New genomic approach links rare immune cells to autoimmune disease risk

Much of how genetic risk leads to disease has remained hidden. In many cases, genetic variants linked to disease do not act on nearby genes along the chromosome. Instead, they influence genes located far away along the DNA sequence. This happens because DNA is folded inside the cell, bringing distant regions into physical contact.

Capturing these long‑distance regulatory connections has been especially difficult in rare immune cells that play important roles in disease. As a result, linking genetic risk to the genes and biological mechanisms that drive disease has remained a major challenge.

A study co-led by researchers at Cincinnati Children’s and MRC Laboratory of Medical Sciences in London published on August 4, 2026 in Nature Genetics uses a new genomic approach to address this challenge. The work links distant DNA regions to the genes they control in type 3 innate lymphoid cells (ILC3s), uncovering previously hidden connections relevant to autoimmune disease.

This work opens the door to studying long‑distance DNA interactions in rare immune cells. Until now, most methods required millions of cells, which limited what we could learn from the cell types most relevant to disease.”

Stephen Waggoner, PhD, scientist, Center of Autoimmune Genomics and Etiology, Cincinnati Children’s

Overcoming the barrier of rarity

ILC3s are tissue‑resident immune cells that play a central role in maintaining barrier integrity and regulating inflammation, particularly in the gut. They are increasingly recognized as contributors to inflammatory bowel disease, but they are difficult to study at scale. This is because ILC3s are rare and don’t replicate well outside the body.

Most existing methods for mapping genome organization require millions of cells. This means analyses are restricted to studying abundant or mixed populations of cells such as those found in circulating blood.

This study overcomes that barrier by applying an approach that works with far fewer cells. Using an optimized promoter capture Hi‑C method, the researchers examined how DNA is folded in human ILC3s and how gene promoters physically interact with distant regulatory elements across the genome. This resulted in a detailed map showing that regulatory DNA elements often act over long distances to influence gene activity. The researchers also found that these promoter contacts can differ between cell types, even though the underlying genetic variants are the same.

“While some disease risk variants act on the genes nearest to them, others do not, so if we only look at the nearest gene, we may get the underlying mechanisms wrong,” says Mikhail Spiakov, PhD, Head of the Functional Gene Control Research Group at MRC Laboratory of Medical Sciences. “What is more, the patterns of genome folding differ across cell types, so it is important to study the 3D connections between variants and the genes they control in the cells that are relevant for the disease.”

Linking 3D genome maps to disease risk

To connect these 3D interaction maps to disease risk, the researchers combined their data with large genome‑wide association studies (GWAS). They used an analysis framework that considers multiple genetic variants at a single genomic region-improving the ability to link genetic variants associated with disease risk to the genes they regulate.

This approach prioritized more than 100 candidate genes linked to Crohn’s disease risk in ILC3s, many of which had not previously been associated with inflammatory bowel disease.

One of the most notable findings involved CLN3. Mutations in this gene cause Batten disease, a rare neurodegenerative disorder, and CLN3 has not typically been studied in diseases driven by the immune system.

Using mouse models, follow‑up experiments showed that Cln3 expression (the mouse version of the gene) decreases when ILC3 cells are activated. In contrast, increasing Cln3 levels reduced inflammatory gene activity and cytokine production.

These findings do not establish CLN3 as a causal gene in inflammatory bowel disease. However, they raise new questions about how immune regulation and neurodevelopmental disease pathways may intersect.

“When you look at how the genome is wired in three dimensions, you start to see that genes linked to rare diseases, like CLN3, can have unexpected roles in immune cells,” says Emily Miraldi, PhD, scientist in the divisions of Immunobiology and Biomedical Informatics at Cincinnati Children’s. “Now, we have tools to study how genetic risk plays out in other rare cell types that were previously out of reach.”

Looking ahead

With these tools in place, a path is open for a range of next steps:

• Clarifying the role of CLN3 in immune cell function, including how it shapes inflammatory activity in ILC3s.
• Exploring potential connections between the immune system and the gut-brain axis which might link inflammatory bowel disease and neurodevelopmental disease pathways.
• Applying these approaches to additional rare immune cell types to uncover new disease‑associated genes.
• Using these techniques to compare genetic regulation across cells and disease contexts that have been difficult to study.

“Studying genetic regulation in rare cell types allows us to move closer to mechanism, not just association, and that’s essential for making genetic findings meaningful across medicine,” says Waggoner.

About the study

Valeriya Malysheva, Helen Ray-Jones, and Nora Lakes were co-first authors of the study. Additional Cincinnati Children’s co-authors included experts from the divisions of Human Genetics; the Center for Autoimmune Genomics and Etiology; Immunobiology; Rheumatology; Developmental Biology; Biomedical Informatics; Allergy and Immunology; Pediatric Otolaryngology; and Pulmonary and Sleep Medicine.

Additional co-authors included national experts from the University of Cincinnati, The Ohio State University, Stanford Research Institute and Florida State University. International co-authors included researchers from the MRC Laboratory of Medical Sciences, Imperial College London, the University of Cambridge, National Health Service Blood and Transplant, the University of Exeter Medical School, the Babraham Institute and the Cambridge Institute of Public Health in the United Kingdom; VIB and the University of Antwerp in Belgium; and Erasmus MC University Medical Center in the Netherlands.

This research was supported by grants from the National Institutes of Health, the Medical Research Council and the Wellcome Trust. Additional support came from the Cincinnati Children’s Research Foundation, the L.B. Research and Education Foundation, the Babraham Institute, VIB, the British Heart Foundation, and the National Institute for Health and Care Research. Research activities were also supported by institutional programs and training grants at Cincinnati Children’s and collaborating institutions.