The Broad Institute and Massachusetts General Hospital are launching a new initiative to perform large-scale exome sequencing in inflammatory bowel disease (IBD), a diagnosis—including Crohn’s disease and ulcerative colitis—that faces considerable unmet therapeutic need.
The recent emergence of rapid, efficient genome-sequencing technologies and the compelling evidence for the role of genetics in these disorders have motivated the founding of a collaborative sequencing effort between the two institutions with ties to Harvard Medical School. The endeavor will be geared toward the discovery of high-impact genetic variants influencing IBD risk that can serve as guides to future therapeutic development and diagnostic tools.
The initiative will be directed by experienced IBD researchers from Mass General and the Broad Institute, but it also aims to develop an exome-sequencing network that will allow researchers to partner and collaborate worldwide. Two large pilot exome-sequencing projects are being launched immediately as part of this initiative based on established genetic study designs that heighten the discovery of rare, high-impact risk and protective variants. The exome is the small portion of the genome that translates DNA into proteins.
Early-onset pediatric IBD
A major focus of the work will surround full-exome sequencing of the earliest-onset childhood IBD cases. It has long been recognized in many diseases that penetrant genetic risk factors—mutations in people who have symptoms—are much more likely to be found in cases with unusually early onset. The Broad Institute has completed more than 50,000 exomes in the past two years. Its technical expertise in generating and processing such sequencing data, along with population-level genetic variation patterns from these experiments, will provide a foundation for obtaining the best outcomes in the interpretation of these cases. Samples with IBD onset before 6 years of age—and in some cases going up to age 10—collected by IBD researchers around the world are welcome for inclusion in this study.
Adult-onset IBD case-control study
Genetic mapping has provided dramatic insights into IBD pathogenesis in recent years, but a substantial amount of heritability—in particular the role of strong-acting rare mutations—is yet to be elucidated. To deliver those insights, IBD cases with an unusually low burden of known genetic risk factors (particularly emphasizing those with positive family history, or from isolated or enriched populations, or both) will be contrasted with population controls that have an extremely high burden of known IBD risk factors, enhancing discovery of critical protective variants that may provide the best clues for therapeutic development. This project will also be initiated as an international collaboration, particularly among researchers with sample sets with Immunochip genotyping that will enable the immediate genetic identification of these enriched target populations. Immunochip is a tool that samples 200,000 sites in the genome previously tied to autoimmune and inflammatory diseases.
The National Human Genome Research Institute Large-Scale Sequencing Program will support pilot work for this project in the next 12 months, with all generated data made publicly available to the research community through standard National Institutes of Health databases.
“Genetics offers a peek into the pathways that protect against—or predispose to—the development of IBD,” said Ramnik Xavier, HMS professor of medicine and chief of gastroenterology at Mass General and a senior associate member at the Broad Institute. “Contributing results to public resources will allow the data to be integrated by researchers from a variety of disciplines. In the current research environment, important advances in biology are often made by finding innovative ways to analyze ‘big data,’ and I believe this open-access exome-sequencing project will provide an example of how publicly available data can inspire significant progress in the field of IBD.”
“This project will enable IBD genetics to take further leaps forward toward a clear and therapeutically actionable understanding of the molecular causes of disease,” said Mark Daly, HMS associate professor of medicine and chief of the Analytic and Translational Genetics Unit at Mass General and a senior associate member at the Broad Institute. “It is extremely exciting to be able to launch this transformative initiative as an international collaboration with rapid and open data sharing.”
Researchers who are interested in collaborating on this initiative may contact Daly or Xavier for more information.
Adapted from a joint Mass General and Broad Institute news release.
