Network modules linking expression and methylation in prefrontal cortex of schizophrenia

Area of Science:

• Neuroscience
• Genetics
• Epigenetics

Background:

• Genetics and epigenetics play critical roles in brain transcriptional regulation and schizophrenia (SZ) pathology.
• While genetic components of SZ risk are increasingly understood, the epigenetic regulatory effects in SZ pathogenesis remain challenging to study.
• The dorsolateral prefrontal cortex (DLPFC) is a key brain region implicated in SZ.

Purpose of the Study:

• To investigate the interplay between DNA methylation and gene expression in the DLPFC of individuals with and without schizophrenia.
• To identify specific molecular networks and cellular pathways associated with SZ and aging.
• To explore the influence of genetic factors on these epigenetic and transcriptomic networks.

Main Methods:

• Utilized a weighted correlation network approach to analyze DNA methylation and gene expression data from DLPFC samples.
• Identified and replicated significant expression and methylation modules associated with schizophrenia.
• Examined overlaps between expression-methylation modules and analyzed quantitative trait loci (QTLs).

Main Results:

• Identified two significant expression and two significant methylation modules linked to SZ.
• Discovered overlapping expression-methylation modules enriched in astrocyte-specific pathways and modules related to oligodendrocyte development and aging.
• Found that expression QTLs, but not methylation QTLs, were enriched for genetic risk across multiple psychiatric disorders.

Conclusions:

• Demonstrated coherence between DNA methylation and gene expression at a network level in the context of schizophrenia.
• Suggests a combinatorial role of genetics and epigenetics in regulating gene expression networks within glial cells (astrocytes and oligodendrocytes).
• Highlights the involvement of these glial-specific networks in both schizophrenia and the aging process.