Lastly, our data draw parallels to an earlier report of enrichment of DNAm changes during fetal life among schizophrenia diagnosis-related CpGs36. Even in our smaller, but regionally-focused, fetal sample, 1986/2104 of the CpGs associated with diagnosis were significantly differentially methylated between fetal and postnatal life (at pbonf < 0.05, OR = 16.5, enrichment p-value < 10−100). In contrast, these CpGs were strongly depleted (OR = 0.26, p = 1.88×10−15) for those CpGs showing significant differences comparing adolescent to adult controls, reflecting age-related changes occurring near the age of onset of schizophrenia – only 31/2104 CpGs associated with age-related changes around schizophrenia onset as well as diagnosis. These contrasts suggest that the diagnosis-associated differentiated CpGs are not related to epigenetic events germane to illness onset, but appear to reflect lifelong epigenetic states established early in development. This is further supported by the observation that these CpGs largely hypomethylated for diagnosis (compared to adult controls) were relatively highly methylated in fetal life (Supplementary Figure 14, ρ= −0.63, p < 10−20), and appeared to further diverge from fetal levels compared to the adult
