title: Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages.
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.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Christofidou
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: 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.
authors.forename: Majid
authors.initials: M
authors.lastname: Nikpay
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Qu
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.affiliation: Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck 23562, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Loley
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Debiec
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Denniff
authors.affiliation: Faculty of Science and Technology, School of Applied and Biomedical Sciences, Federation University Australia, Ballarat, VIC 3350, Australia.
authors.forename: Fadi J
authors.initials: FJ
authors.lastname: Charchar
authors.affiliation: 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.
authors.forename: Ares Rocanin
authors.initials: AR
authors.lastname: Arjo
authors.affiliation: 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.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.affiliation: 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.
authors.forename: Francois
authors.initials: F
authors.lastname: Cambien
authors.affiliation: 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.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany; Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK), Munich 80636, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany; Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK), Munich 80636, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.affiliation: Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19148, USA.
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck 23562, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.affiliation: 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.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck 23562, Germany.
authors.forename: Inke R
authors.initials: IR
authors.lastname: König
authors.affiliation: Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: 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.
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
mesh_terms: D000367:Age Factors; D003324:Coronary Artery Disease / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D012333:RNA, Messenger