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 -