As a sensitivity analysis to assess the specificity of the fetal-postnatal transition and also to contrast possible neurodevelopmental mechanisms with epigenetic alterations around the time of schizophrenia illness diagnosis, we performed a differential methylation analysis comparing controls between 10–25 years old (N=73) to those greater than 25 (N=190) to identify changes in DNAm associated with the typical age of onset of schizophrenia (see Methods). Here, there were 24,685 CpGs significant at pbonf < 0.05 between these two age groups at lesser effect sizes than those associated with the prenatal/postnatal transition – only 58 CpGs showed changes in DNAm greater than 0.1, making it difficult to perform comparable DMR analyses (see Methods). There were only 313 of the 24,685 CpGs linked to the adolescent period in the PGC2 loci (5.7%), which was not enriched compared to these age of onset-associated CpGs outside these loci (5.4%, OR = 1.06, p=0.32). However, we note that stratifying by directionality resulted in significant enrichment among schizophrenia GWAS loci here among a minority of CpGs (N=144) more highly methylated in adolescence than later adulthood (OR=1.42, p=3.38×10−5).
