MBD-seq-realities of a misunderstood method for high-quality methylome-wide association studies

The majority of methylome-wide association studies (MWAS) have been performed using commercially available array-based technologies such as the Infinium Human Methylation 450K and the Infinium MethylationEPIC arrays (Illumina). While these arrays offer a convenient and relatively robust assessment of the probed sites they only allow interrogation of 2-4% of all CpG sites in the human genome. Methyl-binding domain sequencing (MBD-seq) is an alternative approach for MWAS that provides near-complete coverage of the methylome at similar costs as the array-based technologies. However, despite publication of multiple positive evaluations, the use of MBD-seq for MWAS is often fiercely criticized. Here we discuss key features of the method and debunk misconceptions using empirical data. We conclude that MBD-seq represents an excellent approach for large-scale MWAS and that increased utilization is likely to result in more discoveries, advance biological knowledge, and expedite the clinical translation of methylome-wide research findings.