Gene-set analysis is severely biased when applied to genome-wide methylation data

Paul Geeleher, Lori Hartnett, Laurance J. Egan, Aaron Golden, Raja Affendi Raja Ali, Cathal Seoighe

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Motivation: DNA methylation is an epigenetic mark that can stably repress gene expression. Because of its biological and clinical significance, several methods have been developed to compare genome-wide patterns of methylation between groups of samples. The application of gene set analysis to identify relevant groups of genes that are enriched for differentially methylated genes is often a major component of the analysis of these data. This can be used, for example, to identify processes or pathways that are perturbed in disease development. We show that gene-set analysis, as it is typically applied to genome-wide methylation assays, is severely biased as a result of differences in the numbers of CpG sites associated with different classes of genes and gene promoters.Results: We demonstrate this bias using published data from a study of differential CpG island methylation in lung cancer and a dataset we generated to study methylation changes in patients with long-standing ulcerative colitis. We show that several of the gene sets that seem enriched would also be identified with randomized data. We suggest two existing approaches that can be adapted to correct the bias. Accounting for the bias in the lung cancer and ulcerative colitis datasets provides novel biological insights into the role of methylation in cancer development and chronic inflammation, respectively. Our results have significant implications for many previous genome-wide methylation studies that have drawn conclusions on the basis of such strongly biased analysis.Contact: Supplementary information: Supplementary data are available at Bioinformatics online.

Original languageEnglish (US)
Pages (from-to)1851-1857
Number of pages7
JournalBioinformatics
Volume29
Issue number15
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Statistics and Probability
  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Computational Theory and Mathematics
  • Computational Mathematics

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    Geeleher, P., Hartnett, L., Egan, L. J., Golden, A., Raja Ali, R. A., & Seoighe, C. (2013). Gene-set analysis is severely biased when applied to genome-wide methylation data. Bioinformatics, 29(15), 1851-1857. https://doi.org/10.1093/bioinformatics/btt311