Network modules linking expression and methylation in prefrontal cortex of schizophrenia

Abstract

Tremendous work has demonstrated the critical roles of genetics, epigenetics as well as their interplay in brain transcriptional regulations in the pathology of schizophrenia (SCZ). There is great success currently in the dissection of the genetic components underlying risk-conferring transcriptomic networks. However, the study of regulating effect of epigenetics, as a modulator of environmental factors, in the etiopathogenesis of SCZ still faces many challenges. In this work we investigated DNA methylation and gene expression from the dorsolateral prefrontal cortex (DLPFC) region of schizophrenia patients and healthy controls using weighted correlation network approaches. We identified and replicated two expression and two methylation modules significantly associated with SCZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expressionmethylation module pairs were involved aging process with module genes mostly related to oligodendrocyte development and myelination, and specially expressed in oligodendrocytes.Further examination of underlying quantitative trait loci (QTLs) showed significant enrichment in genetic risk of most psychiatric disorders for expression QTLs but not for methylation QTLs.These results support the coherence between methylation and gene expression in a network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation with SCZ and aging process.reported 20~50% of SCZ risk loci [13] showing strong cis-effect to their nearby genes' expression, further elaborating the liability of these risk variants in etiology of SCZ [14, 15]. Coexpression network analyses of brain expression data have identified some modules highly associated with SCZ harboring the SCZ risk loci with strong cis-acting effects [15, 16].However, some co-expression modules show discrepancy in relation with SCZ and the polygenic risk score for SCZ. Several SCZ-related modules fail to be significantly enriched in SCZ genetic susceptibility [14]. In addition, differentially expressed genes could have diverse patterns among brain regions [17], neural cells [18, 19] and neural developmental stages [20]. Collectively, these findings suggest the influence of complex interplay of genetics and environmental factors in determining the process of gene expression.Epigenetics can mediate gene by environment effects in modifying how genes are structured and expressed. DNA methylation is an epigenetic modification widely studied in psychiatric disorders such as SCZ [21, 22]. It changes the genome's response to transcriptional factors by attaching a methyl group in DNA sequence (mostly on cytosine site as CpG). The influence of DNA methylation in gene transcription can be stable and heritable across cell generations, and also reversible according to external condition chang...

Translational Potential of Neuroimaging Genomic Analyses to Diagnosis and Treatment in Mental Disorders

“…one pair presented consistently both expression and methylation association with schizophrenia. The involved genes were specifically expressed in astrocytes and upregulated in schizophrenia patients for which both epigenetic and genetic were suggested to play a role [172]. These findings support integrative studies of epigenetics and transcriptomics, in combination with neuroimaging for mental disorders, in hope of elucidating the pathophysiology of diseases [173].…”