Another caveat of the twin design is that genetic relatedness is indexed by matching for segregating genes which should not be confused with all biological mechanisms that could be in play. Of note, epigenetic mechanisms are not controlled for in the twin design and indeed, it is not uncommon to find epigenetic differences within pairs of MZ twins (93). Epigenetics, broadly defined, refers to heritable variation that cannot be solely attributed to modifications in the sequence of DNA (94). Epigenetic change is a key contributor to psychiatric illnesses (95) and that such mechanisms underlie substance use is becoming more widely accepted (96–99). The extent to which such epigenetic modification can be implicated in discordant MZ correlations (those that reflect causal or shared individual-specific factors) remains to be investigated. For instance, Mill and colleagues have found evidence for discordance in methylation (increased methylation typically indexes gene silencing) signatures for the COMT gene in MZ twin pairs (100). Furthermore, there is evidence for stress-related methylation of the Val158 (rs4680) allele, which in turn, predicts aspects of human cognition, such as working memory (101).
