Lastly, two important limitations of the microarray-based studies reviewed above should be noted. First, some Illumina probes (up to 25% in some studies) have been identified as cross-reactive and non-specific [124,125,126]. Therefore, measurements using these probes will be influenced by methylation levels at multiple sites, which may cause false negative as well as false positives. A second limitation of current array-based technology is that it measures only a small proportion of CpGs in the genome. Future approaches such as whole-genome bisulfite sequencing may allow a much more thorough examination of epigenetic changes across the genome and could provide significantly improved biomarkers for substance use disorders, particularly those mentioned above for which the current technology has provided minimal results.
