Further on this point, while we observed significant enrichment of the PGC loci in CpGs differing between patients and controls, this was a marginal enrichment, small in comparison to the enrichment with loci showing epigenetic alterations from prenatal to postnatal life. These results suggest that the majority of DNAm differences associated with the illness state are likely unrelated to genetic mechanisms of causation and implicate environmental factors. In this context and also germane to the issue of state related epiphenomena, it is worth highlighting that the case control differences mapped to genes implicated in early developmental processes, even if not linked with genetic risk variation. Thus, the epigenetic associations with schizophrenia, both in terms of illness state and genetic risk, implicate factors, both genetic and environmental, that track with early development and not adult life. Consistent with this conclusion is the additional observation that epigenetic changes associated with adolescence and early adulthood, the typical time of onset of schizophrenia, did not show enrichment of either genetic risk loci or illness state associated CpG alterations. This observation has potentially sobering implications for attributing a causative role of environmental influences that appear to coincide with the onset of the clinical disorder.
