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

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. ; C.E.B. was supported by a PhD fellowship from the EU-FP7 project EpiTrain (316758). J.H. was supported by the UCL Cancer Institute Research Trust. V.K.R. was supported by BLUEPRINT (282510). K.D. was funded as a HSST trainee by NHS Health Education England. M.F. was supported by the BHF Cambridge Centre of Excellence (RE/13/6/30180). Research in W.H.O.'s laboratory was supported by EU-FP7 project BLUEPRINT (282510) and by program grants from the National Institute for Health Research (NIHR, http://www.nihr.ac.uk) and the British Heart Foundation under numbers RP-PG-0310-1002 and RG/09/12/28096 (https://www.bhf.org.uk/). W.H.O.'s laboratory receives funding from NHS Blood and Transplant for facilities. We gratefully acknowledge the participation of all NIHR Cambridge BioResource volunteers. We thank the Cambridge BioResource staff for their help with volunteer recruitment. We thank members of the Cambridge BioResource SAB and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. R.S. and his group were supported by the European Union in the framework of the BLUEPRINT Project (HEALTH-F5-2011-282510) and the German Ministry of Science and Education (BMBF) in the framework of the MMML-MYC-SYS project (036166B). We thank Deborah Winter (Weizmann Institute) for supplying a set of microglial enhancers from Lavin et al. (2014). Research in S.B.'s laboratory was supported by the Wellcome Trust (99148), Royal Society Wolfson Research Merit Award (WM100023), and EU-FP7 projects EpiTrain (316758), EPIGENESYS (257082), and BLUEPRINT (282510).