New gene variants linked to Crohn's disease identified

A large-scale genetic analysis has identified ten genes that increase a person's susceptibility to Crohn's disease, expanding scientist's understanding of this complex condition.

In the largest study of Crohn's disease to date, researchers from the Wellcome Sanger Institute, Cambridgeshire, and the Broad Institute of MIT and Harvard, Massachusetts, compared exome sequences from over 30,000 people with Crohn's disease and 80,000 people without the condition. The study found rare variants in genes important for a type of stem cell called mesenchymal cells, highlighting the causal role of these cells for intestinal inflammation. The authors say these findings have the potential to help generate new therapies against inflammatory bowel disease, such as Crohn's disease.

'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,' said Dr Mark Daly, from the Broad Institute, who co-led the study, which is published in Nature Genetics. 'This puts us on a dramatically faster track for converting those observations into a therapeutic hypothesis.'

Crohn's disease is a debilitating disease caused by inflammation of the bowel. It is believed to be triggered by a hyperactive immune response, although the precise causes of the disease are unknown. Both genetic and environmental factors are understood to contribute to disease onset. Currently there is no cure.

Previous research into Crohn's disease used genome-wide association studies (GWAS) to identify more than 200 regions of the genome that influence disease susceptibility. When those regions fell within protein-coding sequences, the genes identified gave valuable insight into genetic causes of the disease. Unfortunately, nonprotein-coding regions have a less clear causal association. GWAS is also partly limited to detecting regions that are commonly variable, leaving rare variants undetected.

In the latest study, researchers applied whole-exome sequencing to sequence all protein-coding regions of a participant's DNA. This has the advantage of finding more relevant protein-coding variation and of detecting rare variants, wrote the authors.

Six variants were identified within genes unknown to be involved in Crohn's disease and four variants confirmed specific genes within regions previously identified by GWAS.

'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,' said Dr Aleksejs Sazonovs, from the Wellcome Sanger Institute and joint first author of the study. 'While the involvement of mesenchymal cells is not completely surprising, it's another piece of the puzzle,' he added.

The researchers plan to expand their analysis by increasing the number of participants to find new genetic variants relevant for ulcerative colitis, another form of inflammatory bowel disease. They hope finding more genes can further support drug development.