Re-annotating the EPICv2 manifest with genes, intragenic features, and regulatory elements

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Motivation The Illumina Infinium MethylationEPIC v2.0 BeadChip (EPICv2 array) is a microarray for quantification of DNA methylation at sites across the human genome, succeeding previous iterations of the platform, including the HumanMethylationEPIC BeadChip (EPICv1 array). An open source manifest file provided by the manufacturer maps array probes to genes and regulatory features. However, due to a change in strategy, it is no longer consistent with annotations for previous versions of the technology. We therefore generated an extended EPICv2 manifest, to improve backwards-compatibility with EPICv1 and provide a more comprehensive framework for interpreting DNA methylation data. Results Using public databases and the genomic coordinates of probes, we mapped the 923,452 sites assayed on the Illumina EPICv2 array, comprehensively annotating genes and regulatory elements. We also replicated the manufacturer’s approach of annotating sites in the regions <=200bp and 201-1500bp upstream of a transcription start site (the TSS200 and TSS1500), ensuring backwards-compatibility with existing pipelines for Illumina methylation array data. We found that 731,759 EPICv2 array sites (79.24% of all sites on the array) are located within a gene body (exon, intron, or UTR) according to the GENCODE Human release 49 (GENCODEv49) database. We additionally labelled sites located in a promoter or enhancer according to the GeneHancer database. Finally, the re-annotated manifest labels which sites are required for the Horvath DNA Methylation Age Calculator and MethylDetectR epigenetic clocks, to facilitate data preparation for these tools. Availability and Implementation The re-annotated manifest is freely available at https://doi.org/10.5281/zenodo.14933468 . The re-annotation code is on GitHub: https://github.com/bethan-mallabar-rimmer/EPICv2_manifest .