Figure 1

Schizophrenia-associated DNA methylation differences in the prefrontal cortex. (A) Probes associated with four genes are significantly associated with schizophrenia at FDR ≤0.05: GSDMD (control = 78.9 ± 3.0, schizophrenia = 83.3 ± 1.3, FDR = 0.03); RASA3 (control = 65.1 ± 4.7, schizophrenia = 56.4 ± 4.1, FDR = 0.03); HTR5A (control = 11.5 ± 1.7, schizophrenia = 9.2 ± 1.2, FDR = 0.03); and PPFIA1 (control = 53.1 ± 3.2, schizophrenia = 47.6 ± 3.2, FDR = 0.03). (B) The top-ranked differentially methylated region is located in an intergenic CpG island in NRN1 where there is coordinated hypomethylation across 29 adjacent CpG sites in schizophrenia patients (red) compared with controls (blue). The mean DNA methylation difference across all 29 sites is -1.77% (FDR = 3.1e-2), with a notable region of hypomethylation (-3.7%) spanning three consecutive DMPs (FDR = 2.4e-2). (C) Selected schizophrenia-associated DMPs were successfully validated and replicated. Shown are technical validation data for the CpG site corresponding to probe cg24803255 in RASA3 confirming significant schizophrenia-associated hypomethylation (control = 70.5 ± 3.7, schizophrenia = 66.4 ± 3.2, P = 0.0002). Additional technical validation data for other loci are shown in Figure S2 in Additional file 1. Also shown are replication data for cg24803255 in RASA3 in PFC from the Montreal cohort confirming significant schizophrenia-associated hypomethylation (control = 65.1 ± 5.5, schizophrenia = 61.3 ± 4.7, P = 0.05). (D) DNA methylation differences at the 100 top-ranked PFC DMPs identified in the London discovery cohort are significantly correlated with schizophrenia-associated differences at the same probes in PFC from the Montreal replication cohort (r = 0.54, P = 6.8e-09).