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

Miri Carmel*, Elena Michaelovsky, Ronnie Weinberger, Amos Frisch, Ehud Mekori-Domachevsky, Doron Gothelf, Abraham Weizman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objectives: 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. Methods: 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. Results: The DMPs (p-value <10−6) and DMRs (p-valueArea <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 PEG10, SGCE (7q21.3), GNAS, GNAS-AS1 (20q13.32) and SNHG14, SNURF-SNRPN, SNORD115 (15q11.2). The differentially methylated genes from the MHC locus included immune HLA-genes and non-immune genes, RNF39, PPP1R18 and NOTCH4, implicated in neurodevelopment and synaptic plasticity. The most significant DMR is located in MHC locus and covered the transcription regulator ZFP57 that is required for control and maintenance of gene imprinting at multiple ICRs. Conclusions: 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.

Original languageEnglish
Pages (from-to)46-57
Number of pages12
JournalWorld Journal of Biological Psychiatry
Issue number1
StatePublished - 2021


FundersFunder number
Brain and Behavior Research Foundation
National Alliance for Research on Schizophrenia and Depression22597
United States-Israel Binational Science Foundation2017369


    • 22q11.2 deletion syndrome
    • MHC locus
    • Schizophrenia spectrum disorders
    • epigenetics/DNA methylation
    • imprinting genes


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