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

Claire Green; Xueyi Shen; Anna J 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

Brain Behav Immun. 2021 Feb:92:39-48. doi: 10.1016/j.bbi.2020.11.024. Epub 2020 Nov 19.

Authors

Claire Green¹, Xueyi Shen², Anna J Stevenson³, Eleanor L S Conole⁴, Mathew A Harris², Miruna C Barbu², Emma L Hawkins², Mark J Adams², Robert F Hillary⁵, Stephen M Lawrie², Kathryn L Evans⁵, Rosie M Walker⁶, Stewart W Morris⁵, David J Porteous⁷, Joanna M Wardlaw⁸, J Douglas Steele⁹, Gordon D Waiter¹⁰, Anca-Larisa Sandu¹⁰, Archie Campbell⁵, Riccardo E Marioni⁵, Simon R Cox¹¹, Jonathan Cavanagh¹², Andrew M McIntosh¹³, Heather C Whalley²

Affiliations

¹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK. Electronic address: claire.green@ed.ac.uk.
² Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
³ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; Lothian Birth Cohorts Group, University of Edinburgh, Edinburgh, UK.
⁵ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁶ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁷ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
⁸ UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁹ Division of Imaging Science and Technology, School of Medicine, University of Dundee, Dundee, UK.
¹⁰ Aberdeen Biomedical Imaging Centre, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
¹¹ Lothian Birth Cohorts Group, University of Edinburgh, Edinburgh, UK.
¹² Institute of Infection, Immunity & Inflammation, College of Medical and Veterinary Life Sciences, University of Glasgow, Glasgow, UK; Institute of Health and Wellbeing, College of Medical and Veterinary Life Sciences, University of Glasgow, Glasgow, UK.
¹³ Division of Psychiatry, University of Edinburgh, Edinburgh, UK; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

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.

Keywords: Brain morphology; Brain structure; C-reactive protein; CRP; Depression; Inflammation; MRI; Major depressive disorder; Methylation; White matter integrity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Brain / diagnostic imaging
Depressive Disorder, Major* / genetics
Epigenesis, Genetic
Humans
Inflammation / genetics
Scotland

Substances

Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding