Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages

Paraskevi Christofidou, Christopher P. Nelson, Majid Nikpay, Liming Qu, Mingyao Li, Christina Loley, Radoslaw Debiec, Peter S. Braund, Matthew Denniff, Fadi J. Charchar, Ares Rocanin Arjo, David Alexandre Trégouët, Alison H. Goodall, Francois Cambien, Willem H. Ouwehand, Robert Roberts, Heribert Schunkert, Christian Hengstenberg, Muredach P. Reilly, Jeanette ErdmannRuth McPherson, Inke R. König, John R. Thompson, Nilesh J. Samani, Maciej Tomaszewski*

*Corresponding author for this work
8 Citations (Scopus)

Abstract

Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4-0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 × 10-9). The average total length of ROHs was approximately 1,046.92 (95% CI: 634.4-1,459.5) kb greater in individuals with coronary artery disease than control subjects (p = 6.61 × 10-7). None of the identified individual ROHs was associated with coronary artery disease after correction for multiple testing. However, in aggregate burden analysis, ROHs favoring increased risk of coronary artery disease were much more common than those showing the opposite direction of association with coronary artery disease (p = 2.69 × 10-33). Individual ROHs showed significant associations with monocyte and macrophage expression of genes in their close proximity - subjects with several individual ROHs showed significant differences in the expression of 44 mRNAs in monocytes and 17 mRNAs in macrophages when compared to subjects without those ROHs. This study provides evidence for an excess of homozygosity in coronary artery disease in outbred populations and suggest the potential biological relevance of ROHs in cells of importance to the pathogenesis of atherosclerosis.

Original languageEnglish
Article number1900
JournalAmerican Journal of Human Genetics
Volume97
Issue number2
Pages (from-to)228-237
Number of pages10
ISSN0002-9297
DOIs
Publication statusPublished - 06.08.2015

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