An international research consortium, led by researchers of the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard, has identified 10 new genetic variants linked to an elevated risk of developing Crohn’s disease (CD).
The study, published today in Nature Genetics, is the largest of its kind to date and highlights the causal role of mesenchymal cells in intestinal inflammation, information that continues to home in on the genetic underpinnings of inflammatory bowel disease (IBD) while providing richer data from which pharmaceutical companies can develop new therapies.
“In thinking about how to develop new therapies, it’s critical that we can pinpoint the specific genetic variants that increase or decrease a person’s risk” said senior author Mark Daly a Professor of Genetics at Harvard Medical School, Chief of the Analytic and Translational Genetic Unit at Massachusetts General Hospital, and a member of the Broad Institute of MIT and Harvard. “When we discover a disease association to a genetic variant within a gene, we can start running experiments the next day to figure out what the variant, the gene, and the protein it encodes is doing to influence disease risk. This puts us on a dramatically faster track for converting those observations into a therapeutic hypothesis.”
Previous research of the disease via genome-wide association studies (GWAS) has identified 250 regions in the genome that influence CD susceptibility. But these studies have been somewhat restricted to testing sites in the genome that often vary from person to person.
For this latest study, the researchers conducted exome sequencing on roughly 30,000 patients with CD and compared them to the exome data from 80,000 people without the disease. The intent was to identify rare genetic variants within protein-coding genes are associated with an increased chance of developing CD. This comparison yielded six genes in regions of the genome that had not been linked to Crohn’s disease in the past. Further, these genes have been shown in previous research to play an important role in mesenchymal cells, potentially indicating that disruption of these cells contributes to intestinal inflammation.
“Most humans will have some of the genetic variants that increase susceptibility to inflammatory bowel disease because they’re so common,” noted first author Dr Aleksejs Sazonovs, research associate, genomics of inflammation and immunity at Wellcome Sanger Institute. “These common variants may increase a person’s risk by 10%, for example, but this increased risk doesn’t necessarily lead to disease. But some rare variants can make someone four or five times more likely to develop inflammatory bowel disease, so it’s especially important to locate these and understand the biological processes they disrupt.”
The other four genes linked to IBD in the study had previously been linked with the disease via GWAS. Unfortunately, the common genetic variants the GWAS associated with disease lie outside of protein coding genes, which has made it challenging to draw insights into disease biology. Now, by identifying the particular genes in these regions that are underpinning susceptibility to Crohn’s disease, researchers can understand the biological pathways in which these genes operate, making them prime targets for the development of new therapeutic approaches.
One of the rare variations identified is in the TAGAP gene, which has been shown to decrease the likelihood of developing the disease. Known as protective mutations, variants of this type are of particular interest to drug developers as they suggest it may be possible to disable a gene without causing adverse effects in people. “Drugs that mimic the mutation, such as by disabling the protein the gene encodes, could confer some of the same protection in patients,” the researchers noted.
Next steps in the research will be to expand the study’s approach to include another disease of intestinal inflammation, ulcerative colitis, and to increase the sampling in an effort to identify all genes and variants associated with IBD. These expanded studies will require recruiting a large number of patients.
“To have the statistical power to spot the rare variants that are driving disease, these studies require tens of thousands of individuals. We need international collaborative teams, such as the International IBD Genetics Consortium, to bring together sufficient DNA samples to make this possible,” added senior author Carl Anderson, a statistical geneticist at the Wellcome Sanger Institute. “We’ve already begun working on our next study, which will use exome sequence data from more than 650,000 individuals and give us unprecedented ability to derive insights into the aberrant biology underpinning inflammatory bowel disease.”