posted on 2015-07-09, 13:45authored byParaskevi Christofidou, Christopher P. Nelson, M. Nikpay, L. Qu, M. Li, C. Loley, Radoslaw Debiec, Peter S. Braund, Matthew Denniff, F. J. Charchar, A. R. Arjo, D-A. Trégouët, Alison H. Goodall, F. Cambien, W. H. Ouwehand, R. Roberts, H. Schunkert, C. Hengstenberg, M. P. Reilly, J. Erdmann, R. McPherson, I. R. König, John R. Thompson, Nilesh J. Samani, Maciej Tomaszewski
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.
This study was supported by the Alumni Association of University of Leicester PhD studentship and
International Mentoring Travel Award by American Heart Association to PC. MT is supported by the
British Heart Foundation. NJS holds a personal chair supported by the British Heart Foundation and is
a UK NIHR senior investigator. CPN is funded by the British Heart Foundation. The Cardiogenics
project was supported by the European Union 6th Framework Program (LSHM-CT-2006-037593).
The UKBS collection of Common Controls has been funded by the Wellcome Trust grant
084183/Z/07/Z and by NIHR programme grant to NHSBT (RP-PG-0310-1002). The collection was
established as part of the WTCCC.
American Journal of Human Genetics 97, 228–237, August 6, 2015
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences