being associated with vessel wall weakening. Some of the GWAS loci associated with both CAD and SCAD have differing risk alleles, indicating a discordance in their direction of effect on disease risk. The shared discordance between their pathologies and GWAS associated loci could offer the opportunity to identify shared pathological pathways and enhance understanding of both conditions.

This study identifies and investigates discordant GWAS loci between CAD and two dissective conditions; SCAD and intracranial aneurysm (IA). A summary statistics-based identification of loci with discordant directions of association identified 18 loci which reached a Bonferroni-corrected significance threshold. Annotation of these loci prioritised likely causal variants and mapped potential functional genes. Functional investigation of one of these discordant loci, lead variant rs6841581, confirmed differential nuclear binding properties of each allele. Integration of smooth muscle cell (SMC) phenotyping data revealed some potential effects of discordant loci on SMC phenotype which did not survive multiple testing significance correction.

Knockdown of three genes prioritised at discordant loci suggested some potential impact of discordant gene expression on cell phenotype, but the effects failed to achieve Bonferroni corrected significance. This study serves as the first formal effort to identify and investigate discordant cardiovascular loci.