Evaluation of commonly used analysis strategies for epigenome- and transcriptome-wide association studies through replication of large-scale population studies

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Abstract

BackgroundA large number of analysis strategies are available for DNA methylation (DNAm) array and RNA-seq datasets, but it is unclear which strategies are best to use. We compare commonly used strategies and report how they influence results in large cohort studies.ResultsWe tested the associations of DNAm and RNA expression with age, BMI, and smoking in four different cohorts (n =similar to 2900). By comparing strategies against the base model on the number and percentage of replicated CpGs for DNAm analyses or genes for RNA-seq analyses in a leave-one-out cohort replication approach, we find the choice of the normalization method and statistical test does not strongly influence the results for DNAm array data. However, adjusting for cell counts or hidden confounders substantially decreases the number of replicated CpGs for age and increases the number of replicated CpGs for BMI and smoking. For RNA-seq data, the choice of the normalization method, gene expression inclusion threshold, and statistical test does not strongly influence the results. Including five principal components or excluding correction of technical covariates or cell counts decreases the number of replicated genes.ConclusionsResults were not influenced by the normalization method or statistical test. However, the correction method for cell counts, technical covariates, principal components, and/or hidden confounders does influence the results.

Original languageEnglish
Article number235
Number of pages14
JournalGenome Biology
Volume20
Issue number1
DOIs
Publication statusPublished - 14 Nov 2019

Keywords

  • Illumina 450k arrays
  • DNA methylation
  • EWAS
  • RNA sequencing
  • Differential gene expression
  • TWAS
  • Statistical methods comparison
  • DIFFERENTIAL DNA METHYLATION
  • NORMALIZATION METHODS
  • BIOCONDUCTOR PACKAGE
  • SMOKING
  • METAANALYSIS
  • SIGNATURES
  • EXPOSURE
  • IMPACT
  • TIME

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