Comparison of novel and existing methods for detecting differentially methylated regions

Samantha Lent,Zhe Wang,Josée Dupuis,Lan Wang,Hanfei Xu,Chloé Sarnowski,Marie-France Hivert

doi:10.1186/s12863-018-0637-4

Abstract

BackgroundSingle-probe analyses in epigenome-wide association studies (EWAS) have identified associations between DNA methylation and many phenotypes, but do not take into account information from neighboring probes. Methods to detect differentially methylated regions (DMRs) (clusters of neighboring probes associated with a phenotype) may provide more power to detect associations between DNA methylation and diseases or phenotypes of interest.ResultsWe proposed a novel approach, GlobalP, and perform comparisons with 3 methods—DMRcate, Bumphunter, and comb-p—to identify DMRs associated with log triglycerides (TGs) in real GAW20 data before and after fenofibrate treatment. We applied these methods to the summary statistics from an EWAS performed on the methylation data. Comb-p, DMRcate, and GlobalP detected very similar DMRs near the gene CPT1A on chromosome 11 in both the pre- and posttreatment data. In addition, GlobalP detected 2 DMRs before fenofibrate treatment in the genes ETV6 and ABCG1. Bumphunter identified several DMRs on chromosomes 1 and 20, which did not overlap with DMRs detected by other methods.ConclusionsOur novel method detected the same DMR identified by two existing methods and detected two additional DMRs not identified by any of the existing methods we compared.

Highlights

Single-probe analyses in epigenome-wide association studies (EWAS) have identified associations between DNA methylation and many phenotypes, but do not take into account information from neighboring probes
Comb-p identified only 1 Differentially methylated region (DMR) associated with both pre- and posttreatment TG in the 5′ untranslated region (UTR) region of the gene CPT1A on chromosome 11
GlobalP identified 2 regions on chromosome 11, the 5′ UTR region of CPT1A and the north shore of a CpG island near CPT1A, both region signals were driven by the 2 probes they share in common, cg00574958 and cg17058475

Summary

Introduction

Single-probe analyses in epigenome-wide association studies (EWAS) have identified associations between DNA methylation and many phenotypes, but do not take into account information from neighboring probes. Methods to detect differentially methylated regions (DMRs) (clusters of neighboring probes associated with a phenotype) may provide more power to detect associations between DNA methylation and diseases or phenotypes of interest. DNA methylation arrays allow for affordable epigenome-wide association studies (EWAS), but there is evidence that the standard single-probe approach is underpowered [2]. Cancer studies have found that hypermethylation of many probes in a gene promoter is associated with gene silencing, indicating that analyzing methylation by region may be more powerful [3]. We compared these 3 existing methods—DMRcate, Bumphunter, and comb-p—to a new algorithm, GlobalP, to detect DMRs using the real GAW20 data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study.

Methods

Results

Discussion

Conclusion