Refined mapping finds over 200 Crohn’s Disease genes

By Joanna Lyford, Senior medwireNews Reporter

Researchers have used a genetic mapping technique to identify more than 200 genes associated with Crohn's Disease (CD), making it the most well-characterized disorder to date.

Senior author Nikolas Maniatis (University College London, UK) said in a press statement: "The discovery of so many gene locations for Crohn's Disease is an important step forward in understanding the disease, which has a very complicated genetic basis. We hope that the method we have used here can be used to identify the genes involved in other diseases which are similarly complex, for example different cancers and diabetes."

Prior to this study, 71 chromosomal intervals were known to be associated with CD, yet these explained less than one quarter of the heritability of the condition. To gain further insight, Maniatis and colleagues used a new mapping approach that localizes causal variants based on high-resolution maps in linkage disequilibrium units (LDU maps).

They applied the technique to datasets from two recently conducted genome-wide association studies: the Wellcome Trust Case Control Consortium (WTCCC), which includes 1698 patients with CD and 2948 controls; and the American National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which includes 813 patients with CD and 947 ethnically matched controls.

Importantly, both datasets include detailed phenotypic information on individual patients, including the location and severity of intestinal inflammation, allowing the researchers to subdivide patients by disease presentation.

Their analysis confirmed associations between CD and 66 of the 71 previously reported loci, as well as giving more precise location estimates for these intervals. Furthermore, the team identified 78 new gene regions that met criteria for genome-wide significance, providing strong evidence of association with CD for 144 genes.

Additionally, they identified 56 nominally significant signals "with more stringent and precise colocalization," write Maniatis et al in The American Journal of Human Genetics. "In total, we provide evidence for 200 gene regions, confirming that CD is truly multifactorial and complex in nature."

The researchers note that the majority of these signals map to single genes, and that many of the identified genes are known to be functionally involved in immune and inflammatory processes; interestingly, their effects extended to people with extra-ileal as well as ileal inflammation.

"The identified genes will facilitate more powerful experimental research designs including a range of functional studies and analytical pathway analyses for CD," the team concludes.

"Given the high-resolution estimates, the results presented here will allow more targeted, intelligently designed resequencing studies, where carefully characterized, homogeneous subgroups of cases can be more thoroughly investigated."

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