Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder

Although the loss of brain laterality is one of the most consistent modalities in schizophrenia (SCZ) and bipolar disorder (BD), its molecular basis remains elusive. Our limited previous studies indicated that epigenetic modifications are key to the asymmetric transcriptomes of brain hemispheres. We used whole ‐genome expression microarrays to profile postmortem brain samples from subjects with SCZ, psychotic BD [BD[+]] or non‐psychotic BD [BD(−)], or matched controls (10/group) and performed whole‐genome DNA methylation (DNAM) profiling of the same samples (3‐4/group) to identify pathways assoc iated with SCZ or BD[+] and genes/sites susceptible to epigenetic regulation. qRT‐PCR and quantitative DNAM analysis were employed to validate findings in larger sample sets (35/group). Gene Set Enrichment Analysis (GSEA) demonstrated that BMP signaling and astrocyte and cerebral cortex developmen t are significantly (FDRq< 0.25) coordinately upregulated in both SCZ and BD[+], and glutamate signaling and TGF β signaling are significantly coordinately upregulated in SCZ. GSEA also indicated that collagens are downregulated in right versus left brain of controls, but not in SCZ or BD[+] patients. Ingenuity Pathway Analysis predicted thatTGFB2 is an upstream regulator of these genes (p =  .0012). While lateralized expression ofTGFB2 in controls (p =  .017) is associated with a corresponding change in DNAM (p≤ .023), lateralized expression and DNAM ofTGFB2 are abse...
Source: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics - Category: Genetics & Stem Cells Authors: Tags: ORIGINAL ARTICLE Source Type: research