Genomewide alteration of histone H3K4 methylation underlies genetic vulnerability to psychopathology.

Dysregulated histone methylation has emerged as a recurring theme in multiple neuropsychiatric disorders. However, it is yet unclear whether the altered histone methylation is associated with aetiologic mechanisms or an outcome of disease manifestation. In this study, we examined the genomewide association studies datasets of three major psychiatric disorders, schizophrenia (SCZ), bipolar disorder (BIP), and major depression disorder (MDD), which represents a total of 231,783 cases and 425,444 controls, to clarify the relationship. Our gene-set enrichment analysis results identified statistically significant association of genes involved in three histone methylation biological processes with the three adult-onset psychiatric disorders, which is mainly driven by the histone H3K4 methylation pathway (GO: 0051568). Further analysis of histone H3K4 methylation pathway genes revealed a widespread role of the genes in brain function and disease; 29 (52%) and 41 genes (73.2%) were associated with at least one brain-related trait or brain disorder, respectively. Spatiotemporal gene expression analysis suggests that these pathway genes play a critical role during the prenatal period and are consistent regulators in the cerebral cortex throughout an individual’s life. AUTS2, DNMT1 and TET2 are genes of particular interest due to their pervasive role in various aspects of brain function. Our findings support a critical aetiologic role of H3K4 methylation genes shared across SCZ, BIP and MDD, providing new direction for the development of epigenetically-focussed drugs targeting common causal factors of these devastating disorders.