A Higher Dysregulation Burden of Brain DNA Methylation in Female Patients Implicated in the Sex Bias of Schizophrenia

Sex differences are pervasive in schizophrenia (SCZ), but the extent and magnitude of DNA methylation (DNAm) changes underlying these differences remain uncharacterized. In this study, sex-stratified differential DNAm analysis was performed in postmortem brain samples from 117 SCZ and 137 controls, partitioned into discovery and replication datasets. Three differentially methylated positions (DMPs) were identified (adj.p < 0.05) in females and 29 DMPs in males without overlap between them. Over 81 % of these sex-stratified DMPs were directionally consistent between sexes but with different effect sizes. Down-sampling analysis revealed more DMPs in females than in males when the sample sizes matched. Females had higher DNAm levels in healthy individuals and larger magnitude of DNAm changes in patients than males. Despite similar proportions of female-related DMPs (fDMPs, 8%) being under genetic control compared with males (10%), significant enrichment of DMP-related SNPs in signals of genome-wide association studies was identified only in fDMPs. One DMP in each sex connected the SNPs and gene expression of CALHM1 in females and CCDC149 in males. PPI subnetworks revealed that both female- and male-related differential DNAm interacted with synapse-related dysregulation. Immune-related pathways were unique for females and neuron-related pathways were associated with males. This study reveals remarkable quantitative differences in DNAm-related sexual dimorphism in SCZ and that females have a higher dysregulation burden of SCZ-associated DNAm than males.