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

doi:10.1038/s41380-018-0306-z

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.

Highlights

The early identification and treatment of subjects with psychiatric disorders, both psychotic and affective, significantly improves their clinical outcome [1]
We identified and quantified all proteins and their peptides listed as contributing to the complement pathway according to KEGG)
Our study provides evidence that altered expression of plasma complement proteins at age 12 is associated with psychotic experiences (PE) at age 18

Summary

Introduction

The early identification and treatment of subjects with psychiatric disorders, both psychotic and affective, significantly improves their clinical outcome [1]. Inflammatory cytokines, chemokines, and growth factors have been assessed in the blood during the perinatal periods and during childhood in subjects who subsequently developed schizophrenia, and in those with a first episode psychosis [12,13,14,15,16] Together these studies demonstrated a picture of enhanced inflammatory tone during and preceding psychosis, and other major mental illnesses [17]. Previous studies based on the ALSPAC cohort, a prospective general population cohort based in the Bristol area in South West England, have shown subgroups of subjects who developed psychotic disorder (PD) and psychotic experiences (PEs) [24] at age 18 These groups showed alterations in cortical white matter microstructure [25], working memory [26], and raised inflammatory markers in childhood [12] in subjects with PE at age 18. The findings of this study are relevant to our understanding of the role of the complement system in vulnerability to major adult psychiatric disorder outcomes

Participants

Study design

Results

Discussion

Compliance with ethical standards