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 Erdmann; Ruth McPherson; Inke R. König; John R. Thompson; Nilesh J. Samani; Maciej Tomaszewski

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, 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

32 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 language	English
Article number	1900
Journal	American Journal of Human Genetics
Volume	97
Issue number	2
Pages (from-to)	228-237
Number of pages	10
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2015.06.001
Publication status	Published - 06.08.2015

Funding

This study was supported by the Alumni Association of University of Leicester PhD studentship and International Mentoring Travel Award by American Heart Association (to P.C.). M.T. is supported by the British Heart Foundation. N.J.S. holds a personal chair supported by the British Heart Foundation and is a UK NIHR senior investigator. C.P.N. 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. We would like to thank the participants and members of the CARDIoGRAM and the Cardiogenics consortia. Members of the Cardiogenics Consortium are listed in the Supplemental Data .

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 5 Gender Equality

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10.1016/j.ajhg.2015.06.001

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Christofidou, P., Nelson, C. P., Nikpay, M., Qu, L., Li, M., Loley, C., Debiec, R., Braund, P. S., Denniff, M., Charchar, F. J., Arjo, A. R., Trégouët, D. A., Goodall, A. H., Cambien, F., Ouwehand, W. H., Roberts, R., Schunkert, H., Hengstenberg, C., Reilly, M. P., ... Tomaszewski, M. (2015). Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages. American Journal of Human Genetics, 97(2), 228-237. Article 1900. https://doi.org/10.1016/j.ajhg.2015.06.001

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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.",

author = "Paraskevi Christofidou and Nelson, \{Christopher P.\} and Majid Nikpay and Liming Qu and Mingyao Li and Christina Loley and Radoslaw Debiec and Braund, \{Peter S.\} and Matthew Denniff and Charchar, \{Fadi J.\} and Arjo, \{Ares Rocanin\} and Tr{\'e}gou{\"e}t, \{David Alexandre\} and Goodall, \{Alison H.\} and Francois Cambien and Ouwehand, \{Willem H.\} and Robert Roberts and Heribert Schunkert and Christian Hengstenberg and Reilly, \{Muredach P.\} and Jeanette Erdmann and Ruth McPherson and K{\"o}nig, \{Inke R.\} and Thompson, \{John R.\} and Samani, \{Nilesh J.\} and Maciej Tomaszewski",

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Christofidou, P, Nelson, CP, Nikpay, M, Qu, L, Li, M, Loley, C, Debiec, R, Braund, PS, Denniff, M, Charchar, FJ, Arjo, AR, Trégouët, DA, Goodall, AH, Cambien, F, Ouwehand, WH, Roberts, R, Schunkert, H, Hengstenberg, C, Reilly, MP, Erdmann, J, McPherson, R, König, IR, Thompson, JR, Samani, NJ & Tomaszewski, M 2015, 'Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages', American Journal of Human Genetics, vol. 97, no. 2, 1900, pp. 228-237. https://doi.org/10.1016/j.ajhg.2015.06.001

TY - JOUR

T1 - Runs of Homozygosity

T2 - Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages

AU - Christofidou, Paraskevi

AU - Nelson, Christopher P.

AU - Nikpay, Majid

AU - Qu, Liming

AU - Li, Mingyao

AU - Loley, Christina

AU - Debiec, Radoslaw

AU - Braund, Peter S.

AU - Denniff, Matthew

AU - Charchar, Fadi J.

AU - Arjo, Ares Rocanin

AU - Trégouët, David Alexandre

AU - Goodall, Alison H.

AU - Cambien, Francois

AU - Ouwehand, Willem H.

AU - Roberts, Robert

AU - Schunkert, Heribert

AU - Hengstenberg, Christian

AU - Reilly, Muredach P.

AU - Erdmann, Jeanette

AU - McPherson, Ruth

AU - König, Inke R.

AU - Thompson, John R.

AU - Samani, Nilesh J.

AU - Tomaszewski, Maciej

PY - 2015/8/6

Y1 - 2015/8/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84938991208

U2 - 10.1016/j.ajhg.2015.06.001

DO - 10.1016/j.ajhg.2015.06.001

M3 - Journal articles

C2 - 26166477

AN - SCOPUS:84938991208

SN - 0002-9297

VL - 97

SP - 228

EP - 237

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

M1 - 1900

ER -

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

Abstract

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UN SDGs

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