Atlas of immune cells explains how genetic variants cause disease

Modified from an article by Sarah C.P. Williams, Broad Institute (September 30, 2026).

Scientists have identified thousands of genetic differences that change a person’s risk of disease, but working out how they actually impact biology — an important step toward creating new treatments —has been much more challenging. One reason is that many of the genetic variants associated with disease aren’t found in genes themselves, but within the vast stretches of DNA that regulate gene activity.

Now, scientists have developed a new approach to connecting disease-linked regulatory variants to the actual genes they control. Their results, in Nature, reveal that these variants are more likely to influence disease risk if they alter chromatin accessibility — the openness of a section of the genome — in a way that then changes expression of a specific gene, compared to variants that affect only chromatin accessibility or gene expression alone. The finding could help other scientists prioritize the genetic variants that are most important in a particular disease.

The research team applied their method to millions of immune cells from more than 1,100 blood donors enrolled in FinnGen. The resulting atlas revealed likely molecular mechanisms by which tens of thousands of genetic variants cause hundreds of different diseases and health traits, including autoimmune hypothyroidism, inflammatory bowel disease, asthma, Alzheimer’s disease, and skin cancer.

The new work was led by researchers at the Broad Institute, Massachusetts General Hospital, and the Institute for Molecular Medicine Finland (FIMM) at the University of Helsinki, in collaboration with the Finnish Red Cross Blood Service and BioBank Japan.

Many weak regulatory switches rather than a single strong one

Geneticists have long struggled to find the mechanisms by which many disease-linked genetic variants actually cause disease. In this study, the research team wanted to connect previously identified FinnGen disease risk variants to their molecular consequences.

In the millions of immune cells from FinnGen donors, the researchers measured both gene expression and chromatin accessibility in the same cells. This let them connect whether a genetic variant was correlated to a change in that openness in a particular cell type, and then whether that change in openness was also correlated with a change in gene expression.

The team found that many of the genes most critical to health and survival are wired to dozens of regulatory elements in the genome at once, each contributing only a small change to gene expression. That redundancy, they found, keeps the expression of these important genes relatively stable and is also why these genes have been so hard to study using traditional methods.

“We think the body wants precise control over the expression of its most important genes; it doesn’t want any single genetic variant to be able to swing that expression too far on its own,” said Masahiro Kanai, first author of the study, a postdoctoral scholar at the Broad Institute and an instructor in medicine at the Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School.

Connecting genetic signals to disease mechanisms

The researchers chose to build their atlas from immune cells because immune dysregulation is at the root of many seemingly different diseases affecting different tissues.

Across eight broad types of immune cells, the team carried out the full analysis of chromatin accessibility and gene expression for thousands of different disease-linked genes. They then traced the precise molecular mechanisms behind several disease-linked genetic variants.

One, inside a gene called TNRC18, had been flagged in the 2023 FinnGen study as being linked to inflammatory bowel disease, with no known mechanism. The new data show the variant reduces TNRC18 expression in T cells, and it does this most strongly in a subset called T helper 1 cells, pushing those cells toward a more inflammatory state.

Another example, involving the genes IL4R and IL21R, helped explain why one variant lowers the risk of asthma while another variant in the same genetic region instead raises the risk of autoimmune hypothyroidism.

“One of the biggest gaps in human genetics has been between finding a disease-associated variant and understanding its function,” said Mark Daly, co-senior author, an institute member at the Broad Institute, co-director of Broad’s Program in Medical and Population Genetics, and founding chief of the Analytical and Translational Genetics Unit at Massachusetts General Hospital. 

“This atlas provides reliable evidence that we can now systematically connect genetic association signals to molecular switches affecting specific genes and cells at scale. With confirmatory editing experiments now possible, we have a path to unlocking the power of human genetics to provide novel insights into causal disease mechanisms.”

The team has made its data and methods freely available to spur new research. They caution that many of the connections they’ve mapped are still hypotheses rather than confirmed mechanisms.

Original publication: 

Kanai M, Delorey TM, et al. Population-scale immune multiome atlas reveals regulatory disease mechanisms. Nature. Online September 30, 2026. DOI: 10.1038/s41586-026-11078-2