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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

Common networks identified in both families. a. Two cell death and survival networks independently identified in each affected twin in our study. Ingenuity Pathway Analysis (IPA) was used to identify the networks in both affected twins in our study. Shading represents genes in our study that are differentially methylated in the network. b. Two cellular movement and immune cell trafficking networks independently identified in each affected twin in our study. Ingenuity Pathway Analysis (IPA) was used to identify the networks in both affected twins in our study. Shading represents genes in our study that are differentially methylated in the network.
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Fig5: Common networks identified in both families. a. Two cell death and survival networks independently identified in each affected twin in our study. Ingenuity Pathway Analysis (IPA) was used to identify the networks in both affected twins in our study. Shading represents genes in our study that are differentially methylated in the network. b. Two cellular movement and immune cell trafficking networks independently identified in each affected twin in our study. Ingenuity Pathway Analysis (IPA) was used to identify the networks in both affected twins in our study. Shading represents genes in our study that are differentially methylated in the network.

Mentions: This analysis also identified two functional networks that were affected in both unrelated twin pairs (Figure 5). They included a cell death and survival network (ratio of differentially methylated genes to total number of genes in the network was 12/35 and 9/35, in Family 1 and Family 2, respectively) (Figure 5a) and a cellular movement and immune cell trafficking network (14/35 and 11/35 genes in Family 1 and 2, respectively) (Figure 5b). In Family 1, the Cell Death and Survival network identified IL1B (Entrez Gene: 3553) as the primary hub gene of the network, while in Family 2, TP53 (Entrez Gene: 7157) was identified as the primary hub gene in this network. Similarly, the cellular movement and immune cell trafficking networks involves TNF (Entrez Gene: 7124) and IFNG (Entrez Gene: 3458) as hub genes in Family 1 and IGF1R (Entrez Gene: 3480) and EGFR (Entrez Gene: 1956) as hub genes in Family 2. The results may argue that networks rather than genes may ultimately underlie the etiology of schizophrenia and related disorders.Figure 5


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)

Common networks identified in both families. a. Two cell death and survival networks independently identified in each affected twin in our study. Ingenuity Pathway Analysis (IPA) was used to identify the networks in both affected twins in our study. Shading represents genes in our study that are differentially methylated in the network. b. Two cellular movement and immune cell trafficking networks independently identified in each affected twin in our study. Ingenuity Pathway Analysis (IPA) was used to identify the networks in both affected twins in our study. Shading represents genes in our study that are differentially methylated in the network.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4494167&req=5

Fig5: Common networks identified in both families. a. Two cell death and survival networks independently identified in each affected twin in our study. Ingenuity Pathway Analysis (IPA) was used to identify the networks in both affected twins in our study. Shading represents genes in our study that are differentially methylated in the network. b. Two cellular movement and immune cell trafficking networks independently identified in each affected twin in our study. Ingenuity Pathway Analysis (IPA) was used to identify the networks in both affected twins in our study. Shading represents genes in our study that are differentially methylated in the network.
Mentions: This analysis also identified two functional networks that were affected in both unrelated twin pairs (Figure 5). They included a cell death and survival network (ratio of differentially methylated genes to total number of genes in the network was 12/35 and 9/35, in Family 1 and Family 2, respectively) (Figure 5a) and a cellular movement and immune cell trafficking network (14/35 and 11/35 genes in Family 1 and 2, respectively) (Figure 5b). In Family 1, the Cell Death and Survival network identified IL1B (Entrez Gene: 3553) as the primary hub gene of the network, while in Family 2, TP53 (Entrez Gene: 7157) was identified as the primary hub gene in this network. Similarly, the cellular movement and immune cell trafficking networks involves TNF (Entrez Gene: 7124) and IFNG (Entrez Gene: 3458) as hub genes in Family 1 and IGF1R (Entrez Gene: 3480) and EGFR (Entrez Gene: 1956) as hub genes in Family 2. The results may argue that networks rather than genes may ultimately underlie the etiology of schizophrenia and related disorders.Figure 5

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