Complement Pathway Changes in Childhood are Associated with Incidence and Persistence of Psychotic Experiences in Adolescence: Evidence from the ALSPAC Birth Cohort

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

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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 hypothesis-driven 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 first 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↑, C5↑).Using the same methods, we examined participants with Persistent Psychotic Experiences (PPE) at both
age 12 and age 18 (n=38) compared to age-matched controls who only experienced PEs at age 12 (n=38). Here, we observed that five of 29 targeted complement proteins were differentially expressed (C1RL↑, C2↑, C4BPB↑, C9↑, CFD↑). Finally, we undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 10 complement proteins including five that were altered in the same direction in individuals with either PE or PPE (C1R↑, CFH↑, C4BP↑, C5↑, C9↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated
with incidence and persistence of psychotic experiences and that these changes may reflect exposure to stress.
Original languageEnglish
Number of pages16
JournalMolecular Psychiatry
Early online date11 Jan 2019
DOIs
Publication statusE-pub ahead of print - 11 Jan 2019

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    NIHR BRC Mental Health

    Gunnell, D. J.

    1/04/1731/03/22

    Project: Research, Parent

    Cite this

    Föcking, M., Sabherwal, S., Cates, H. M., Scaife, C., Dicker, P., Hryniewiecka, M., Wynne, K., Rutten, B. P. F., Lewis, G. H., Cannon, M., Nestler, E. J., Heurich, M., Cagney, G., Zammit, S., & Cotter, D. R. (2019). Complement Pathway Changes in Childhood are Associated with Incidence and Persistence of Psychotic Experiences in Adolescence: Evidence from the ALSPAC Birth Cohort. Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0306-z