Miri Carmel1,2, Elena Michaelovsky1,2, Ronnie Weinberger3, Amos Frisch1,2, Ehud Mekori-Domachevsky1,3, Doron Gothelf1,3,4, Abraham Weizman1,2,4,5. 1. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 2. Felsenstein Medical Research Center, Petach Tikva, Israel. 3. The Behavioral Neurogenetics Center and Child Psychiatry Division, Sheba Medical Center, Ramat Gan, Israel. 4. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. 5. Geha Mental Health Center, Petach Tikva, Israel.
Abstract
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.
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.
Authors: Bernard F Fuemmeler; Mikhail G Dozmorov; Elizabeth K Do; Junfeng Jim Zhang; Carole Grenier; Zhiqing Huang; Rachel L Maguire; Scott H Kollins; Cathrine Hoyo; Susan K Murphy Journal: Environ Health Perspect Date: 2021-05-19 Impact factor: 9.031
Authors: Anne K Bozack; Sheryl L Rifas-Shiman; Brent A Coull; Andrea A Baccarelli; Robert O Wright; Chitra Amarasiriwardena; Diane R Gold; Emily Oken; Marie-France Hivert; Andres Cardenas Journal: Clin Epigenetics Date: 2021-11-19 Impact factor: 6.551