Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Claire Green; Xueyi Shen; Anna Stevenson; Eleanor L. S. Conole; Mathew A. Harris; Miruna C. Barbu; Emma L. Hawkins; Mark J. Adams; Robert F. Hillary; Stephen M. Lawrie; Kathryn L. Evans; Rosie M. Walker; Stewart W. Morris; David J. Porteous; Joanna M. Wardlaw; J. Douglas Steele; Gordon D. Waiter; Anca-Larisa Sandu; Archie Campbell; Riccardo E.  Marioni; Simon R. Cox; Jonathan Cavanagh; Andrew M. McIntosh; Heather C. Whalley

doi:10.1016/j.bbi.2020.11.024

Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Claire Green (Lead / Corresponding author), Xueyi Shen, Anna Stevenson, Eleanor L. S. Conole, Mathew A. Harris, Miruna C. Barbu, Emma L. Hawkins, Mark J. Adams, Robert F. Hillary, Stephen M. Lawrie, Kathryn L. Evans, Rosie M. Walker, Stewart W. Morris, David J. Porteous, Joanna M. Wardlaw, J. Douglas Steele, Gordon D. Waiter, Anca-Larisa Sandu, Archie Campbell, Riccardo E. MarioniSimon R. Cox, Jonathan Cavanagh, Andrew M. McIntosh, Heather C. Whalley

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Abstract

Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers.

Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; N_MDD _cases=271, N_controls=609).

Serum-CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β= 0.145, P_FDR = 6×10-4) and energy levels (β= 0.101, P_FDR = 0.027), along with reduced entorhinal cortex thickness (β= -0.095, P_FDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, β_FA=- -0.12 to -0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = -0.15 versus βaverage = 0.01 respectively).

These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.

Original language	English
Pages (from-to)	39-48
Number of pages	10
Journal	Brain, Behavior, and Immunity
Volume	92
Early online date	19 Nov 2020
DOIs	https://doi.org/10.1016/j.bbi.2020.11.024
Publication status	Published - Feb 2021

Keywords

Major Depressive Disorder
Depression
Inflammation
C-reactive Protein
CRP
Methylation
Brain Morphology
Brain Structure
White Matter Integrity
MRI
C-reactive protein
White matter integrity
Brain structure
Major depressive disorder
Brain morphology

ASJC Scopus subject areas

Endocrine and Autonomic Systems
Behavioral Neuroscience
Immunology

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10.1016/j.bbi.2020.11.024Licence: CC BY

Final Published VersionFinal published version, 1.55 MBLicence: CC BY

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STRADL - Provision of MRI Scans
Steele, D. (Investigator)
23/06/16 → 23/07/19
Project: Research

60 Citations
1 Article

Spectral Clustering Based on Structural Magnetic Resonance Imaging and its Relationship with Major Depressive Disorder and Cognitive Ability
Yeung, H. W. (Lead / Corresponding author), Shen, X., Stolicyn, A., Harris, M. A., Romaniuk, L., Buchanan, C. R., Waiter, G. D., Sandu, A.-L., McNeil, C. J., Murray, A. D., Steele, D., Campbell, A., Porteous, D. J., Lawrie, S. M., McIntosh, A. M., Cox, S. R., Smith, K. M. & Whalley, H. C. (Lead / Corresponding author), Sept 2021, In: European Journal of Neuroscience. 54, 6, p. 6281-6303 23 p.
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Green, C., Shen, X., Stevenson, A., Conole, E. L. S., Harris, M. A., Barbu, M. C., Hawkins, E. L., Adams, M. J., Hillary, R. F., Lawrie, S. M., Evans, K. L., Walker, R. M., Morris, S. W., Porteous, D. J., Wardlaw, J. M., Steele, J. D., Waiter, G. D., Sandu, A.-L., Campbell, A., ... Whalley, H. C. (2021). Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder. Brain, Behavior, and Immunity, 92, 39-48. https://doi.org/10.1016/j.bbi.2020.11.024

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title = "Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder",

abstract = "Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers.Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases=271, Ncontrols=609).Serum-CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β= 0.145, PFDR = 6×10-4) and energy levels (β= 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (β= -0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, βFA=- -0.12 to -0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = -0.15 versus βaverage = 0.01 respectively).These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.",

keywords = "Major Depressive Disorder, Depression, Inflammation, C-reactive Protein, CRP, Methylation, Brain Morphology, Brain Structure, White Matter Integrity, MRI, C-reactive protein, White matter integrity, Brain structure, Major depressive disorder, Brain morphology",

author = "Claire Green and Xueyi Shen and Anna Stevenson and Conole, {Eleanor L. S.} and Harris, {Mathew A.} and Barbu, {Miruna C.} and Hawkins, {Emma L.} and Adams, {Mark J.} and Hillary, {Robert F.} and Lawrie, {Stephen M.} and Evans, {Kathryn L.} and Walker, {Rosie M.} and Morris, {Stewart W.} and Porteous, {David J.} and Wardlaw, {Joanna M.} and Steele, {J. Douglas} and Waiter, {Gordon D.} and Anca-Larisa Sandu and Archie Campbell and Marioni, {Riccardo E.} and Cox, {Simon R.} and Jonathan Cavanagh and McIntosh, {Andrew M.} and Whalley, {Heather C.}",

note = "Funding Information: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). CG is supported by The Medical Research Council and The University of Edinburgh through the Precision Medicine Doctoral Training program. SRC is supported by the UK Medical Research Council [MR/R024065/1] and a National Institutes of Health (NIH) research grant R01AG054628. Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2021",

month = feb,

doi = "10.1016/j.bbi.2020.11.024",

language = "English",

volume = "92",

pages = "39--48",

journal = "Brain, Behavior, and Immunity",

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publisher = "Academic Press Inc.",

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Green, C, Shen, X, Stevenson, A, Conole, ELS, Harris, MA, Barbu, MC, Hawkins, EL, Adams, MJ, Hillary, RF, Lawrie, SM, Evans, KL, Walker, RM, Morris, SW, Porteous, DJ, Wardlaw, JM, Steele, JD, Waiter, GD, Sandu, A-L, Campbell, A, Marioni, RE, Cox, SR, Cavanagh, J, McIntosh, AM & Whalley, HC 2021, 'Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder', Brain, Behavior, and Immunity, vol. 92, pp. 39-48. https://doi.org/10.1016/j.bbi.2020.11.024

TY - JOUR

T1 - Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

AU - Green, Claire

AU - Shen, Xueyi

AU - Stevenson, Anna

AU - Conole, Eleanor L. S.

AU - Harris, Mathew A.

AU - Barbu, Miruna C.

AU - Hawkins, Emma L.

AU - Adams, Mark J.

AU - Hillary, Robert F.

AU - Lawrie, Stephen M.

AU - Evans, Kathryn L.

AU - Walker, Rosie M.

AU - Morris, Stewart W.

AU - Porteous, David J.

AU - Wardlaw, Joanna M.

AU - Steele, J. Douglas

AU - Waiter, Gordon D.

AU - Sandu, Anca-Larisa

AU - Campbell, Archie

AU - Marioni, Riccardo E.

AU - Cox, Simon R.

AU - Cavanagh, Jonathan

AU - McIntosh, Andrew M.

AU - Whalley, Heather C.

N1 - Funding Information: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). CG is supported by The Medical Research Council and The University of Edinburgh through the Precision Medicine Doctoral Training program. SRC is supported by the UK Medical Research Council [MR/R024065/1] and a National Institutes of Health (NIH) research grant R01AG054628. Publisher Copyright: © 2020 The Authors

PY - 2021/2

Y1 - 2021/2

N2 - Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers.Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases=271, Ncontrols=609).Serum-CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β= 0.145, PFDR = 6×10-4) and energy levels (β= 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (β= -0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, βFA=- -0.12 to -0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = -0.15 versus βaverage = 0.01 respectively).These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.

AB - Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers.Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases=271, Ncontrols=609).Serum-CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β= 0.145, PFDR = 6×10-4) and energy levels (β= 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (β= -0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, βFA=- -0.12 to -0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = -0.15 versus βaverage = 0.01 respectively).These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.

KW - Major Depressive Disorder

KW - Depression

KW - Inflammation

KW - C-reactive Protein

KW - CRP

KW - Methylation

KW - Brain Morphology

KW - Brain Structure

KW - White Matter Integrity

KW - MRI

KW - C-reactive protein

KW - White matter integrity

KW - Brain structure

KW - Major depressive disorder

KW - Brain morphology

U2 - 10.1016/j.bbi.2020.11.024

DO - 10.1016/j.bbi.2020.11.024

M3 - Article

C2 - 33221487

SN - 0889-1591

VL - 92

SP - 39

EP - 48

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Abstract

Keywords

ASJC Scopus subject areas

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Projects

STRADL - Provision of MRI Scans

Research output

Spectral Clustering Based on Structural Magnetic Resonance Imaging and its Relationship with Major Depressive Disorder and Cognitive Ability

Cite this