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DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder

BACKGROUND: Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD...

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Autores principales: Walker, Rosie May, Christoforou, Andrea Nikie, McCartney, Daniel L., Morris, Stewart W., Kennedy, Nicholas A., Morten, Peter, Anderson, Susan Maguire, Torrance, Helen Scott, Macdonald, Alix, Sussmann, Jessika Elizabeth, Whalley, Heather Clare, Blackwood, Douglas H. R., McIntosh, Andrew Mark, Porteous, David John, Evans, Kathryn Louise
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721115/
https://www.ncbi.nlm.nih.gov/pubmed/26798408
http://dx.doi.org/10.1186/s13148-016-0171-z
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author Walker, Rosie May
Christoforou, Andrea Nikie
McCartney, Daniel L.
Morris, Stewart W.
Kennedy, Nicholas A.
Morten, Peter
Anderson, Susan Maguire
Torrance, Helen Scott
Macdonald, Alix
Sussmann, Jessika Elizabeth
Whalley, Heather Clare
Blackwood, Douglas H. R.
McIntosh, Andrew Mark
Porteous, David John
Evans, Kathryn Louise
author_facet Walker, Rosie May
Christoforou, Andrea Nikie
McCartney, Daniel L.
Morris, Stewart W.
Kennedy, Nicholas A.
Morten, Peter
Anderson, Susan Maguire
Torrance, Helen Scott
Macdonald, Alix
Sussmann, Jessika Elizabeth
Whalley, Heather Clare
Blackwood, Douglas H. R.
McIntosh, Andrew Mark
Porteous, David John
Evans, Kathryn Louise
author_sort Walker, Rosie May
collection PubMed
description BACKGROUND: Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI. RESULTS: Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes. CONCLUSIONS: Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on neurologically important pathways. Further work is required to investigate the underlying mechanisms and functional consequences of the observed differences in methylation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-016-0171-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-47211152016-01-22 DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder Walker, Rosie May Christoforou, Andrea Nikie McCartney, Daniel L. Morris, Stewart W. Kennedy, Nicholas A. Morten, Peter Anderson, Susan Maguire Torrance, Helen Scott Macdonald, Alix Sussmann, Jessika Elizabeth Whalley, Heather Clare Blackwood, Douglas H. R. McIntosh, Andrew Mark Porteous, David John Evans, Kathryn Louise Clin Epigenetics Research BACKGROUND: Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI. RESULTS: Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes. CONCLUSIONS: Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on neurologically important pathways. Further work is required to investigate the underlying mechanisms and functional consequences of the observed differences in methylation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-016-0171-z) contains supplementary material, which is available to authorized users. BioMed Central 2016-01-20 /pmc/articles/PMC4721115/ /pubmed/26798408 http://dx.doi.org/10.1186/s13148-016-0171-z Text en © Walker et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Walker, Rosie May
Christoforou, Andrea Nikie
McCartney, Daniel L.
Morris, Stewart W.
Kennedy, Nicholas A.
Morten, Peter
Anderson, Susan Maguire
Torrance, Helen Scott
Macdonald, Alix
Sussmann, Jessika Elizabeth
Whalley, Heather Clare
Blackwood, Douglas H. R.
McIntosh, Andrew Mark
Porteous, David John
Evans, Kathryn Louise
DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder
title DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder
title_full DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder
title_fullStr DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder
title_full_unstemmed DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder
title_short DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder
title_sort dna methylation in a scottish family multiply affected by bipolar disorder and major depressive disorder
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721115/
https://www.ncbi.nlm.nih.gov/pubmed/26798408
http://dx.doi.org/10.1186/s13148-016-0171-z
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