Altered DNA methylation associated with a translocation linked to major mental illness

Daniel L. McCartney; Rosie M. Walker; Stewart W. Morris; Susan M. Anderson; Barbara J. Duff; Riccardo E. Marioni; J. Kirsty Millar; Shane E McCarthy; Niamh M. Ryan; Stephen M. Lawrie; Andrew R. Watson; Douglas H. R. Blackwood; Pippa A. Thomson; Andrew M. McIntosh; W Richard McCombie; David J. Porteous; Kathryn L. Evans

doi:10.1038/s41537-018-0047-7

Altered DNA methylation associated with a translocation linked to major mental illness

Daniel L. McCartney, Rosie M. Walker, Stewart W. Morris, Susan M. Anderson, Barbara J. Duff, Riccardo E. Marioni, J. Kirsty Millar, Shane E McCarthy, Niamh M. Ryan, Stephen M. Lawrie, Andrew R. Watson, Douglas H. R. Blackwood, Pippa A. Thomson, Andrew M. McIntosh, W Richard McCombie, David J. Porteous, Kathryn L. Evans

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.

Original language	English
Pages (from-to)	5
Journal	npj Schizophrenia
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s41537-018-0047-7
Publication status	Published - 19 Mar 2018

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Journal Article

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10.1038/s41537-018-0047-7

Altered DNA methylation associated with a translocation linked to major mental illness
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https://www.nature.com/articles/s41537-018-0047-7

Stratifying Resilience and Depression Longitudinally
McIntosh, A., Deary, I., Evans, K., Haley, C. & Porteous, D.
UK-based charities
1/01/15 → 30/06/21
Project: Research
Modelling psychosis using DISC1 human induced pluripotent stem cells
McIntosh, A. & Chandran, S.
MRC
1/06/12 → 31/05/15
Project: Research

Kathy Evans
- Kathy.Evansigmm.ed.acuk
Person: Academic: Research Active

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McCartney, D. L., Walker, R. M., Morris, S. W., Anderson, S. M., Duff, B. J., Marioni, R. E., Millar, J. K., McCarthy, S. E., Ryan, N. M., Lawrie, S. M., Watson, A. R., Blackwood, D. H. R., Thomson, P. A., McIntosh, A. M., McCombie, W. R., Porteous, D. J., & Evans, K. L. (2018). Altered DNA methylation associated with a translocation linked to major mental illness. npj Schizophrenia, 4(1), 5. https://doi.org/10.1038/s41537-018-0047-7

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abstract = "Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.",

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McCartney, DL , Walker, RM, Morris, SW, Anderson, SM, Duff, BJ, Marioni, RE, Millar, JK, McCarthy, SE, Ryan, NM, Lawrie, SM, Watson, AR, Blackwood, DHR, Thomson, PA , McIntosh, AM, McCombie, WR, Porteous, DJ & Evans, KL 2018, 'Altered DNA methylation associated with a translocation linked to major mental illness', npj Schizophrenia, vol. 4, no. 1, pp. 5. https://doi.org/10.1038/s41537-018-0047-7

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T1 - Altered DNA methylation associated with a translocation linked to major mental illness

AU - McCartney, Daniel L.

AU - Walker, Rosie M.

AU - Morris, Stewart W.

AU - Anderson, Susan M.

AU - Duff, Barbara J.

AU - Marioni, Riccardo E.

AU - Millar, J. Kirsty

AU - McCarthy, Shane E

AU - Ryan, Niamh M.

AU - Lawrie, Stephen M.

AU - Watson, Andrew R.

AU - Blackwood, Douglas H. R.

AU - Thomson, Pippa A.

AU - McIntosh, Andrew M.

AU - McCombie, W Richard

AU - Porteous, David J.

AU - Evans, Kathryn L.

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N2 - Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.

AB - Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.

KW - Journal Article

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DO - 10.1038/s41537-018-0047-7

M3 - Article

C2 - 29555928

SN - 2334-265X

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JO - npj Schizophrenia

JF - npj Schizophrenia

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Altered DNA methylation associated with a translocation linked to major mental illness

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Stratifying Resilience and Depression Longitudinally

Modelling psychosis using DISC1 human induced pluripotent stem cells

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Kathy Evans

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