Abstract
Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in major psychosis neurons. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene responsible for dopamine synthesis. In patients, we find hypomethylation of the IGF2 enhancer is associated with increased TH protein levels. In mice, Igf2 enhancer deletion disrupts the levels of TH protein and striatal dopamine, and induces transcriptional and proteomic abnormalities affecting neuronal structure and signaling. Our data suggests that epigenetic activation of the enhancer at IGF2 may enhance dopamine synthesis associated with major psychosis.
Highlights
Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear
In sum, we identified a decrease in repressive epigenetic marks at an enhancer linked to tyrosine hydroxylase (TH) gene regulation in neurons of patients with major psychosis
Hypomethylation of the enhancer at insulin-like growth factor 2 (IGF2) may be an important contributor to the pathogenesis of psychotic symptoms
Summary
Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. We find that Igf[2] enhancer disruption in mice affects levels of TH protein and dopamine, as well as pathways involved in synaptic signaling and neuronal structure. Pre- and post-natal transcriptional dynamics of genes differentially expressed in psychosis showed a significantly higher correlation with those of synaptic development genes, relative to randomly-sampled sets (BrainSpan; p < 0.001; resampling, onesided test; Supplementary Fig. 7b). Together, these findings suggests that in neurons of major psychosis patients, DNA methylation and transcriptional changes converge to affect early development, disrupt neurotransmission, and raise immune responses. Neurons of major psychosis patients show significant changes in DNA methylation, some of which may be mediated by genetic state
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