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

Paraskevi Christofidou¹, Christopher P Nelson², Majid Nikpay³, Liming Qu⁴, Mingyao Li⁴, Christina Loley⁵, Radoslaw Debiec¹, Peter S Braund¹, Matthew Denniff¹, Fadi J Charchar⁶, Ares Rocanin Arjo⁷, David-Alexandre Trégouët⁷, Alison H Goodall², Francois Cambien⁷, Willem H Ouwehand⁸, Robert Roberts³, Heribert Schunkert⁹, Christian Hengstenberg⁹, Muredach P Reilly¹⁰, Jeanette Erdmann¹¹, Ruth McPherson³, Inke R König⁵, John R Thompson¹², Nilesh J Samani², Maciej Tomaszewski¹³

Affiliations

¹ Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
² Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK.
³ Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada; Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON K1Y 3V5, Canada.
⁴ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck 23562, Germany.
⁶ Faculty of Science and Technology, School of Applied and Biomedical Sciences, Federation University Australia, Ballarat, VIC 3350, Australia.
⁷ ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 1166, Paris 75013, France.
⁸ Department of Haematology, Cambridge Biomedical Campus, University of Cambridge and NHS Blood and Transplant, Cambridge CB2 0PT, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
⁹ Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany; Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK), Munich 80636, Germany.
¹⁰ Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19148, USA.
¹¹ Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck 23562, Germany.
¹² Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK.
¹³ Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK. Electronic address: mt142@le.ac.uk.

PMID: 26166477
PMCID: PMC4573243
DOI: 10.1016/j.ajhg.2015.06.001

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

Paraskevi Christofidou et al. Am J Hum Genet. 2015.

. 2015 Aug 6;97(2):228-37.

doi: 10.1016/j.ajhg.2015.06.001. Epub 2015 Jul 9.

Authors

Affiliations

¹ Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
² Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK.
³ Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada; Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON K1Y 3V5, Canada.
⁴ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck 23562, Germany.
⁶ Faculty of Science and Technology, School of Applied and Biomedical Sciences, Federation University Australia, Ballarat, VIC 3350, Australia.
⁷ ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 1166, Paris 75013, France.
⁸ Department of Haematology, Cambridge Biomedical Campus, University of Cambridge and NHS Blood and Transplant, Cambridge CB2 0PT, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
⁹ Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany; Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK), Munich 80636, Germany.
¹⁰ Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19148, USA.
¹¹ Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck 23562, Germany.
¹² Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK.
¹³ Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK. Electronic address: mt142@le.ac.uk.

PMID: 26166477
PMCID: PMC4573243
DOI: 10.1016/j.ajhg.2015.06.001

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.

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Figures

**Figure 1**
Overview of the Project Strategy

**Figure 2**
Analysis of Association between the Presence of Consensus ROHs and Gene Expression in the Cardiogenics Study: Genome-wide Signal-Intensity Plot (A) Human monocytes. (B) Human macrophages. The y axis shows the logarithmic level of statistical significance (p value) for association of each consensus ROH with expression. The x axis shows 22 autosomal chromosomes in numerical order.

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References

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

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

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