Immunological Drivers and Potential Novel Drug Targets for Major Psychiatric, Neurodevelopmental, and Neurodegenerative Conditions

Immune dysfunction is implicated in the aetiology of psychiatric, neurodevelopmental, and neurodegenerative conditions, but the issue of causality remains unclear impeding attempts to develop new interventions. We have tested evidence for causality for 735 immune response-related biomarkers on 7 neuropsychiatric conditions, using cutting-edge genomic causal inference methods (Mendelian randomization and genetic colocalization) applied to genomic data on protein and gene expression across blood and brain. We provide robust evidence of causality for 21 biomarkers, including two previously unreported ( LATS1 , and FCN1 ), confirming a role of both brain specific and systemic immune response in the pathogenesis of several neuropsychiatric conditions especially schizophrenia, Alzheimer’s disease, depression, and bipolar disorder. Furthermore, 18 of the identified biomarkers are therapeutically tractable, including ACE , TNFRSF17 , and CD40, with drugs approved or in advanced clinical trials, offering an opportunity for repurposing existing drugs for neuropsychiatric indications. ### Competing Interest Statement JWR is a full-time employee of Boehringer Ingelheim but undertook all relevant work when at the University of Bristol. TGR is a full-time employee of GlaxoSmithKline outside of this work. No funding body has influenced data collection, analyses, or their interpretation. ### Funding Statement This work is funded by a UK Medical Research Council (MRC) grant to GMK via the Integrative Epidemiology Unit (IEU) at the University of Bristol (MC\_UU\_00032/06). This grant also supports CD. 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 the UK National Institute of Health and Care Research (NIHR) Bristol Biomedical Research Centre (NIHR 203315). GMK, TRG and AMM acknowledge funding support from the MRC (The CHECKPOINT Hub, APP4735-GTEE-2024). AMM is supported by the Wellcome Trust (220857/Z/20/Z) and UKRI (MR/W014386/1). GDS, HJ, DR are supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. RG acknowledges funding support from the Swedish Research Council (VR2017-02900; 2022-00592). AH was supported by grants from the South-Eastern Norway Regional Health Authority (2020022, 2018059) and the Research Council of Norway (274611, 288083, 336085). The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit (MC\_UU\_00011/1, MC\_UU\_00011/3, MC\_UU\_00011/5). This research was funded in part, by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The UK Medical Research Council 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 CD, GMK will serve as guarantors for the contents of this paper. Genomewide genotyping data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. ### Author Declarations 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: ALSPAC data used as reference panel: ethical approval was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. GWAS data: across all analyses summary data were used. These data are publicly available for research purposes. Details on the ethics declarations for each GWAS study can be found in the original publications. 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 All GWAS data used in this work is publicly available for research purposes. Individual-level data from the ALSPAC birth cohort are not publicly available for reasons of clinical confidentiality. Data can be accessed after application to the ALSPAC Executive Team who will respond within 10 working days. Application instructions and data use agreements are available at .