Genome-wide DNA methylomic differences between dorsolateral prefrontal and temporal pole cortices of bipolar disorder

Ada M.C. Ho, Stacey J. Winham, Sebastian M. Armasu, Caren J. Blacker, Vincent Millischer, Catharina Lavebratt, James C. Overholser, George J. Jurjus, Lesa Dieter, G. Mahajan, Grazyna Rajkowska, Eric J. Vallender, Craig A. Stockmeier, Keith D. Robertson, Mark A. Frye, Doo Sup Choi, M. Veldic

Research output: Contribution to journalArticle

Abstract

Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation — an epigenetic mechanism both heritable and sensitive to the environment — may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.

Original languageEnglish (US)
Pages (from-to)45-54
Number of pages10
JournalJournal of Psychiatric Research
Volume117
DOIs
StatePublished - Oct 1 2019

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Temporal Lobe
Bipolar Disorder
Genome
DNA
Brain
Prefrontal Cortex
Methylation
Depression
Neuronal Plasticity
DNA Methylation
Mood Disorders
Epigenomics
Gene Expression

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Genome-wide DNA methylomic differences between dorsolateral prefrontal and temporal pole cortices of bipolar disorder. / Ho, Ada M.C.; Winham, Stacey J.; Armasu, Sebastian M.; Blacker, Caren J.; Millischer, Vincent; Lavebratt, Catharina; Overholser, James C.; Jurjus, George J.; Dieter, Lesa; Mahajan, G.; Rajkowska, Grazyna; Vallender, Eric J.; Stockmeier, Craig A.; Robertson, Keith D.; Frye, Mark A.; Choi, Doo Sup; Veldic, M.

In: Journal of Psychiatric Research, Vol. 117, 01.10.2019, p. 45-54.

Research output: Contribution to journalArticle

Ho, AMC, Winham, SJ, Armasu, SM, Blacker, CJ, Millischer, V, Lavebratt, C, Overholser, JC, Jurjus, GJ, Dieter, L, Mahajan, G, Rajkowska, G, Vallender, EJ, Stockmeier, CA, Robertson, KD, Frye, MA, Choi, DS & Veldic, M 2019, 'Genome-wide DNA methylomic differences between dorsolateral prefrontal and temporal pole cortices of bipolar disorder', Journal of Psychiatric Research, vol. 117, pp. 45-54. https://doi.org/10.1016/j.jpsychires.2019.05.030
Ho, Ada M.C. ; Winham, Stacey J. ; Armasu, Sebastian M. ; Blacker, Caren J. ; Millischer, Vincent ; Lavebratt, Catharina ; Overholser, James C. ; Jurjus, George J. ; Dieter, Lesa ; Mahajan, G. ; Rajkowska, Grazyna ; Vallender, Eric J. ; Stockmeier, Craig A. ; Robertson, Keith D. ; Frye, Mark A. ; Choi, Doo Sup ; Veldic, M. / Genome-wide DNA methylomic differences between dorsolateral prefrontal and temporal pole cortices of bipolar disorder. In: Journal of Psychiatric Research. 2019 ; Vol. 117. pp. 45-54.
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abstract = "Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation — an epigenetic mechanism both heritable and sensitive to the environment — may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.",
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AU - Ho, Ada M.C.

AU - Winham, Stacey J.

AU - Armasu, Sebastian M.

AU - Blacker, Caren J.

AU - Millischer, Vincent

AU - Lavebratt, Catharina

AU - Overholser, James C.

AU - Jurjus, George J.

AU - Dieter, Lesa

AU - Mahajan, G.

AU - Rajkowska, Grazyna

AU - Vallender, Eric J.

AU - Stockmeier, Craig A.

AU - Robertson, Keith D.

AU - Frye, Mark A.

AU - Choi, Doo Sup

AU - Veldic, M.

PY - 2019/10/1

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N2 - Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation — an epigenetic mechanism both heritable and sensitive to the environment — may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.

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