Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress

Melanie Föcking; Sophie Sabherwal; Hannah M Cates; Caitriona Scaife; Patrick Dicker; Magdalena Hryniewiecka; Kieran Wynne; Bart P F Rutten; Glyn Lewis; Mary Cannon; Eric J Nestler; Meike Heurich; Gerard Cagney; Stanley Zammit; David R Cotter

doi:10.1038/s41380-018-0306-z

Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress

Melanie Föcking^*, Sophie Sabherwal, Hannah M Cates, Caitriona Scaife, Patrick Dicker, Magdalena Hryniewiecka, Kieran Wynne, Bart P F Rutten, Glyn Lewis, Mary Cannon, Eric J Nestler, Meike Heurich, Gerard Cagney, Stanley Zammit, David R Cotter^*

^*Corresponding author for this work

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

Abstract

The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We undertook a directed proteomic analysis of the complement signalling pathway (n = 29 proteins) using data-independent acquisition. Participants were recruited from the UK avon longitudinal study of parents and children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12 among individuals who reported psychotic experiences (PEs) at age 18 (n = 64) were compared with age-matched controls (n = 67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, and C5↑). We then undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 11 complement proteins, including three that were altered in the same direction in individuals with PE (C1R↑, CFH↑, and C5↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence of psychotic experiences and that these changes may reflect exposure to stress.

Original language	English
Pages (from-to)	524-533
Number of pages	10
Journal	Molecular Psychiatry
Volume	26
Issue number	2
Early online date	11 Jan 2019
DOIs	https://doi.org/10.1038/s41380-018-0306-z
Publication status	Published - Feb 2021

Keywords

1ST EPISODE PSYCHOSIS
BRAIN
DATA-INDEPENDENT ACQUISITION
MENTAL-DISORDERS
PROTEIN-PHOSPHORYLATION PATTERNS
PROTEOMICS
SCHIZOPHRENIA-PATIENTS
SOCIAL DEFEAT
SYSTEM
ULTRA-HIGH RISK

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Föcking, M., Sabherwal, S., Cates, H. M., Scaife, C., Dicker, P., Hryniewiecka, M., Wynne, K., Rutten, B. P. F., Lewis, G., Cannon, M., Nestler, E. J., Heurich, M., Cagney, G., Zammit, S., & Cotter, D. R. (2021). Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress. Molecular Psychiatry, 26(2), 524-533. https://doi.org/10.1038/s41380-018-0306-z

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title = "Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress",

abstract = "The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We undertook a directed proteomic analysis of the complement signalling pathway (n = 29 proteins) using data-independent acquisition. Participants were recruited from the UK avon longitudinal study of parents and children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12 among individuals who reported psychotic experiences (PEs) at age 18 (n = 64) were compared with age-matched controls (n = 67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, and C5↑). We then undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 11 complement proteins, including three that were altered in the same direction in individuals with PE (C1R↑, CFH↑, and C5↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence of psychotic experiences and that these changes may reflect exposure to stress.",

keywords = "1ST EPISODE PSYCHOSIS, BRAIN, DATA-INDEPENDENT ACQUISITION, MENTAL-DISORDERS, PROTEIN-PHOSPHORYLATION PATTERNS, PROTEOMICS, SCHIZOPHRENIA-PATIENTS, SOCIAL DEFEAT, SYSTEM, ULTRA-HIGH RISK",

author = "Melanie F{\"o}cking and Sophie Sabherwal and Cates, {Hannah M} and Caitriona Scaife and Patrick Dicker and Magdalena Hryniewiecka and Kieran Wynne and Rutten, {Bart P F} and Glyn Lewis and Mary Cannon and Nestler, {Eric J} and Meike Heurich and Gerard Cagney and Stanley Zammit and Cotter, {David R}",

note = "Funding Information: Acknowledgements We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole-ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. S.Z. is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. MC was supported by a European Research Council Consolidator Award (Grant Ref: 724809 iHEAR). This research was specifically funded by the Irish Health Research Board through a Clinician Scientist Award to D.R.C. This publication is the work of the authors and will serve as guarantors for the contents of this paper. We also thank Prof Matthias Wilm and the Mass Spectrometry Core Facility at UCD Conway Institute, UCD, for support in the development of our proteomic workflows. In addition, we would like to thank everyone at the Mac-Coss Lab of Biological Mass Spectrometry, University of Washington, and everyone at the H. Choi Lab, National University of Singapore, for support and access to Skyline and MapDIA, respectively. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2021",

month = feb,

doi = "10.1038/s41380-018-0306-z",

language = "English",

volume = "26",

pages = "524--533",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

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Föcking, M, Sabherwal, S, Cates, HM, Scaife, C, Dicker, P, Hryniewiecka, M, Wynne, K, Rutten, BPF, Lewis, G, Cannon, M, Nestler, EJ, Heurich, M, Cagney, G, Zammit, S & Cotter, DR 2021, 'Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress', Molecular Psychiatry, vol. 26, no. 2, pp. 524-533. https://doi.org/10.1038/s41380-018-0306-z

TY - JOUR

T1 - Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study

T2 - evidence for a role of stress

AU - Föcking, Melanie

AU - Sabherwal, Sophie

AU - Cates, Hannah M

AU - Scaife, Caitriona

AU - Dicker, Patrick

AU - Hryniewiecka, Magdalena

AU - Wynne, Kieran

AU - Rutten, Bart P F

AU - Lewis, Glyn

AU - Cannon, Mary

AU - Nestler, Eric J

AU - Heurich, Meike

AU - Cagney, Gerard

AU - Zammit, Stanley

AU - Cotter, David R

N1 - Funding Information: Acknowledgements We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole-ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. S.Z. is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. MC was supported by a European Research Council Consolidator Award (Grant Ref: 724809 iHEAR). This research was specifically funded by the Irish Health Research Board through a Clinician Scientist Award to D.R.C. This publication is the work of the authors and will serve as guarantors for the contents of this paper. We also thank Prof Matthias Wilm and the Mass Spectrometry Core Facility at UCD Conway Institute, UCD, for support in the development of our proteomic workflows. In addition, we would like to thank everyone at the Mac-Coss Lab of Biological Mass Spectrometry, University of Washington, and everyone at the H. Choi Lab, National University of Singapore, for support and access to Skyline and MapDIA, respectively. Publisher Copyright: © 2019, The Author(s).

PY - 2021/2

Y1 - 2021/2

N2 - The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We undertook a directed proteomic analysis of the complement signalling pathway (n = 29 proteins) using data-independent acquisition. Participants were recruited from the UK avon longitudinal study of parents and children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12 among individuals who reported psychotic experiences (PEs) at age 18 (n = 64) were compared with age-matched controls (n = 67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, and C5↑). We then undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 11 complement proteins, including three that were altered in the same direction in individuals with PE (C1R↑, CFH↑, and C5↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence of psychotic experiences and that these changes may reflect exposure to stress.

AB - The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We undertook a directed proteomic analysis of the complement signalling pathway (n = 29 proteins) using data-independent acquisition. Participants were recruited from the UK avon longitudinal study of parents and children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12 among individuals who reported psychotic experiences (PEs) at age 18 (n = 64) were compared with age-matched controls (n = 67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, and C5↑). We then undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 11 complement proteins, including three that were altered in the same direction in individuals with PE (C1R↑, CFH↑, and C5↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence of psychotic experiences and that these changes may reflect exposure to stress.

KW - 1ST EPISODE PSYCHOSIS

KW - BRAIN

KW - DATA-INDEPENDENT ACQUISITION

KW - MENTAL-DISORDERS

KW - PROTEIN-PHOSPHORYLATION PATTERNS

KW - PROTEOMICS

KW - SCHIZOPHRENIA-PATIENTS

KW - SOCIAL DEFEAT

KW - SYSTEM

KW - ULTRA-HIGH RISK

U2 - 10.1038/s41380-018-0306-z

DO - 10.1038/s41380-018-0306-z

M3 - Article

C2 - 30635638

SN - 1359-4184

VL - 26

SP - 524

EP - 533

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 2

ER -