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Title: Runs of homozygosity – association with coronary artery disease and gene expression in monocytes and macrophages
Authors: Christofidou, Paraskevi
Nelson, Christopher P.
Nikpay, M.
Qu, L.
Li, M.
Loley, C.
Debiec, Radoslaw
Braund, Peter S.
Denniff, Matthew
Charchar, F. J.
Arjo, A. R.
Trégouët, D-A.
Goodall, Alison H.
Cambien, F.
Ouwehand, W. H.
Roberts, R.
Schunkert, H.
Hengstenberg, C.
Reilly, M. P.
Erdmann, J.
McPherson, R.
König, I. R.
Thompson, John R.
Samani, Nilesh J.
Tomaszewski, Maciej
First Published: 9-Jul-2015
Publisher: Elsevier (Cell Press)
Citation: American Journal of Human Genetics 97, 228–237, August 6, 2015
Abstract: Runs of homozygosity (ROHs) are recognised 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 controls (P=1.49x10-9 ). The average total length of ROHs was approximately 1046.92 (95% CI: 634.4-1459.5) kb greater in individuals with coronary artery disease than controls (P=6.61x10-7 ). None of the identified individual ROHs was associated with coronary artery disease after correction for multiple testing. However, in aggregate burden analysis, ROHs favouring increased risk of coronary artery disease were much more common than those showing the opposite direction of association with coronary artery disease (P=2.69x10-33). 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.
DOI Link: 10.1016/j.ajhg.2015.06.001
ISSN: 0002-9297
eISSN: 1537-6605
Type: Journal Article
Rights: © 2015. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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