Landmark studies map how genetic differences drive human diseases

In three landmark studies published in Nature today, Australian researchers have made major advances in our understanding of how genetic differences between people influence disease. The team from 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, identifying nearly 1,500 genes that may contribute to a range of diseases. These discoveries are set to accelerate drug development and precision medicine across many diseases, ranging from cancers to immune and neurological conditions. 

The work is the first major output of the TenK10K project, which seeks to map genetic variation and gene activity in immune cells from 10,000 people.

With our findings, we've gone from understanding very few to thousands of the potential causal mechanisms connecting genetic variation to disease risk, which is huge."

Professor Joseph Powell, Director of the Translational Genomics Program at Garvan, Director of the UNSW Institute for Genomics and Health and senior co-author on all three papers

"This is a fundamental shift in what's possible. When you know which genetic variant is driving a disease – and in which cell, through which mechanism – you can start to identify patients who are likely to respond to a particular treatment, and develop drugs toward targets we didn't know existed."

Professor Daniel MacArthur, co-senior author on two of the three papers and Director of the Centre for Population Genomics, a collaboration between the Garvan Institute and Murdoch Children's Research Institute, adds: "This is the most detailed map to date of how genetic variation shapes the immune system. We're already seeing the data being used to create new tools for understanding human biology and disease, which is incredibly exciting. This is the kind of foundational resource that researchers will be drawing on for years."

Analyzing gene expression in more than 5 million immune cells

Technological advancements over the past three decades have made it far easier to read a person's DNA. But pinpointing how these differences in gene sequences lead to disease requires vast amounts of data that have been difficult to generate and analyze at the single-cell level – until now.

"In the first phase of our TenK10K project, we've 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," says Professor Powell. "That let us trace tens of millions of genetic variants to the specific cell types they act in and link them to 16 diseases and 44 blood characteristics, to identify likely mechanisms that are driving that disease."

"Most of the biological mechanisms we uncovered were invisible to prior studies. This pinpoints the immune cell type involved, which could help target future treatments," said Professor Powell.

"For example, we found a genetic variant that increases the expression of a gene called OSM in natural killer immune cells and increases the risk of developing irritable bowel disease. This uncovered a specific immune pathway that could potentially be targeted with future treatments."

Decoding the genome from all angles

The three studies each examine a different layer of gene regulation, together building a fuller picture of how DNA variation affects gene expression and shapes immune cell function.

The first study 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. 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.

They compared these findings with genetic studies of 16 diseases, including cancers, immune conditions and neurological disorders. This revealed 893 genes linked to diseases or blood traits whose activity had not previously been linked to genetic variation. Many of these were found in specific cell types rather than across all blood cells, which may explain why earlier whole-blood studies missed them.

The second turns to a part of the genome that has been hard to study: tandem repeats. These are repetitive DNA sequences important for gene regulation that occupy more genetic 'real estate' than all protein-coding genes. They have historically been too difficult 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, revealing potential new targets for treating a range of disease.

The third maps a further layer of regulation: chromatin accessibility. This detects how open or tightly packed DNA is in a cell and controls which genes can be switched on or off. The team identified more than 240,000 genetic variants linked to chromatin accessibility. They then 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.

Resource for accelerating drug discovery

Summary results from all three studies are now freely available.

"We're excited to see how this resource can be leveraged by other scientists and organisations to guide new therapies and deliver better care for patients. And this is just the start. In the next phase, we'll be significantly expanding the number of people and disease areas analyzed in TenK10K and increasing the genetic diversity of participants so that our findings can be representative of more people around the world," says Professor Powell.