Atlas of immune cells explains how genetic variants cause disease

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, a large medical research project in Finland. 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.

“Immune dysregulation sits at the root of an enormous range of human diseases, from autoimmunity to cancer to neurodegeneration,” said Ramnik Xavier, a co-senior author of the study, a core institute member at the Broad Institute, and Kurt Isselbacher Professor at Massachusetts General Hospital and Harvard Medical School. “What excites me about this work is that it doesn't just tell us that a gene matters; it tells us the molecular mechanism, which can point toward therapeutic strategies."

The team also 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.

“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.”

Open or closed

Daly, Xavier, and their colleagues had previously analyzed data from FinnGen—a research project that integrates genomic information and health records for more than 500,000 people in Finland. The 2023 study using FinnGen data pinpointed hundreds of genomic regions linked to diseases.  

In this new work, they wanted to connect those 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.

By collecting and analyzing this data from each of the millions of individual cells, the team had enough statistical power to show how cells maintain stable expression of genes that are important for life: by hooking these genes up to many weak regulatory switches rather than a single strong one. That explained why studies looking only at gene expression often missed the full story: a switch that matters for disease may move expression only slightly — too little for those studies to detect. 

“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. “So instead of relying on one strong switch, these genes are controlled by many weaker ones. We call this regulatory buffering, because it dampens the effect of any single chromatin change before it reaches gene expression, like a shock absorber.”

From signal to mechanism

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. The thyroid-risk variant turns up IL21R, the receptor for an immune signal called IL-21, and mice lacking that receptor on their T cells are protected from the same thyroid complication. The finding points toward blocking IL-21 as a potential way to treat a similar thyroid complication that can occur as a side effect of cancer immunotherapy.

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.

They are now working to profile immune cells from diseased tissue directly rather than relying only on samples from healthy individuals.

“This is a launching pad for future research,” said Daniel Graham, a study co-author and an institute scientist at Broad. “There’s a lot of reason to be optimistic about the power of using this type of data to uncover mechanisms of disease.”