Differential methylation of imprinting genes and MHC locus in 22q11.2 deletion syndrome-related schizophrenia spectrum disorders

<b>Objectives:</b> 22q11.2 deletion syndrome (DS) is the strongest known genetic risk for schizophrenia. Methylome screening was conducted to elucidate possible involvement of epigenetic alterations in the emergence of schizophrenia spectrum disorders (SZ-SD) in 22q11.2DS. <b>Methods:</b> Sixteen adult men with/without SZ-SD were recruited from a 22q11.2DS cohort and underwent genome-wide DNA methylation profile analysis. Differentially methylated probes (DMPs) and regions (DMRs) were analysed using the ChAMP software. <b>Results:</b> The DMPs (<i>p</i>-value &lt;10⁻⁶) and DMRs (<i>p</i>-valueArea &lt;0.01) were enriched in two gene sets, ‘imprinting genes’ and ‘chr6p21’, a region overlapping the MHC locus. Most of the identified imprinting genes are involved in neurodevelopment and located in clusters under imprinting control region (ICR) regulation, including <i>PEG10, SGCE</i> (7q21.3), <i>GNAS, GNAS-AS1</i> (20q13.32) and <i>SNHG14, SNURF-SNRPN, SNORD115</i> (15q11.2). The differentially methylated genes from the MHC locus included immune <i>HLA</i>-genes and non-immune genes, <i>RNF39</i>, <i>PPP1R18</i> and <i>NOTCH4</i>, implicated in neurodevelopment and synaptic plasticity. The most significant DMR is located in MHC locus and covered the transcription regulator <i>ZFP57</i> that is required for control and maintenance of gene imprinting at multiple ICRs. <b>Conclusions:</b> The differential methylation in imprinting genes and in chr6p21-22 indicate the neurodevelopmental nature of 22q11.2DS-related SZ and the major role of MHC locus in the risk to develop SZ.