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Inflammatory Bowel Disease Genetics Understanding Expands With East Asian Analyses

NEW YORK – Researchers have uncovered new genetic contributors to inflammatory bowel diseases (IBD) such as Crohn's disease or ulcerative colitis based on a meta-analysis of genetic data from individuals of East Asian and European ancestry. Based on the results, they also put together a cross-ancestry polygenic risk score for IBD that outperformed prior versions.

"For the first time, our IBD genetics research included a large number of individuals of Asian ancestries, leading to the discovery of many new genes connected to IBD risk through genetic variations that are common in Asian populations and alter protein coding," co-senior and co-corresponding author Hailiang Huang, a researcher affiliated with Harvard Medical School, Massachusetts General Hospital, and the Broad Institute, said in an email.

"These insights shed light on previously unknown IBD pathogenesis pathways that were missed in studies focused on people of European ancestries," he explained.

As they reported in Nature Genetics on Monday, Huang and his colleagues initially performed an IBD genome-wide association study on 14,393 IBD cases and nearly 15,500 controls of East Asian ancestry, identifying 80 IBD-linked loci in that population. From there, they brought in data for some 370,000 more IBD cases and controls of European ancestry from the International IBD Genetics Consortium and FinnGen for a meta-analysis that led to 320 new or known IBD risk loci.

Along with sites associated with IBD in the past, the collection spanned some 320 new and known IBD-related loci, including risk variants falling in or around genes with ancestry-specific or cross-ancestry ties to Crohn's disease or ulcerative colitis.

"Although IBD genetic effects are generally consistent across ancestries, genetics underlying [Crohn's disease] appears more ancestry dependent than [ulcerative colitis]," the authors reported. They also noted that minor allele frequency (MAF) patterns in the East Asian or European ancestry groups "contributes, to a greater extent than genetic effects, to the heterogeneity in IBD genetic loci."

Tapping into the new and known IBD genetic risk loci, the team was also able to bolster the performance of a predictive model aimed at identifying individuals with high or low risk of developing IBD, making it more accurate in Asian individuals.

"This new model will promote equitable application of genetic risk information, particularly for those of Asian ancestries," Huang said.

A PRS model trained with summary statistics for non-Finnish Europeans could explain roughly 3.3 percent of Crohn's disease risk, 3 percent of the risk of ulcerative colitis, and 3.5 percent of overall IBD risk in individuals of Chinese ancestry, for example. On the other hand, the PRS trained on data from the East Asian GWAS was able to explain 6.4 percent, 3.2 percent, and 4.7 percent of Crohn's disease, ulcerative colitis, and IBD risk, respectively, in Chinese participants.

The performance improved further when the researchers relied on training data from both East Asian and European individuals. In particular, Chinese individuals in the highest PRS risk group appeared to be at 11.8 times higher risk of Crohn's disease compared to individuals in the low-risk group, on average, while average ulcerative colitis risk was more than sevenfold higher in the high PRS group and average IBD risk exceeded fivefold, on average.

The current IBD findings underscore the importance of including individuals from a range of populations and ancestry backgrounds in genetic studies, the authors noted.

"New findings and resources from this study represent an advance in diversifying IBD genetics across global ancestries and highlight the need for future efforts in increasing the sample size, diversity, genome coverage, and clinical phenotyping in genetic studies of IBD and other human complex disorders," they wrote.