Contribution of differential cell-specific methylation to schizophrenia [RNA-seq]

To address the heterogeneity of gene regulation and expression in cell types of a brain region with strong evidence for relevance to schizophrenia, we carried out whole genome methylation and expression analyses using post-mortem brain tissue from BA46 that underwent fluorescence-activated nuclei sorting (FANS). Importantly, we used whole genome bisulfite sequencing (WGBS) for methylation quantification to have an unbiased assessment of epigenetic modifications associated with schizophrenia, and additionally carried out whole genome sequencing (WGS) of the brain samples to account for genetic background differences. We found that a number of schizophrenia GWAS loci overlap with sites of cell-specific differential methylation in schizophrenia brain tissue. Differential methylation is also associated with differential gene expression in a cell-specific manner. Co-expression network analysis can identify groups of genes that are enriched for differentially methylated regions in each cell type, and these groups of co-expressed genes underscore shared molecular pathways that might be at risk in schizophrenia. Together, these data indicate that the integration of multiple levels of data in a cell-specific manner can provide novel biological insights into complex genetic disorders such as schizophrenia. We carried out RNA-sequencing (RNA-seq) of NeuN and OLIG2 positive nuclei from Brodmann area 46 of schizophrenia and matched controls of adult human neocortex.