Deviations from these essential developmental trajectories during critical windows of development from conception to young adulthood may interfere with the carefully coordinated temporal and spatial dynamics of gene expression through a combination of genetic and epigenetic factors3,5,38,39 that may contribute to risk for schizophrenia and other neurodevelopmental disorders. Indeed, the CpGs that track this changing neuronal phenotype, e.g. those that differ in DNAm levels comparing pre- and post-natal samples, were enriched by genomic location of regions that confer genetic risk for schizophrenia25 as have changes in transcriptome across brain development22,40,41. However the mechanisms by which DNAm changes that track shifting neuronal phenotypes alter risk for schizophrenia appears largely unknown, and will likely require more cell type-specific assays to focus on individual cell populations across brain development to reduce the strong composition effects observed in homogenate brain tissue. This is likely to be a complex conundrum, as composition measures in homogenate tissue did not differ between cases and control samples and controlling for composition did not alter the CpG differences between patients and controls.
