Immunological drivers and potential novel drug targets for major psychiatric, neurodevelopmental, and neurodegenerative conditions, 2025, Dardani+

Immunological drivers and potential novel drug targets for major psychiatric, neurodevelopmental, and neurodegenerative conditions

Christina Dardani, Jamie W. Robinson, Hannah J. Jones, Dheeraj Rai, Evie Stergiakouli, Jakob Grove, Renee Gardner, Andrew M. McIntosh, Alexandra Havdahl, Gibran Hemani, George Davey Smith, Tom G. Richardson, Tom R. Gaunt & Golam M. Khandaker

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Abstract
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.

Using genomic data on protein and gene expression across blood and brain, we assessed evidence of a potential causal role for 736 immune response-related biomarkers on 7 neuropsychiatric conditions by applying Mendelian randomization (MR) and genetic colocalisation analyses. A systematic three-tier approach, grouping biomarkers based on increasingly stringent criteria, was used to appraise evidence of causality (passing MR sensitivity analyses, colocalisation, False Discovery Rate and Bonferroni thresholds).

We provide evidence for a potential causal role of 29 biomarkers for 7 conditions. The identified biomarkers suggest a role of both brain specific and systemic immune response in the aetiology of schizophrenia, Alzheimer’s disease, depression, and bipolar disorder.

Of the identified biomarkers, 20 are therapeutically tractable, including ACE, TNFRSF17, SERPING1, AGER and CD40, with drugs currently approved or in advanced clinical trials.

Based on the largest available selection of plasma immune-response related biomarkers, our study provides insight into possible influential biomarkers for the aetiology of neuropsychiatric conditions. These genetically prioritised biomarkers now require examination to further evaluate causality, their role in the aetiological mechanisms underlying the conditions, and therapeutic potential.

Link | PDF (Molecular Psychiatry) [Open Access]

 

GeneCards links and associated conditions for the 29 potentially causal genes, transcribed from figure 2:


ACE - Alzheimer's, Schizophrenia
AGER - Schizophrenia
AMN - Depression
ANXA1 - Autism
APOC1 - Alzheimer's
BTN2A1 - Schizophrenia, Depression, Bipolar Disorder
CD40 - Schizophrenia, Bipolar Disorder
CEBPA - Autism
CHRDL1 - Alzheimer's
CR1 - Alzheimer's
DNER - Schizophrenia
DNPH1 - Bipolar Disorder
EP300 - Depression
EVI5 - Schizophrenia
FCN1 - Depression
GCHFR - ADHD
KLRB1 - Alzheimer's
MYOM3 - Schizophrenia
NAGA - Schizophrenia
PAPPA - Depression
PDIA3 - Schizophrenia
PRSS8 - Alzheimer's
RABEP1 - Schizophrenia
RABGAP1L - Depression
SCRN1 - Bipolar Disorder
SEPP1 - Depression
SERPING1 - Schizophrenia
SERPINI1 - Schizophrenia
TNFRSF17 - Schizophrenia

 

My favorite gene

 

I've never heard of it. What's special about it?

 

It's a cell-cell adhesion molecule. I like it because it seems to have opposite regulatory roles in innate vs. adaptive immune cells. I enjoy a contradiction. And I happened to spend a lot of time with it for an old project.