While disease-discordant monozygotic twin studies pose a unique study design because they control for confounding by genotype as well as shared environment between twins raised together,[62,63] they remain subject to some of the limitations discussed above. First and principally, while in some circumstances, epigenetic-discordance in the setting of disease-discordance may imply epigenetic mechanisms in the etiology of disease, the relationship between epigenetic change and the outcome of interest may still be confounded by differential environmental exposures acting both to produce the epigenetic modifications of interest but also independently to influence the likelihood of the outcome. In that regard, while investigators have argued that monozygotic twin studies can address “unknown confounders”,[59] these studies only address several known sources of confounding, confounding by genotype and some sources of confounding by shared environment. Moreover, while twins raised together often share environmental exposures at the level of the locality, the household, and the family, experiences within those environments may differ, and it may not be appropriate to assume exchangeability across environmental exposures between these twins. This is particularly true with respect to psychopathology, where environmental exposures of interest—such as parental affection or perceived stress—are impossible to aggregate at the family or household level.
