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eFORGE: A Tool for Identifying Cell Type-Specific Signal in Epigenomic Data

View Article: PubMed Central - PubMed

ABSTRACT

Epigenome-wide association studies (EWAS) provide an alternative approach for studying human disease through consideration of non-genetic variants such as altered DNA methylation. To advance the complex interpretation of EWAS, we developed eFORGE (http://eforge.cs.ucl.ac.uk/), a new standalone and web-based tool for the analysis and interpretation of EWAS data. eFORGE determines the cell type-specific regulatory component of a set of EWAS-identified differentially methylated positions. This is achieved by detecting enrichment of overlap with DNase I hypersensitive sites across 454 samples (tissues, primary cell types, and cell lines) from the ENCODE, Roadmap Epigenomics, and BLUEPRINT projects. Application of eFORGE to 20 publicly available EWAS datasets identified disease-relevant cell types for several common diseases, a stem cell-like signature in cancer, and demonstrated the ability to detect cell-composition effects for EWAS performed on heterogeneous tissues. Our approach bridges the gap between large-scale epigenomics data and EWAS-derived target selection to yield insight into disease etiology.

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eFORGE Analysis of Autoimmune EWASTop panel shows a blood (predominantly T cell), intestine, and thymus-specific signal for 86 probes from an EWAS on SLE. Middle panel shows a more general pattern of enrichment, with a strong blood signal, with CD14+ cells as the highest category, for a set of 100 RA EWAS probes. Bottom panel shows a blood (predominantly T cell) and thymus-specific enrichment for a set of 753 probes for an EWAS on Sjögren’s syndrome. Probe lists were obtained from the supplementary files of the studies (Coit et al., 2013, Liu et al., 2013, Altorok et al., 2014).
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fig5: eFORGE Analysis of Autoimmune EWASTop panel shows a blood (predominantly T cell), intestine, and thymus-specific signal for 86 probes from an EWAS on SLE. Middle panel shows a more general pattern of enrichment, with a strong blood signal, with CD14+ cells as the highest category, for a set of 100 RA EWAS probes. Bottom panel shows a blood (predominantly T cell) and thymus-specific enrichment for a set of 753 probes for an EWAS on Sjögren’s syndrome. Probe lists were obtained from the supplementary files of the studies (Coit et al., 2013, Liu et al., 2013, Altorok et al., 2014).

Mentions: Second, to provide specific examples of eFORGE analysis, we assessed the ability of eFORGE to predict disease-relevant cell types from EWAS conducted on immune blood cells for three autoimmune diseases: rheumatoid arthritis (RA) (Liu et al., 2013), systemic lupus erythematosus (SLE) (Coit et al., 2013), and Sjögren’s syndrome (Altorok et al., 2014). For these diseases, it is assumed that blood is the main affected tissue. We performed eFORGE analyses for each of these diseases using the reported top 100, 86, and 753 probes and consistently found tissue-specific enrichment for immune effector cells and thymus (Figure 5). Specifically, eFORGE results for the EWAS on RA pointed to CD14+ cells as the most highly enriched cell type (q value = 5.53e-04), indicating a tendency for cell-composition-corrected RA-associated DNAm changes to co-locate with CD14+ DHSs. Indeed, the accelerated maturation of CD14+ cells is a hallmark in RA (Hirohata et al., 1996). For the EWAS on SLE, we observed confirmatory enrichment in DHSs specific to T cells (q value = 2.56e-05). T cells, in particular CD4+ T cells, play an essential role in the development of SLE (Yin et al., 2015) and have previously been proposed as targets for the treatment of Sjögren’s syndrome (Singh and Cohen, 2012). Consistent with these findings, eFORGE also pointed to an independent T cell signal for DMPs identified in the Sjögren’s syndrome EWAS (q value = 1.31e-49).


eFORGE: A Tool for Identifying Cell Type-Specific Signal in Epigenomic Data
eFORGE Analysis of Autoimmune EWASTop panel shows a blood (predominantly T cell), intestine, and thymus-specific signal for 86 probes from an EWAS on SLE. Middle panel shows a more general pattern of enrichment, with a strong blood signal, with CD14+ cells as the highest category, for a set of 100 RA EWAS probes. Bottom panel shows a blood (predominantly T cell) and thymus-specific enrichment for a set of 753 probes for an EWAS on Sjögren’s syndrome. Probe lists were obtained from the supplementary files of the studies (Coit et al., 2013, Liu et al., 2013, Altorok et al., 2014).
© Copyright Policy - CC BY
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5120369&req=5

fig5: eFORGE Analysis of Autoimmune EWASTop panel shows a blood (predominantly T cell), intestine, and thymus-specific signal for 86 probes from an EWAS on SLE. Middle panel shows a more general pattern of enrichment, with a strong blood signal, with CD14+ cells as the highest category, for a set of 100 RA EWAS probes. Bottom panel shows a blood (predominantly T cell) and thymus-specific enrichment for a set of 753 probes for an EWAS on Sjögren’s syndrome. Probe lists were obtained from the supplementary files of the studies (Coit et al., 2013, Liu et al., 2013, Altorok et al., 2014).
Mentions: Second, to provide specific examples of eFORGE analysis, we assessed the ability of eFORGE to predict disease-relevant cell types from EWAS conducted on immune blood cells for three autoimmune diseases: rheumatoid arthritis (RA) (Liu et al., 2013), systemic lupus erythematosus (SLE) (Coit et al., 2013), and Sjögren’s syndrome (Altorok et al., 2014). For these diseases, it is assumed that blood is the main affected tissue. We performed eFORGE analyses for each of these diseases using the reported top 100, 86, and 753 probes and consistently found tissue-specific enrichment for immune effector cells and thymus (Figure 5). Specifically, eFORGE results for the EWAS on RA pointed to CD14+ cells as the most highly enriched cell type (q value = 5.53e-04), indicating a tendency for cell-composition-corrected RA-associated DNAm changes to co-locate with CD14+ DHSs. Indeed, the accelerated maturation of CD14+ cells is a hallmark in RA (Hirohata et al., 1996). For the EWAS on SLE, we observed confirmatory enrichment in DHSs specific to T cells (q value = 2.56e-05). T cells, in particular CD4+ T cells, play an essential role in the development of SLE (Yin et al., 2015) and have previously been proposed as targets for the treatment of Sjögren’s syndrome (Singh and Cohen, 2012). Consistent with these findings, eFORGE also pointed to an independent T cell signal for DMPs identified in the Sjögren’s syndrome EWAS (q value = 1.31e-49).

View Article: PubMed Central - PubMed

ABSTRACT

Epigenome-wide association studies (EWAS) provide an alternative approach for studying human disease through consideration of non-genetic variants such as altered DNA methylation. To advance the complex interpretation of EWAS, we developed eFORGE (http://eforge.cs.ucl.ac.uk/), a new standalone and web-based tool for the analysis and interpretation of EWAS data. eFORGE determines the cell type-specific regulatory component of a set of EWAS-identified differentially methylated positions. This is achieved by detecting enrichment of overlap with DNase I hypersensitive sites across 454 samples (tissues, primary cell types, and cell lines) from the ENCODE, Roadmap Epigenomics, and BLUEPRINT projects. Application of eFORGE to 20 publicly available EWAS datasets identified disease-relevant cell types for several common diseases, a stem cell-like signature in cancer, and demonstrated the ability to detect cell-composition effects for EWAS performed on heterogeneous tissues. Our approach bridges the gap between large-scale epigenomics data and EWAS-derived target selection to yield insight into disease etiology.

No MeSH data available.


Related in: MedlinePlus