MPS 01-02 GENOME WIDE HOMOZYGOSITY ANALYSIS - ASSOCIATION WITH CORONARY ARTERY DISEASE AND GENE EXPRESSION IN MONOCYTES AND MACROPHAGES

    loading  Checking for direct PDF access through Ovid

Abstract

Objective:

Homozygosity mapping is a strategy with a potential to identify and quantify the recessive component of inheritance - long stretches (usually >1Mb) of consecutive homozygous genotypes are known as runs of homozygosity (ROHs). A comprehensive analysis was undertaken regarding the contribution of ROHs to the genetic architecture of coronary artery disease (CAD) and regulation of gene expression in monocytes and macrophages.

Design and Method:

Approximately 2.5 million single nucleotide polymorphisms (SNPs) from previously conducted genome-wide association (GWA) studies in 12,123 individuals with CAD and 12,197 CAD-free controls from 11 European populations were used to explore differences in the genetic architecture of homozygosity between the two groups. Consensus ROHs overlapping across studies were identified and their relevance to CAD was examined individually and at the aggregate level. Finally, we combined genome-wide consensus ROHs with data from monocyte and macrophage transcriptome profiling in the Cardiogenics study to explore whether the presence of ROHs was related to expression of genes that map to specific ROHs.

Results:

Individuals with CAD had approximately 0.63 (95% CI: 0.4–0.8, P = 1.49 × 10−9) excess of ROHs when compared to CAD-free controls. The average total length of ROHs was approximately 1046.92 kb (95% CI: 634.4–1459.5, P = 6.61 × 10−7) greater in individuals with CAD than control subjects. Overlapping consensus ROHs favouring increased risk of CAD were much more common than those showing the opposite direction of association with CAD (P = 2.69 × 10−33). Subjects with ROHs showed significant differences in the expression of 44 mRNAs in monocytes and 17 mRNAs in macrophages when compared to subjects without those ROHs.

Conclusions:

This study provides evidence for an excess of homozygosity in CAD and suggest the potential biological relevance of ROHs in cells of importance to the pathogenesis of atherosclerosis. Our data suggest that recessive variants may be an important factor in the genetic architecture of CAD.

Related Topics

    loading  Loading Related Articles