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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

Overlap of differentially methylation regions. Venn diagram showing the number of genes differentially methylated in each patient (138 and 330 respectively) as well as the genes enriched in both affected twins in the study (27).
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Fig3: Overlap of differentially methylation regions. Venn diagram showing the number of genes differentially methylated in each patient (138 and 330 respectively) as well as the genes enriched in both affected twins in the study (27).

Mentions: The genome-wide DNA methylation profiles have revealed differentially methylated peaks and regions (DMRs) between the MZ twin pairs in our study (p ≤ 0.001). Further, the availability of parental data has allowed us to assess each DMR for its presence/absence in the two parents. The results show that methylation profiles in twins include both shared and de novo events (arising from environmental exposures or random events). We note that in Family 1 as well as in Family 2 (Figure 1), most of the DMRs appear de novo (are not found in Mom or Dad) as only 25% and 13% of the DMRs, respectively, were present in either Mom or Dad. The results have also allowed identification of specific genes that are differentially methylated between the affected twin and their identical unaffected twin. Specifically, we note that 138 genes are differentially methylated in the twin pair from Family 1 (see Additional file 1) and 330 genes are differentially methylated in Family 2 (see Additional file 2). A visual representation of these results is given in Figure 2, specifically the outside track of the Circos diagram represents DMRs in Family 2, the middle track represents DMRs in Family 1 and the inside track represents 27 overlapping DMRs annotated with gene identity. An overlap between the DMRs present in the affected member of the two unrelated families (Figure 3) suggests that most (80-92%) of the DMRs are twin pair specific. Chromosome 1 (19 and 36 DMRs respectively) and Chromosome 15 (21 and 30 DMRs respectively) show the most DMRs in Family 1 as well as in Family 2. Family 2 also has a large number of DMRs on Chromosome 19 (30 DMRs).Figure 2


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)

Overlap of differentially methylation regions. Venn diagram showing the number of genes differentially methylated in each patient (138 and 330 respectively) as well as the genes enriched in both affected twins in the study (27).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Overlap of differentially methylation regions. Venn diagram showing the number of genes differentially methylated in each patient (138 and 330 respectively) as well as the genes enriched in both affected twins in the study (27).
Mentions: The genome-wide DNA methylation profiles have revealed differentially methylated peaks and regions (DMRs) between the MZ twin pairs in our study (p ≤ 0.001). Further, the availability of parental data has allowed us to assess each DMR for its presence/absence in the two parents. The results show that methylation profiles in twins include both shared and de novo events (arising from environmental exposures or random events). We note that in Family 1 as well as in Family 2 (Figure 1), most of the DMRs appear de novo (are not found in Mom or Dad) as only 25% and 13% of the DMRs, respectively, were present in either Mom or Dad. The results have also allowed identification of specific genes that are differentially methylated between the affected twin and their identical unaffected twin. Specifically, we note that 138 genes are differentially methylated in the twin pair from Family 1 (see Additional file 1) and 330 genes are differentially methylated in Family 2 (see Additional file 2). A visual representation of these results is given in Figure 2, specifically the outside track of the Circos diagram represents DMRs in Family 2, the middle track represents DMRs in Family 1 and the inside track represents 27 overlapping DMRs annotated with gene identity. An overlap between the DMRs present in the affected member of the two unrelated families (Figure 3) suggests that most (80-92%) of the DMRs are twin pair specific. Chromosome 1 (19 and 36 DMRs respectively) and Chromosome 15 (21 and 30 DMRs respectively) show the most DMRs in Family 1 as well as in Family 2. Family 2 also has a large number of DMRs on Chromosome 19 (30 DMRs).Figure 2

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