Bringing light to Crohn's disease
Image courtesy of Bang Wong, Broad Institute
The origins of Crohn’s disease — an inflammatory disorder that strikes the gut — have puzzled researchers and clinicians for decades. Though DNA is probably one of the most obvious culprits, few clear genetic risk factors have been found despite years of intensive effort. Now, through a systematic, genome-wide hunt described in the April 15 advance online edition of Nature Genetics, an international team of scientists reports five additional DNA regions that likely contribute to Crohn’s disease. Importantly, studies of the most strongly associated gene implicate a previously unsuspected molecular pathway, providing a key window on the disease’s biological underpinnings.
Bolstered by the recent availability of genome-scale tools for studying human genetic variation, the paper is among the first flock of so-called “genome-wide association studies” to be published. It involves scanning individuals’ entire genomes for single letter changes (“single nucleotide polymorphisms” or SNPs) to determine which changes lie within the DNA of Crohn’s patients but not in healthy patients. Such connections serve to illuminate discrete regions of the genome — and potentially genes — that may play a causative role in the disease.
“Our discovery of several new genetic risk factors for Crohn’s should improve understanding of the true causes of this disease and reveal new causal pathways that can be targeted therapeutically,” said co-senior author Mark Daly, an assistant professor in the Center for Human Genetic Research at Massachusetts General Hospital (MGH) and a Broad senior associate member. “The study takes advantage of new knowledge of genetic variation patterns and new technology for assessing genetic variation that have only been available recently.”
Laying the groundwork
The Nature Genetics paper stems from the work of the Inflammatory Bowel Disease Genetics Consortium (IBDGC), which includes Daly; first author John Rioux, an associate professor at the Montreal Heart Institute and the Université de Montréal and a visiting Broad scientist; and several other investigators throughout the United States and Canada. It builds upon more than a decade of research throughout the scientific community to uncover the genetic underpinnings of Crohn’s and other inflammatory bowel diseases. While there are two known genetic risk factors for Crohn’s disease — one of which was identified by Daly, Rioux and other colleagues at the Broad Institute (then part of the Whitehead Institute/MIT Center for Genome Research) in 2001 — these genetic differences explain a relatively small fraction of disease cases, suggesting that there are others yet to be found.
Recent advances in genomic research have accelerated the task of finding “disease” genes especially for complex diseases like Crohn’s, which involves not one gene but probably many genes, in addition to environmental influences. One of the most dramatic advances is the recently completed HapMap project, an international effort to catalog common patterns of human genetic variation by mapping SNPs in hundreds of individuals across the globe. In fact, the HapMap shares a history with Crohn’s disease research. It was through the study of Crohn’s disease genes several years ago that Daly, Rioux and their Broad colleagues gained early insight into the structure of human genetic variation, a finding that spurred the HapMap effort.
Scouring the genome
To begin their genome-wide search for genes involved in Crohn’s disease, Daly, Rioux and the other IBDGC scientists scanned the genomes of roughly 2,000 individuals — half of whom suffer from Crohn’s disease and half of whom do not. Analyses of more than 300,000 SNPs uncovered several discrete sections of the genome that appear to be associated with the disease, including known disease genes CARD15 and IL23R, the latter of which was reported late last year in Science by the IBDGC. To verify the new genetic associations, the researchers undertook two successive rounds of DNA analyses in independent groups of healthy and Crohn’s patients.
The work unearthed five regions of the human genome that are significantly associated with Crohn’s disease in both the initial and follow-up samples, and upon close examination, revealed that the strongest signal arises within a single gene. Interestingly, the DNA code of this gene, ATG16L1, is frequently altered in Crohn’s patients by just one SNP, a change that affects the corresponding protein. While the biological consequences of this change are not yet clear, another research team recently uncovered the same SNP in a genomic analysis of Crohn’s patients, lending further support for its genetic role.
ATG16L1 appeared even more intriguing because of its suspected biological function. It is one of a family of genes that are thought to drive autophagy, a process through which cells chew up their insides, often as a way of defending the body against microbes. This process could be important, particularly as the community of bacteria that normally reside in the gut have been strongly implicated in Crohn’s disease.
Functional studies carried out in collaboration with MGH’s Gastroenterology Unit/Center for the Study of Inflammatory Bowel Disease and its Center for Computational and Integrative Biology suggest that ATG16L1 activity is in fact required for autophagy. This work, led by co-author Ramnik Xavier, an assistant professor at Harvard Medical School and MGH, also indicates that the gene is highly active within epithelial cells and immune cells — two groups of cells that are considered critical to the development and progression of Crohn’s disease. Future studies of ATG16L1 will be required to fully dissect how it contributes to Crohn’s disease. Moreover, analyses of the other implicated regions, the strongest of which is a gene-free region on chromosome 10, may also reveal important clues to the disease’s origins.
The Nature Genetics study was led by co-senior authors and Steven Brant of Johns Hopkins University; Judy Cho of Yale University; and Mark Daly of the Center for Human Genetic Research at Massachusetts General Hospital, Harvard Medical School, and the Broad Institute. Other authors who contributed to the paper include Todd Green of the Broad Institute and Ramnik Xavier, Alan Huett and Petric Kuballa of the Gastrointestinal Unit and Center for Computational and Integrative Biology at Massachusetts General Hospital. The Inflammatory Bowel Disease Genetics Consortium (IBDGC) is funded by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health.
Rioux JD et al. (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genetics; DOI 10.1038/ng2032