EbGSEA: an improved Gene Set Enrichment Analysis method for Epigenome-Wide-Association Studies.

Danyue Dong,Yuan Tian,Andrew E Teschendorff,Shijie C Zheng,Inanc Birol

doi:10.1093/bioinformatics/btz073

Abstract

MotivationThe biological interpretation of differentially methylated sites derived from Epigenome-Wide-Association Studies (EWAS) remains a significant challenge. Gene Set Enrichment Analysis (GSEA) is a general tool to aid biological interpretation, yet its correct and unbiased implementation in the EWAS context is difficult due to the differential probe representation of Illumina Infinium DNA methylation beadchips.ResultsWe present a novel GSEA method, called ebGSEA, which ranks genes, not CpGs, according to the overall level of differential methylation, as assessed using all the probes mapping to the given gene. Applied on simulated and real EWAS data, we show how ebGSEA may exhibit higher sensitivity and specificity than the current state-of-the-art, whilst also avoiding differential probe representation bias. Thus, ebGSEA will be a useful additional tool to aid the interpretation of EWAS data.Availability and implementation ebGSEA is available from https://github.com/aet21/ebGSEA, and has been incorporated into the ChAMP Bioconductor package (https://www.bioconductor.org).Supplementary information Supplementary data are available at Bioinformatics online.

Highlights

The number of Epigenome-Wide-Association Studies (EWAS) has grown rapidly, yet the biological interpretation of the differentially methylated sites found in these studies remains a significant problem (Lappalainen and Greally, 2017; Teschendorff and Relton, 2018)
This is similar to the well-known bias of RNA-Seq differential expression calls towards longer genes, and for this reason, methods that adjust for this bias in RNA-Seq data have been adapted to the DNA methylation (DNAm) context (Phipson et al, 2016)
Drawing an analogy between RNA-Seq and DNAm data is misleading, because in the RNA-Seq context the length of the gene only affects the reliability of the measured expression level, whereas in the DNAm context, the reliability of the measured DNAm level at a given CpG site does not depend on the number of probes mapping to the VC The Author(s) 2019

Summary

Introduction

The number of Epigenome-Wide-Association Studies (EWAS) has grown rapidly, yet the biological interpretation of the differentially methylated sites found in these studies remains a significant problem (Lappalainen and Greally, 2017; Teschendorff and Relton, 2018). EWAS typically use Illumina Infinium beadchips to measure DNA methylation (DNAm) at over 480 000 or 850 000 CpGs, depending on the beadchip version (Beck, 2010; Moran et al, 2016), and genes represented on these chips may have widely different numbers of probes mapping to them (Phipson et al, 2016).

Results

Conclusion