Un-explored regions of the human genome and predisposition to coronary artery disease

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Previous genome-wide association (GWA) studies have identified several common variants underlying the risk of CAD. However, the collective contribution of these variants to CAD risk is modest and explains only a small proportion (~10%) of its overall heritability. There are largely un-explored regions/variants of human genome that may harbor alleles/genes/loci/pathways associated with susceptibility to CAD and account for a portion of its missing heritability. Runs of homozygosity (ROHs), rare alleles and pseudoautosomal regions (PARs) are amongst most overlooked regions/variants by GWA studies. Genome-wide homozygosity analysis in CARDIoGRAM Consortium revealed statistically significant differences in the overall homozygosity levels between 10,548 CAD patients and 10,273 CAD-free controls. The distribution of consensus regions of overlapping ROHs showed over-representation amongst patients with CAD, suggesting that accumulation of recessive alleles may increase the risk of CAD. The aggregate association analysis of low-frequency and rare variants represented on the HumanCVD 50K array in >13,000 CAD patients and >14,000 controls from the IBC 50K CAD Consortium validated previously reported association between LPA and CAD in populations of European ancestry. This analysis also revealed new associations between F10, F7 and TRAF2 genes and CAD in South Asians. Common intergenic variant in PAR1 was associated with CAD risk in 9,536 women in the meta-analysis of CARDIoGRAM Consortium. New generation RNA-sequencing analysis provided first glimpse into PARs transcriptome in human monocytes and macrophages and uncovered expression of a lincRNA in close proximity to the PAR1 association signal. Sex-stratified comparative gene expression analysis in human monocytes and macrophages revealed statistically significant differences in PAR1 gene expression levels between men and women. These data revealed novel associations between CAD and ROHs as well as PAR1 and showed that in-depth exploration of regions commonly neglected by previous GWA studies has a potential to provide new insights into genetic architecture of common complex diseases.