A team at the Garvan Institute of Medical Research, working with the Murdoch Children’s Research Institute, UNSW and other partners, has published three studies in Nature that tie genetic risk regions for 16 diseases to possible causes in specific immune cells. Together, the papers identify nearly 1,500 genes that may contribute to conditions including cancers and immune and neurological disorders.
The studies are the first major output of TenK10K, a project that aims to map genetic variation and gene activity in immune cells from 10,000 people. Reading a person’s DNA has become far easier over the past three decades. Working out how sequence differences lead to disease, however, requires large amounts of single-cell data, which have been difficult to generate and analyze 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 Joseph Powell, senior co-author on all three papers. “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.”
Each paper looks at a different layer of gene regulation. The first study examines how common and rare variants affect gene activity in individual immune cell types. Across 21,000 genes, the team found more than 180,000 effects on gene expression. Nearly 5,000 of the affected genes, about a quarter, had not been linked to a genetic effect on their activity in the largest previous whole-blood study. Comparing the results with genetic studies of 16 diseases revealed 893 genes tied to diseases or blood traits whose activity had not previously been connected to genetic variation. Many of these effects appeared only in specific cell types, which may be why whole-blood studies missed them.
The second study focuses on tandem repeats. These repetitive DNA sequences help regulate genes and take up more of the genome than all protein-coding genes, but they have long been too difficult to analyze accurately. Using new methods for analyzing whole-genome sequencing data, the researchers found more than 69,000 tandem repeat variants associated with changes in gene expression. They also found over 200 genes where repeats may help explain genetic links to immune and blood traits.
The third study maps chromatin accessibility, meaning 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 variants linked to chromatin accessibility and connected more than 28,000 of these regions to the genes they help regulate. Looking at chromatin accessibility explained the likely role of up to 23% more disease-linked genetic regions than looking at gene activity alone.
Powell gave one example of what the data can show. “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.”
“We’re excited to see how this resource can be leveraged by other scientists and organizations 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 Powell.
The studies are the first major output of TenK10K, a project that aims to map genetic variation and gene activity in immune cells from 10,000 people. Reading a person’s DNA has become far easier over the past three decades. Working out how sequence differences lead to disease, however, requires large amounts of single-cell data, which have been difficult to generate and analyze 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 Joseph Powell, senior co-author on all three papers. “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.”
Each paper looks at a different layer of gene regulation. The first study examines how common and rare variants affect gene activity in individual immune cell types. Across 21,000 genes, the team found more than 180,000 effects on gene expression. Nearly 5,000 of the affected genes, about a quarter, had not been linked to a genetic effect on their activity in the largest previous whole-blood study. Comparing the results with genetic studies of 16 diseases revealed 893 genes tied to diseases or blood traits whose activity had not previously been connected to genetic variation. Many of these effects appeared only in specific cell types, which may be why whole-blood studies missed them.
The second study focuses on tandem repeats. These repetitive DNA sequences help regulate genes and take up more of the genome than all protein-coding genes, but they have long been too difficult to analyze accurately. Using new methods for analyzing whole-genome sequencing data, the researchers found more than 69,000 tandem repeat variants associated with changes in gene expression. They also found over 200 genes where repeats may help explain genetic links to immune and blood traits.
The third study maps chromatin accessibility, meaning 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 variants linked to chromatin accessibility and connected more than 28,000 of these regions to the genes they help regulate. Looking at chromatin accessibility explained the likely role of up to 23% more disease-linked genetic regions than looking at gene activity alone.
Powell gave one example of what the data can show. “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.”
“We’re excited to see how this resource can be leveraged by other scientists and organizations 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 Powell.