to controls (N=2,043, 97. 1%) with much smaller differences in methylation levels than those that found in the prenatal/postnatal contrast analysis (mean absolute proportion change: 0.013, IQR: 0.010–0.01.8). This pattern of diagnosis (i.e. state) associated hypomethylated CpGs contrasts with the association of risk associated GWAS loci (i.e. trait) with principally relatively hypermethylated CpGs during the fetal and adolescent timeframe. Nevertheless, these differentially methylated CpGs were in or near (within 10kb) genes significantly enriched for embryo development (p=1.9×10−9), cell fate commitment (p=2.68×10−7), and nervous system differentiation (p=1.9×10−7) by Gene Ontology analysis33 (Supplementary Table 11). One of the top differentially methylated CpGs lies in the promoter of HAT1, a histone acetyltransferase primarily targeting lysines on the H4 nucleosome34, perhaps manifesting as differences in histone acetylation in conjunction with DNAm changes35. These hypomethylated CpGs were enriched for being in TSS chromatin states (70.6% compared to 21.7% for the entire array), and depleted for enhancer, repressor and quiescent chromatin states (Supplementary Table 7), suggesting that they may be influencing gene expression. The lack of enrichment of these diagnosis-associated CpGs with adult associated biology suggest that these CpGs reflect environmental influences on early developmental events that increase risk independent of genetic risk influences.
