Australian researchers have produced the most detailed map to date of how genetic differences between individuals influence disease, focusing specifically on the immune cells where these genetic variations act. The work, published in three landmark studies in Nature, represents the first major output of the TenK10K project, a large-scale initiative designed to map genetic variation and gene activity in immune cells from 10,000 people. By analyzing the gene sequence and activity of more than 5 million individual immune cells from nearly 2,000 people, the team created the largest dataset of its kind in the world. This unprecedented scale allows for a granular understanding of the biological mechanisms that connect DNA to health outcomes, moving beyond previous studies that lacked the resolution to identify specific cell types involved in disease processes.

The research team, led by the Garvan Institute of Medical Research in collaboration with the Murdoch Children’s Research Institute, UNSW, and other partners, linked genetic risk regions for 16 diseases to possible causes in specific immune cells. Through this analysis, they identified nearly 1,500 genes that may contribute to a wide range of conditions, including autoimmune disorders like multiple sclerosis, neurological conditions such as Alzheimer’s, and cancers including breast and prostate. The findings are expected to accelerate drug development and precision medicine by providing a clearer picture of which genetic variants drive disease and in which specific cellular contexts.

Professor Joseph Powell, Director of the Translational Genomics Program at Garvan and a senior co-author on all three papers, described the findings as a fundamental shift in what is possible for medical research. He noted that the team has moved from understanding very few potential causal mechanisms to identifying thousands that connect genetic variation to disease risk. When researchers know which specific genetic variant is driving a disease, and in which cell type and through which mechanism, they can begin to identify patients likely to respond to particular treatments. This knowledge also enables the development of drugs targeting mechanisms that were previously unknown, offering new avenues for therapeutic intervention in complex diseases.

The technological advancements over the past three decades have made it significantly easier to read a person’s DNA, but pinpointing how these differences lead to disease requires vast amounts of data at the single-cell level. In the first phase of the TenK10K project, the researchers sequenced the genomes of nearly 2,000 Australians and used the latest single-cell technologies to measure gene activity in more than 5 million of their immune cells. This approach allowed them to trace tens of millions of genetic variants to the specific cell types they act in, linking them to 16 diseases and 44 blood characteristics to identify likely driving mechanisms.

The first of the three studies maps how common and rare genetic variants influence gene activity in individual immune cell types. The team focused on 21,000 genes and found over 180,000 common and rare effects on gene expression. Notably, nearly 5,000 of the genes with these effects, about a quarter, had not been linked to a genetic effect on their activity in the largest previous study of whole blood. By comparing these findings with genetic studies of 16 diseases, including cancers, immune conditions, and neurological disorders, the researchers revealed 893 genes linked to diseases or blood traits whose activity had not previously been linked to genetic variation. Many of these genes were found in specific cell types rather than across all blood cells, which may explain why earlier whole-blood studies missed them.

The second study addresses a part of the genome that has historically been difficult to study: tandem repeats. These repetitive DNA sequences are important for gene regulation and occupy more genetic real estate than all protein-coding genes combined. They have been challenging to analyze accurately, but with new methods for analyzing whole-genome sequencing data, the team identified more than 69,000 tandem repeat variants associated with changes in gene expression. They also found over 200 genes where repeated DNA sequences may help explain genetic links to immune and blood traits. These findings reveal potential new targets for treating a range of diseases, expanding the scope of genetic factors that can be considered in therapeutic development.

The third study maps a further layer of regulation: chromatin accessibility. This process detects how open or tightly packed DNA is in a cell, which controls which genes can be switched on or off. The team identified more than 240,000 genetic variants linked to chromatin accessibility and linked more than 28,000 of these DNA regions to the genes they help regulate. Importantly, the team showed that focusing on chromatin accessibility explained the likely role of up to 23% more disease-linked genetic regions than by looking at gene activity alone. This additional layer of regulation provides a more comprehensive understanding of how DNA variation affects gene expression and shapes immune cell function, highlighting the importance of considering multiple regulatory mechanisms in disease research.

Professor Daniel MacArthur, co-senior author on two of the three papers and Director of the Centre for Population Genomics, emphasized that this is the most detailed map to date of how genetic variation shapes the immune system. He noted that the data is already being used to create new tools for understanding human biology and disease, which is incredibly exciting for the research community. This kind of foundational resource is expected to be drawn on by researchers for years, providing a robust framework for future studies.

One specific example of the research’s impact is the identification of a genetic variant that increases the expression of a gene called OSM in natural killer immune cells, which also increases the risk of developing irritable bowel disease. This finding uncovered a specific immune pathway that could potentially be targeted with future treatments. By pinpointing the immune cell type involved, the research provides a clearer path for developing targeted therapies. Professor Powell noted that most of the biological mechanisms uncovered were invisible to prior studies, and this ability to pinpoint the specific cell type involved could help target future treatments more effectively.

The summary results from all three studies are now freely available, allowing other scientists and organizations to leverage this resource to guide new therapies and deliver better care for patients. The research team views this as just the start of the TenK10K project. In the next phase, they plan to significantly expand the number of people and disease areas analyzed, increasing the genetic diversity of participants. This expansion aims to ensure that the findings are representative of more people around the world, addressing the current limitations in genetic diversity and broadening the applicability of the research to a global population.

The work was supported by Australia’s National Health and Medical Research Council, Illumina, the John Brown Cook Foundation, the Fok Family Fellowship, and several other foundations. The researchers also thanked the participants of the Tasmanian Ophthalmic Biobank, BioHEART, and Liquid Biopsy Biobank studies, whose samples and data made this research possible.

The Garvan Institute of Medical Research brings together world-leading researchers and clinicians, collaborating locally and globally to advance the understanding of disease, particularly cancer, immune diseases, and genetic disorders. The institute sees a future where all diseases can be prevented, treated, or cured, building on its scientific strengths in genomics, cancer, and immunology. Enabled by cutting-edge technology and world-class facilities, Garvan aims to drive more of its discoveries to clinical and societal impact.

Murdoch Children’s Research Institute, one of the world’s top three child health research institutes, is dedicated to improving the health of children and adolescents in Australia and around the world. In 2026, MCRI celebrates its 40th anniversary, marking four decades of transforming child health through research, discovery, and innovation. Its breakthroughs have improved diagnosis, informed global vaccine strategies, advanced precision medicine, and continue to redefine what’s possible for sick children.

UNSW Sydney, a world-leading university known for driving progress that benefits everyone, aims to make a positive global societal impact, improving and transforming lives through excellence in research and outstanding education. As a member of the prestigious Group of Eight, a coalition of Australia’s leading research-intensive universities, UNSW is ranked in the top 20 universities globally. The university has an international reputation for breakthroughs in a range of fields, including inequality, climate change, renewable energy, and quantum computing. UNSW ranks number one in Australia for employment outcomes, with work integrated learning a key part of its job-ready education approach, ensuring students graduate with relevant, sought-after skills.

Subject of Research: Three landmark studies reveal the hidden layers between DNA and disease

Article Title: Three landmark studies reveal the hidden layers between DNA and disease

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