At the same time, however, the measurement of epigenetic changes in postmortem brain tissue may also impose limitations with respect to when to measure. First, post-mortem brains can only be harvested after death—and therefore after the occurrence of the outcome of interest. Hence, the measurement of the epigenetic modification can only occur after the outcome has already taken place, imposing a necessary limitation on our ability to ascertain temporality of epigenetic exposure prior to outcome, discussed above. Second, the process of death often involves acidosis secondary to hypoxemia. Both acidosis and hypoxemia may contribute to the instability of genetic material,[50–52] which increases the potential for misclassification of epigenetic modification and spurious findings. Third, limiting studies to post-mortem brains may introduce a source of selection bias into epigenetic studies because factors associated with psychopathology may predict cause of death, which in turn is likely to predict the viability of brain tissue. This imposes considerable limitations to internal validity. On a similar note, the time-horizon of epigenetic changes is unclear—it is possible, therefore, that epigenetic changes that may not induce concomitant changes
