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DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks.

Castellani CA, Laufer BI, Melka MG, Diehl EJ, O'Reilly RL, Singh SM - BMC Med Genomics (2015)

Bottom Line: The genome-wide results show that differentially methylated regions (DMRs) exist between members representing discordant monozygotic twins.We found twenty-seven genes affected by DMR changes that were shared in the affected member of two discordant monozygotic pairs from unrelated families.Also, this may be accomplished by the direct effect of gene specific methylation changes on specific biological networks rather than individual genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, The University of Western Ontario, N6A 5B7, London, Ontario, Canada. ccastel3@uwo.ca.

ABSTRACT

Background: Despite their singular origin, monozygotic twin pairs often display discordance for complex disorders including schizophrenia. It is a common (1%) and often familial disease with a discordance rate of ~50% in monozygotic twins. This high discordance is often explained by the role of yet unknown environmental, random, and epigenetic factors. The involvement of DNA methylation in this disease appears logical, but remains to be established.

Methods: We have used blood DNA from two pairs of monozygotic twins discordant for schizophrenia and their parents in order to assess genome-wide methylation using a NimbleGen Methylation Promoter Microarray.

Results: The genome-wide results show that differentially methylated regions (DMRs) exist between members representing discordant monozygotic twins. Some DMRs are shared with parent(s) and others appear to be de novo. We found twenty-seven genes affected by DMR changes that were shared in the affected member of two discordant monozygotic pairs from unrelated families. Interestingly, the genes affected by pair specific DMRs share specific networks. Specifically, this study has identified two networks; "cell death and survival" and a "cellular movement and immune cell trafficking". These two networks and the genes affected have been previously implicated in the aetiology of schizophrenia.

Conclusions: The results are compatible with the suggestion that DNA methylation may contribute to the discordance of monozygotic twins for schizophrenia. Also, this may be accomplished by the direct effect of gene specific methylation changes on specific biological networks rather than individual genes. It supports the extensive genetic, epigenetic and phenotypic heterogeneity implicated in schizophrenia.

No MeSH data available.


Related in: MedlinePlus

Manhattan plot representing methylation in the 15q11.2-15q12 region in the twin pairs of Family 1. This region spans from SNRPN to UBE3A and encompasses members of the SNORD115 and SNORD116 gene families (top). A red dot indicates a decrease in methylation in the affected twin. A blue dot indicates an increase in methylation in the affected twin (Family 1). This region contains a complex regulatory ncRNA involved in imprinting control and neurodevelopment.
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Fig4: Manhattan plot representing methylation in the 15q11.2-15q12 region in the twin pairs of Family 1. This region spans from SNRPN to UBE3A and encompasses members of the SNORD115 and SNORD116 gene families (top). A red dot indicates a decrease in methylation in the affected twin. A blue dot indicates an increase in methylation in the affected twin (Family 1). This region contains a complex regulatory ncRNA involved in imprinting control and neurodevelopment.

Mentions: Interestingly, a subset of common genes identified (5 genes), belong to either the HIST2H cluster on Chromosome 1 or the HIST1H region on Chromosome 6 (Table 1). Further, 17 of the 27 genes belong to either the SNORD115 (Entrez Gene: 692218) or SNORD116 (Entrez Gene: 692236) clusters on chromosome 15. All seventeen of the SNORD genes identified in two patients are known to be genomically imprinted and produce ncRNA transcripts that undergo extensive processing and form many functional classes of non-coding regulatory RNA (Table 1). This region can be seen in detail in Figure 4 that extends from the SNRPN gene (Entrez Gene: 6638) to the UBE3A gene (Entrez Gene: 7337) and encompasses the SNORD115 and SNORD116 gene families. Ingenuity Pathway Analysis (IPA) involving the shared genes has identified Protein Kinase A Signaling as the most enriched canonical pathway (p = 3.09E-04). In addition, Granzyme A Signaling (p = 6.83E-03), G Protein Signaling Mediated by Tubby (p = 1.24E-02), Serotonin Receptor Signaling (p = 1.72E-02) and UVB-Induced MAPK Signaling (p = 2.12E-02) were identified as canonical pathways of interest (Table 2c). IPA also identified DRD4 (Entrez Gene: 1815), a dopamine receptor gene, to be the top upstream regulator of the twenty-seven common genes. Similarly, IPA identified developmental disorders (p = 4.03E-04-1.21E-03) as a top disease associated with this gene set while, Cell Signaling (p = 4.03E-04-3.73E-02), Nucleic Acid Metabolism (p = 4.03E-04-3.73E-02) and gene expression (p = 3.62E-03-9.63E-03) have been revealed as significant molecular and cellular functions. Also, Nervous System Development and Function (p = 1.61E-03-1.61E-03) has been revealed as one of the top physiological systems related to this gene set. Further, Infectious Disease, Hereditary Disorders, Embryonic Development and Cell Death and Survival were notable associated network functions related to the differentially methylated gene set in both schizophrenic twins. When the 27 genes were analyzed using Enrichr [25], expression in whole brain was identified as the top human gene atlas finding. Enrichr also identified OMIM disease classifications related to neurodevelopment to be enriched in our gene list; these include Asperger’s syndrome (p = 0.039) and mental retardation (p = 0.065).Figure 4


DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks.

Castellani CA, Laufer BI, Melka MG, Diehl EJ, O'Reilly RL, Singh SM - BMC Med Genomics (2015)

Manhattan plot representing methylation in the 15q11.2-15q12 region in the twin pairs of Family 1. This region spans from SNRPN to UBE3A and encompasses members of the SNORD115 and SNORD116 gene families (top). A red dot indicates a decrease in methylation in the affected twin. A blue dot indicates an increase in methylation in the affected twin (Family 1). This region contains a complex regulatory ncRNA involved in imprinting control and neurodevelopment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4494167&req=5

Fig4: Manhattan plot representing methylation in the 15q11.2-15q12 region in the twin pairs of Family 1. This region spans from SNRPN to UBE3A and encompasses members of the SNORD115 and SNORD116 gene families (top). A red dot indicates a decrease in methylation in the affected twin. A blue dot indicates an increase in methylation in the affected twin (Family 1). This region contains a complex regulatory ncRNA involved in imprinting control and neurodevelopment.
Mentions: Interestingly, a subset of common genes identified (5 genes), belong to either the HIST2H cluster on Chromosome 1 or the HIST1H region on Chromosome 6 (Table 1). Further, 17 of the 27 genes belong to either the SNORD115 (Entrez Gene: 692218) or SNORD116 (Entrez Gene: 692236) clusters on chromosome 15. All seventeen of the SNORD genes identified in two patients are known to be genomically imprinted and produce ncRNA transcripts that undergo extensive processing and form many functional classes of non-coding regulatory RNA (Table 1). This region can be seen in detail in Figure 4 that extends from the SNRPN gene (Entrez Gene: 6638) to the UBE3A gene (Entrez Gene: 7337) and encompasses the SNORD115 and SNORD116 gene families. Ingenuity Pathway Analysis (IPA) involving the shared genes has identified Protein Kinase A Signaling as the most enriched canonical pathway (p = 3.09E-04). In addition, Granzyme A Signaling (p = 6.83E-03), G Protein Signaling Mediated by Tubby (p = 1.24E-02), Serotonin Receptor Signaling (p = 1.72E-02) and UVB-Induced MAPK Signaling (p = 2.12E-02) were identified as canonical pathways of interest (Table 2c). IPA also identified DRD4 (Entrez Gene: 1815), a dopamine receptor gene, to be the top upstream regulator of the twenty-seven common genes. Similarly, IPA identified developmental disorders (p = 4.03E-04-1.21E-03) as a top disease associated with this gene set while, Cell Signaling (p = 4.03E-04-3.73E-02), Nucleic Acid Metabolism (p = 4.03E-04-3.73E-02) and gene expression (p = 3.62E-03-9.63E-03) have been revealed as significant molecular and cellular functions. Also, Nervous System Development and Function (p = 1.61E-03-1.61E-03) has been revealed as one of the top physiological systems related to this gene set. Further, Infectious Disease, Hereditary Disorders, Embryonic Development and Cell Death and Survival were notable associated network functions related to the differentially methylated gene set in both schizophrenic twins. When the 27 genes were analyzed using Enrichr [25], expression in whole brain was identified as the top human gene atlas finding. Enrichr also identified OMIM disease classifications related to neurodevelopment to be enriched in our gene list; these include Asperger’s syndrome (p = 0.039) and mental retardation (p = 0.065).Figure 4

Bottom Line: The genome-wide results show that differentially methylated regions (DMRs) exist between members representing discordant monozygotic twins.We found twenty-seven genes affected by DMR changes that were shared in the affected member of two discordant monozygotic pairs from unrelated families.Also, this may be accomplished by the direct effect of gene specific methylation changes on specific biological networks rather than individual genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, The University of Western Ontario, N6A 5B7, London, Ontario, Canada. ccastel3@uwo.ca.

ABSTRACT

Background: Despite their singular origin, monozygotic twin pairs often display discordance for complex disorders including schizophrenia. It is a common (1%) and often familial disease with a discordance rate of ~50% in monozygotic twins. This high discordance is often explained by the role of yet unknown environmental, random, and epigenetic factors. The involvement of DNA methylation in this disease appears logical, but remains to be established.

Methods: We have used blood DNA from two pairs of monozygotic twins discordant for schizophrenia and their parents in order to assess genome-wide methylation using a NimbleGen Methylation Promoter Microarray.

Results: The genome-wide results show that differentially methylated regions (DMRs) exist between members representing discordant monozygotic twins. Some DMRs are shared with parent(s) and others appear to be de novo. We found twenty-seven genes affected by DMR changes that were shared in the affected member of two discordant monozygotic pairs from unrelated families. Interestingly, the genes affected by pair specific DMRs share specific networks. Specifically, this study has identified two networks; "cell death and survival" and a "cellular movement and immune cell trafficking". These two networks and the genes affected have been previously implicated in the aetiology of schizophrenia.

Conclusions: The results are compatible with the suggestion that DNA methylation may contribute to the discordance of monozygotic twins for schizophrenia. Also, this may be accomplished by the direct effect of gene specific methylation changes on specific biological networks rather than individual genes. It supports the extensive genetic, epigenetic and phenotypic heterogeneity implicated in schizophrenia.

No MeSH data available.


Related in: MedlinePlus