Cambridge

Mary-Ellen Lynall
Academic lead

Immune cell targets

Objectives

1

Primary: To identify specific immune cell subsets and molecular pathways through which genetic risk contributes causally to severe mental illness.

2

Secondary: To determine whether genetic risk variants act differently across immune cell types and activation states; to test whether changes in immune cell gene expression are likely to play a causal role in mental illness; and to generate biologically grounded targets that could be prioritised for drug discovery or repurposing.

Genetic studies have shown that risk for severe mental illnesses (SMI), including schizophrenia and bipolar disorder, is not only linked to the brain but also to the immune system. Many of the genetic variants that increase risk for these disorders are active in specific subsets of immune cells circulating in the blood.

This research aims to identify which immune cell types and states are most directly involved in the biology of severe mental illness, and how genetic risk influences their behaviour. By combining large-scale genetic data with detailed molecular information from immune cells, we hope to pinpoint cellular pathways that could become new targets for treatment or prevention.

Why this matters

Most existing molecular studies of severe mental illness focus on the brain. However, growing evidence suggests that adaptive immune cells may play a causal role, rather than simply reflecting downstream effects of illness or treatment.

By identifying immune cell types and pathways that are genetically linked to disease risk, this work could:

Reveal new biological mechanisms underlying mental illness
Help explain why immune-related drugs may benefit some patients
Enable more targeted and stratified approaches to treatment

What we are doing

We are integrating multiple types of large-scale data, including:

Genome-wide association studies (GWAS) of severe mental illness
Functional genomic datasets from sorted immune cells and single immune cells
Molecular QTL (molQTL) data describing how genetic variation influences gene expression, epigenetic regulation, and chromatin structure

Using advanced statistical genetics methods, including colocalisation and Mendelian randomisation, we will test whether genetic risk variants directly influence immune cell biology in ways that contribute to disease.

We are working closely with international experts in immunogenomics and statistical genetics, and making extensive use of openly available datasets from large normative cohorts.

What we are planning to do

To move beyond studies of healthy individuals, we will analyse emerging immune cell data from people with severe mental illness. This includes single-cell RNA sequencing of immune cells from patients with bipolar disorder and schizophrenia.

These data will allow us to:

Identify disease-specific immune gene regulation
Link immune cell molecular profiles to clinical features such as symptom severity and outcomes
Validate genetically prioritised pathways directly in patient samples

The results will feed into downstream analyses that link immune biology to drug-related molecular signatures, helping to identify promising therapeutic directions.

Find out more

This work builds on a growing international literature showing that genetic risk for psychiatric disorders is enriched in immune-related regulatory regions and immune cell–specific molecular pathways.

By combining genetics, immunology, and advanced data science, ImmunoMIND aims to deliver mechanistically informed targets that can accelerate the development of better treatments for people living with severe mental illness.

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