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 (SZ). 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 in the etiopathogenesis of SZ 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 approach. We identified and replicated two expression and two methylation modules significantly associated with SZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were significantly enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expression-methylation module pairs were involved ageing process with module genes mostly related to oligodendrocyte development and myelination, and specifically 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 at the network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation to SZ and ageing process.

KEYWORDS:

• DNA methylation
• gene expression
• brain post-mortem
• schizophrenia
• ageing

Authors’ contributions

DDL, VDC, and JYL designed and performed the computational analyses, analyzed the data, and interpreted the results. JYC, KKD and JS contributed the data collection and data analysis. NPB contributed with ideas and participated in evaluating results and discussions. DDL, VDC and JYL wrote the manuscript with input from all authors. All authors approved the final manuscript.

Acknowledgements

We would like to thank Dr. Andrew Jaffe from the Lieber Institute for Brain Development for sharing the meQTL results from brain tissue.

Disclosure statement

The authors declare that they have no competing interests.

Declarations Availability of data and materials

The datasets generated during the current study are available in the dbGAP repository (Accession: phs000979.v1.p1) and GEO database (GSE74193, GSE36192, GSE21138, GSE61380, GSE36194, GSE73721 and GSE41826).

Ethics approval and consent to participate

Since all of datasets were from public database, this work subjected to ethic approval from each study.

Additional files

Additional File 1: Figure S1. The plots of module membership vs. group difference significance for the expression modules. Figure S2. The plots of module membership vs. group difference significance for the methylation modules. Figure S3. Permutation test of generalized clustering coefficient (GCC) for identified expression and methylation modules. Figure S4. Enrichment test of genes from all of expression and methylation modules. Figure S5. Overlap test between expression and methylation modules. Figure S6. Enrichment test of the overlap genes between yellow expression and yellow methylation modules in GO terms and KEGG pathways. Figure S7. The enrichment plot for the overlap genes in blueExp-blueMethy and blueExp-redMethy link, respectively. Figure S8. The characteristics of blue expression module and red methylation module. Figure S9. The KEGG pathway enrichment of genes from yellow expression module and yellow methylation module. Table S1. Demographic information of subjects from all datasets. Table S2. The list of PGC SZ risk genes from SZ-related yellow expression and yellow methylation modules. Table S3. SZ associations for CpGs(yellow methylation module) and expression probes(yellow expression module) involving neurotransmitter pathways. Table S4. The CpGs from oligodendrocyte expressed genes in blue and red modules and their associations with age. Table S5. Expression-methylation associations in blueExp-blueMethy and blueExp-redMethy links.

Supplementary File 2: Supplementary data file listing the genes from yellow expression module.

Supplementary File 3: Supplementary data file listing the CpGs from yellow methylation module.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This study was funded by the National Institutes of Health, grant number: P20GM103472, and R01EB005846, and National Science Foundation, grant number: 1539067.