The findings help illuminate key cells and biological pathways involved in the disease, which could help inform the development of future treatments.
Large sequencing effort links new genes to Crohn’s disease risk
An international consortium of researchers has identified 10 new genes that elevate or lower a person’s risk of Crohn’s disease, a form of inflammatory bowel disease. Six of those genes had no previous links to the disorder, and four are in regions of the genome that other studies had linked to Crohn’s disease.
Led by scientists at the Broad Institute of MIT and Harvard and the Wellcome Sanger Institute, the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) surveyed more than 100,000 participants from 12 countries. Their study, published in Nature Genetics, uses exome sequencing, which sequences protein-coding regions of the genome, to survey more than 30,000 patients with Crohn’s and 80,000 healthy participants. By identifying specific genes and genetic variants, the study points to key cells and biological pathways that contribute to Crohn’s disease susceptibility and may help researchers develop treatments that target those genes or pathways.
Mark Daly, a geneticist and institute member at the Broad, co-led the study along with Hailiang Huang, a Broad associate member and an assistant investigator at Massachusetts General Hospital, and Wellcome Sanger Institute group leader Carl Anderson. The team’s analysis is an ongoing effort that regularly releases findings to the research community.
“This consortium has been really collaborative, and that’s made all of this possible,” said Christine Stevens, a co-first author on the study. Stevens, associate director of the Medical and Population Genetics Program at Broad, has managed the IBD sequencing program for the past 10 years. “It’s been one of the most functional disease collaboratives, working together extremely effectively for two decades now,” she said.
An inflammation of the digestive tract, Crohn’s disease can cause uncomfortable to debilitating symptoms and can even lead to anemia, kidney stones, and potentially colorectal cancer. Genome-wide association studies (GWAS) have implicated common variants and regions of the genome, or loci, in Crohn’s, but most of the variants are in regions of the genome that do not encode proteins, which can make it difficult for scientists to study their function and generate strong therapeutic hypotheses.
To complement GWAS studies, researchers often use exome sequencing, which reveals rare variants that might not be detected by GWAS and pinpoints specific genes and genetic variants that increase or decrease a person’s risk of disease. “This is critical because in thinking about how to therapeutically attack a disease, almost all of the therapeutic strategies we have start with genes,” Daly said. “When we discover a genetic association that’s a protein-coding variant in a gene, we can start running experiments the next day to figure out what the variant is doing. That sets us on a dramatically faster track for converting those observations into a therapeutic hypothesis that can be tested in cell and animal models.”
Using this approach, Daly’s team identified six genes that had not been previously connected to Crohn’s disease. Several are linked to a type of stem cell in the gut called mesenchymal cells, suggesting that these cells play an active role in developing and maintaining inflammation there.
The team also identified four genes located near non-coding regions that were previously discovered by GWAS, providing additional evidence that these regions are a place to start studying the biological mechanisms of Crohn’s. One variant, in the TAGAP gene, decreases a person’s likelihood of developing the disease. Such variants, called “protective mutations,” are appealing to researchers in part because they suggest that a certain gene can be disabled without adverse side effects in people. Drugs that mimic the function of such mutations could potentially confer the same protection to patients.
As Daly and his team continue to collect data in the Crohn’s study, they are also working on a new sequencing effort that will include people of non-European ancestry, who have not been well represented in genetics research. “We are super enthusiastic to work towards this in the upcoming years both for scientific discovery and as an ethical imperative to bring equity and diversity to genetics,” he said.
Huang, for instance, is working with researchers in Japan, Korea, and China to study the genetics of inflammatory bowel diseases in East Asian populations. Huang said their work, after only a year, has already yielded new genetic insights. “Already, with only half as many participants as the European study, we discovered more than 10 novel coding variants enriched in East Asian populations. These mutations implicated new genomic regions associated with inflammatory bowel disease, directly pinpointed new genes in known regions, and deepened our understanding of the different mutation forms of genes and their impact on the disease,” Huang said. “This highlights the importance of including all ancestral populations in genetics research for both scientific and ethical reasons.”
Others are studying the biological function of the genes Daly’s team has already uncovered. Researchers led by Broad core institute member Ramnik Xavier, who is also director of the Klarman Cell Observatory at Broad, are working to understand the connection between Crohn’s and the genes identified by the study.
“Our groups work together in real time so that the functional studies overlap with our genetic studies all the time,” said Daly. “This really shows the importance of rapid data-sharing and having an effective interface between gene discovery activities and collaborators with expertise in molecular and mouse models. We’re really just laying a foundation for functional studies and ultimately in some cases, the clinical value that comes from discovering these mechanisms of disease.”
This work was supported in part by the National Human Genome Research Initiative at the National Institutes of Health, the Wellcome Trust, and the Leona M. & Harry B. Helmsley Charitable Trust.
Sazonovs A, Stevens CR, Venkataraman GR, Yuan K, et al. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility. Nature Genetics. Online August 29, 2022. DOI: 10.1038/s41588-022-01156-2.