Cell-type specific global reprogramming of the transcriptome and epigenome in induced neurons with the 16p11.2 neuropsychiatric CNVs.

Copy number variants (CNVs), either deletions or duplications, at the 16p11.2 locus in the human genome are known to increase the risk for autism spectrum disorders (ASD), schizophrenia, and several other developmental conditions. Here, we investigate the global effects on gene expression and DNA methylation using an induced pluripotent stem cell (iPSC) to induced neuron (iN) cell model system derived from 16p11.2 CNV patients and controls. This approach revealed genome-wide and cell-type specific alterations to both gene expression and DNA methylation patterns and also yielded specific leads on genes potentially contributing to some of the phenotypes in 16p11.2 patients. There is global reprogramming of both the transcriptome and the DNA methylome. We observe sets of differentially expressed genes and differentially methylated regions, respectively, that are localized genome wide and that are shared, and with changes in the same direction, between the deletion and duplication genotypes. The gene PCSK9 is identified as a possible contributing factor to symptoms seen in carriers of the 16p11.2 CNVs. The protocadherin (PCDH) gene family is found to have altered DNA methylation patterns in the CNV patient samples. The iPSC lines used for this study are available through a repository as a resource for research into the molecular etiology of the clinical phenotypes of 16p11.2 CNVs and into that of neuropsychiatric and neurodevelopmental disorders in general.