Psychotic disorder is associated with altered levels of various inflammatory markers in blood, but existing studies have typically focused on a few selected biomarkers, have not examined specific symptom domains notably negative symptoms, and are based on individuals with established/chronic illness. Based on data from young people aged 24 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort, we have examined the associations of 67 plasma immune/inflammatory proteins assayed using the Olink Target 96 Inflammation panel with psychotic disorder, positive (any psychotic experiences and definite psychotic experiences) and negative symptoms, using linear models with empirical Bayes estimation. The analyses included between 2641 and 2854 individuals. After adjustment for age, sex, body mass index and smoking and correction for multiple testing, upregulation of CDCP1 and IL-6 were consistently associated with positive symptoms and psychotic disorder, while psychotic disorder was additionally associated with upregulation of MMP-10. Negative symptoms were associated with upregulation of the highest number of proteins (n=11), including cytokines, chemokines and growth factors which partly overlap with proteins associated with positive symptoms or psychotic disorder (CDCP1, IL-6 and MMP-10). Our findings highlight associations of inflammatory proteins involved in immune regulation, immune cell activation/migration, blood-brain barrier disruption, and extracellular matrix abnormalities with psychosis or psychotic symptoms in young people, consistent with a role of inflammation and immune dysfunction in the pathogenesis of psychotic disorders.

The authors have declared no competing interest.

RSMT is supported by the Tackling Multimorbidity at Scale Strategic Priorities Fund programme (MR/W014416/1) delivered by the Medical Research Council and the National Institute for Health Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council. NJT is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z). GMK acknowledges funding support from the Medical Research Council (MRC), UK (MC_UU_00032/06) which forms part of the Integrative Epidemiology Unit (IEU) at the University of Bristol. GMK acknowledges additional funding support from the Wellcome Trust (201486/Z/16/Z and 201486/B/16/Z), MRC (MR/W014416/1; MR/S037675/1; and MR/Z50354X/1), and the UK National Institute of Health and Care Research (NIHR) Bristol Biomedical Research Centre (NIHR 203315). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care, UK. The UK Medical Research Council (MRC) and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and RSMT and GMK will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Data collection on psychotic symptoms at the age 24 research clinic was specifically funded by the MRC (grant: MR/M006727/1) awarded to Prof. Stan Zammit. The funders had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

ALSPAC data access is through a system of managed open access. Information on how to request access to ALSPAC data can be found on the ALSPAC website (http://www.bristol.ac.uk/alspac/researchers/access/).