BACKGROUNDEpigenetic factors (such as DNA methylation) have been widely reported to be associated with schizophrenia (SCZ). However, the causal relationships between epigenetic factors and SCZ remain largely unknown.METHODSHere we conducted a Mendelian randomization study to investigate the causal relationships between DNA methylation and SCZ. Brain methylation quantitative trait loci (mQTL) (N = 1,160) and blood mQTL data (N = 27,750) were used as exposures, and genome-wide association data of SCZ (53,386 cases and 77,258 controls) were used as outcome.RESULTSWe identified 172 (mapped to 160 genes) and 157 (mapped to 155 genes) methylation sites whose methylation levels in the brain and blood are causally associated with SCZ, respectively. Among the mapped genes, 36 overlapping genes were identified. Interestingly, three methylation sites (near BRD2, CNNM2, and RERE) showed significant associations in both brain and blood, with the same direction of effect. We further performed MR analysis using brain expression quantitative trait (eQTL) as exposures and identified 123 genes whose expression levels were causally associated with SCZ. Comparing the significant genes from eQTL and brain mQTL prioritized 15 overlapping genes, suggesting that both epigenetic modification and expression of these genes confer risk of SCZ. Finally, we validated our findings with genome editing and animal model experiments.CONCLUSIONSOur study identified methylation sites whose methylation levels are causally associated with SCZ and demonstrated the important roles of epigenetic factors in SCZ. Besides, our findings also reveal pivotal risk genes whose expression and epigenetic regulation are causally associated with SCZ.
