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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

Pedigrees of families included in the study. Shaded circles represent the affected twins.
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Fig1: Pedigrees of families included in the study. Shaded circles represent the affected twins.

Mentions: This study on monozygotic twins received ethics approval by the University of Western Ontario’s Committee on research involving human subjects. All subjects provided written informed consent to participate in this study. Further, they have agreed to the sharing of data (genetic and clinical) in any publication. All of the patients were adults at the time of consent. Capacity for consent was ensured using three measures 1) Schizophrenic patients gave consent only during a “normal” phase (no psychosis present), 2) Both twins of the twin pair were present and gave consent at the same time (the normal twin and their affected sibling), 3) If R.O’Reilly felt that capacity to consent was compromised, the patients were not included in our study. They were interviewed and clinically assessed by a single senior Psychiatrist (R. O’Reilly) using the SCID-I and SCID-II [23,24]. Past clinical notes were available to aid in diagnosis. Both families were comprised of identical female twins. The twins from Family 1 (Figure 1) were Caucasian females aged 43. The affected member of twin pair 1 was diagnosed with schizoaffective disorder at age 27. The twins were discordant for 16 years at the time of sample collection. The twins from Family 2 (Figure 1) were Afro-American females aged 53. The affected member of twin pair 2 was diagnosed with schizophrenia at age 22. The twins were discordant for 31 years at the time of sample collection. The twins and their parents (Figure 1) included in this study contributed whole blood samples for DNA isolation. Both pairs of monozygotic twins were female twins. DNA was extracted from whole blood using the 5 Prime Perfect Pure DNA Blood Kit (Gaithersburg, MD, USA), following the manufacturer’s protocol. It should be noted that the Father of Twin Pair 2 was diagnosed with Chronic Leukemia (CLL) at age 69. The affected patient from Family 1 was treated for schizophrenia symptoms using a combination of the medications Seroquel, Effexor and Topiramate. The affected patient from Family 2 was treated for schizophrenia symptoms using a combination of the medications Clozapine, Divalproex and Benztropine. Zygosity was confirmed by Affymetrix 6.0 microarray and specifically using the Affymetrix Genotyping Console 4.0 concordance feature [6].Figure 1


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)

Pedigrees of families included in the study. Shaded circles represent the affected twins.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Pedigrees of families included in the study. Shaded circles represent the affected twins.
Mentions: This study on monozygotic twins received ethics approval by the University of Western Ontario’s Committee on research involving human subjects. All subjects provided written informed consent to participate in this study. Further, they have agreed to the sharing of data (genetic and clinical) in any publication. All of the patients were adults at the time of consent. Capacity for consent was ensured using three measures 1) Schizophrenic patients gave consent only during a “normal” phase (no psychosis present), 2) Both twins of the twin pair were present and gave consent at the same time (the normal twin and their affected sibling), 3) If R.O’Reilly felt that capacity to consent was compromised, the patients were not included in our study. They were interviewed and clinically assessed by a single senior Psychiatrist (R. O’Reilly) using the SCID-I and SCID-II [23,24]. Past clinical notes were available to aid in diagnosis. Both families were comprised of identical female twins. The twins from Family 1 (Figure 1) were Caucasian females aged 43. The affected member of twin pair 1 was diagnosed with schizoaffective disorder at age 27. The twins were discordant for 16 years at the time of sample collection. The twins from Family 2 (Figure 1) were Afro-American females aged 53. The affected member of twin pair 2 was diagnosed with schizophrenia at age 22. The twins were discordant for 31 years at the time of sample collection. The twins and their parents (Figure 1) included in this study contributed whole blood samples for DNA isolation. Both pairs of monozygotic twins were female twins. DNA was extracted from whole blood using the 5 Prime Perfect Pure DNA Blood Kit (Gaithersburg, MD, USA), following the manufacturer’s protocol. It should be noted that the Father of Twin Pair 2 was diagnosed with Chronic Leukemia (CLL) at age 69. The affected patient from Family 1 was treated for schizophrenia symptoms using a combination of the medications Seroquel, Effexor and Topiramate. The affected patient from Family 2 was treated for schizophrenia symptoms using a combination of the medications Clozapine, Divalproex and Benztropine. Zygosity was confirmed by Affymetrix 6.0 microarray and specifically using the Affymetrix Genotyping Console 4.0 concordance feature [6].Figure 1

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