Crohn's disease (CD) is one of the two main forms of inflammatory bowel disease (the other being ulcerative colitis). It affects the gastrointestinal tract, and may cause pain, diarrhea, and vomiting, and can result in significant weight loss. The genetic associations of CD have remained elusive. In 2008, we pioneered an alternative strategy for examining the disorder by focusing on age-of-onset. To this end, we carried out a genome-wide association study of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated two previously unreported regions on chromosome 20 and chromosome 21 that predicted childhood IBD. These regions were located near the genes TNFRSF6B and PSMG1 respectively. The first of these genes is now thought to be intimately linked to the biology of IBD. This paper was published in Nature Genetics.
In a subsequent paper, we applied pathway analysis to focus on multiple regions in the genome that may interact to cause Crohn’s disease. We identified an association between CD and a network of 20 genes. The network contains many interleukins – proteins that are critical components of the immune system. Interestingly, many of the genes in the pathway did not correlate significantly with CD independently. However, when analyzed together, the network of genes did significantly associate with the disorder. This finding represents an important proof-of-principle as the first demonstration of the power of a pathway approach to understanding human genomics. Kai Wang was lead author on this paper, which was published in 2009 in the American Journal of Human Genetics.
In 2009, we also published a genome-wide association study of inflammatory bowel diseases (Crohn's disease and ulcerative colitis) in 3,426 affected individuals and 11,963 genetically matched controls. We identified five new regions associated with early-onset IBD, and detected associations at a number of loci previously implicated in adult-onset IBD. This provides an important demonstration of the close genetic relationship between early- and adult-onset IBD. The paper was published in Nature Genetics.