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Meta-Analysis Implicates 30 New Loci in Crohn's Disease

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Through a meta-analysis of published genome-wide association studies, researchers have identified dozens of new Crohn's disease-associated sites in the genome, bringing the number of loci linked to the condition up to 71.

The international team brought together data on tens of thousands of Crohn's cases and controls evaluated through several past GWAS. The research, which appeared online yesterday in Nature Genetics, turned up 30 Crohn's disease-associated loci not previously detected through individual GWAS or a smaller meta-analysis published in 2008.

"The current study has approximately doubled the number of confirmed Crohn's disease susceptibility loci," corresponding author Miles Parkes, a researcher with the Addenbrooke's Hospital Inflammatory Bowel Disease Research Group at the University of Cambridge, and co-authors wrote. "For many of these loci we have identified potentially causal genes, though confirmation of their role must await detailed fine mapping, expression, and functional studies."

Crohn's disease, a gastrointestinal problem in which the digestive system becomes inflamed, belongs to a larger set of conditions known as inflammatory bowel disease. Although environmental factors such as gut microbes contribute to the disease, the researchers explained, host genetic factors also play a part.

For instance, past studies have uncovered dozens of loci that appear to make certain individuals more susceptible to Crohn's disease. Nevertheless, the team added, genetic factors identified so far only explain a fraction of the condition's heritability.

For the current study, researchers involved in the International IBD Genetic Consortium compiled data from half a dozen GWAS in several countries involving 6,333 individuals with Crohn's disease and 15,056 unaffected control individuals.

Between directly genotyped SNPs and SNPs imputed using information from HapMap3, they were able to assess more than 950,000 autosomal SNPs, identifying more than 2,000 SNPs at 107 new or previously identified loci that appeared to be associated with Crohn's disease.

When they followed up on 51 of these signals in another 15,694 Crohn's cases, 14,026 controls, and 414 parent-child trios, the researchers found that 30 of the newly detected loci remained associated with the disease. Among them: loci linked to other complex diseases and conditions, including chronic inflammation disorders such as ankylosing spondylitis.

Together, the researchers noted, loci identified through this and other studies explain an estimated 23 percent of the Crohn's disease heritability.

The team then narrowed in on variants that appear most likely to cause functional changes based on data from the 1000 Genomes Project, HapMap3, an expression quantitative trait loci database, and the Broad Institute's Gene Relationships Across Implicated Loci resource.

In the process, they found numerous candidate genes that may contribute to Crohn's disease, including the DNA methyltransferase coding gene DNMT3, SMAD3, a gene coding for a protein involved in TGF-beta signaling, and immune genes such as IL10 and IL2RA.

The researchers emphasized that more research is needed to understand the roles that such candidate genes play in Crohn's disease, if any.

They also noted that there are likely more yet undetected Crohn's associated variants, though they argued that "larger GWAS alone will not explain all of the missing heritability in Crohn's disease." Instead, they say, a combination of more refined epidemiological data and additional genetic studies, including sequencing studies, may help to further narrow this gap.

"[D]etailed future analyses will play a key role in helping us to understand the absolute contribution of common causal alleles, as well as in identifying lower frequency variants and rare (even family-specific) mutations," the authors explained, noting that "extensive resequencing, and large-scale fine mapping exercises using custom array-based technologies, are already underway and will elucidate the pathogenic mechanisms of [inflammatory bowel disease]."

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