A wealth of data implicates inflammation in the pathophysiology of psychiatric and many other disorders. Childhood adversity is a risk factor for later psychiatric disorder and it is associated chronic inflammation as measured by the soluble urokinase-type plasminogen activator receptor [suPAR]). We have shown that suPAR is elevated among ALSPAC participants who have psychotic experiences and psychotic disorder at age 24. We have also shown that the complement pathway in the blood, which contributes to inflammation, is upregulated in the blood 6 years prior to the identification of psychotic disorder (PMID 29036721). Similarly we have shown that people at clinical high risk for psychosis who later develop a psychotic disorder show increased baseline levels of markers of the complement pathway (PMID 32857162). Most recently we have shown (preliminary data) that the complement pathway is upregulated among those in the first episode of psychosis who respond well to antipsychotic drugs. These findings implicate the complement pathway in psychosis. Of the members of the complement pathway that have been shown to be dysregulated, C1r, has been most consistently and strongly altered and has been validated using ELISA (PMID 32857162; PMID 32857162). C1r is linked to the activation of C4A variant implicated so strongly in schizophrenia genomic studies (PMID: 26814963) and is associated with other medical diseases such SLE and Hereditary Angioedema.
What is not known is:

1. what is the relationship of this marker of chronic inflammation [suPAR] and this plasma marker of the complement pathway, C1r, at age 24 to adversity in childhood and adolescence

2. what is the relationship between plasma suPAR and plasma C1r.

3. do measures of suPAR and C1r at age 24 mediate the relationship between adversity in childhood and adolescence and psychiatric outcomes at age 24.

We propose to answer these questions by quantifying these markers of chronic inflammation and complement activation in all young people who gave bloods in the ALSPAC clinics at age 24 to investigate the relationship to adversity and psychiatric outcomes at age 24.

We note that chronic inflammation and complement pathway function is an important contributing factor to many medical diseases and that this information can therefore be applied broadly and will find relevance far beyond the field of psychiatry.