David Cotter1, Melanie Focking1, Glyn Lewis2, Lorna Lopez1, Jane English1, Pat Dicker1, Bart Rutten4, Mary Cannon1, Stan Zammit3; 1RCSI, 2University College London, 3University of Bristol & Univerisity Cardiff, 4University of Maastricht
Background: 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. Methods: We undertook a hypothesis-driven proteomic analysis of the complement signalling pathway (n=33 proteins). Participants were recruited from the UK ALSPAC cohort who participated in psychiatric assessment interviews at ages 11 and 18. Protein expression levels at age 11 among individuals who first reported psychotic experiences (PE Study) at age 18 (n=64) were compared with age-matched controls (n=67). Using the same methods we examined participants with Persistent Psychotic Experiences (PPE Study) and we compared complement protein expression between individuals who reported psychotic experiences at both age 11 and age 18 (n=38) compared to age-matched controls who only experienced PEs at age 11 (n=38). Results: In the PE study, 6 out of the 32 targeted complement proteins were significantly upregulated (C1RL↑, VTN↑, C8B↑, C8A↑, CFH↑, C5↑). In the PPE study, we observed that 5 of 32 targeted complement proteins were differentially expressed (C1RL↑,C2↑, C4BPB↑, C9↑ and CFD↑). Finally, we undertook a plasma proteomic analysis of mice exposed to stress and observed dysregulation of 11 complement proteins including 3 of which were altered in the same direction in psychosis (C1RL, CFH↑, C5↑, C9↑). Conclusion: Our findings indicate that the complement protein pathway is dysregulated in the blood at age 11 of those with PE and PPE at age 18 and suggest that these changes may reflect exposure to stress.
