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Inflammatory Bowel Disease Genetic Risk Architecture Appears Distinct in African Americans

NEW YORK – The genetic architecture behind inflammatory bowel disease (IBD) appears to be distinct in African Americans compared to European Americans, according to a new study, despite some sharing of risk genes and alleles between the two groups.

"[S]ubtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk," co-senior and corresponding author Subra Kugathasan, a professor of pediatrics and human genetics at Emory University School of Medicine and a researcher at Children's Healthcare of Atlanta, and colleagues wrote.

As they reported in the American Journal of Human Genetics on Wednesday, investigators at Emory University, Rutgers University, the Georgia Institute of Technology, and elsewhere sequenced the genomes of nearly 1,800 African Americans with IBD and more than 1,600 unaffected controls with African ancestry from the US.

While the team's search did not unearth new loci with genome-wide significant ties to IBD, the genome sequence data and subsequent fine-mapping analyses suggested that several risk alleles occurred at different frequencies or had different effect sizes in the African American participants compared to individuals of European descent.

The results also underscored the importance of taking ancestry into account when designing polygenic risk scores for IBD, Kugathasan explained in an email, calling the study "an example of how to account for ancestry in polygenic analysis."

In addition to reporting that IBD PRS performance was affected by ancestry, he and his colleagues demonstrated that risk prediction could be improved with "weighted" PRSs that account for allele differences between populations.

"Our analyses … provide an example of how polygenic analysis needs to be adjusted for ancestry when considering ethnic disparities in healthcare," the authors reported, noting that "frequency distributions of PRSs can differ markedly across populations, mostly because of deviations in allele frequencies, although ascertainment biases in discovering common variant associations are also a concern."

With genome sequence data for 1,335 individuals with Crohn's disease, 407 ulcerative colitis cases, 32 individuals with inflammatory bowel disease-type unknown (IBDU), and 1,644 individuals with non-inflammatory bowel disease, the team tracked down more than 90 million common, low frequency, or rare variants.

The massive scale of the effort made it possible to rule out a role for rare variants alone in explaining the missing heritability previously described in IBD, Kugathasan noted, while helping to tease out distinct IBD-related allelic architecture in the African American individuals included in the study.

The team's subsequent fine-mapping analyses suggested the PTGER4 gene strongly contributed to Crohn's disease risk in the African American individuals, though the specific risk SNPs at that locus differed from those described in Crohn's disease risk in Europeans. In contrast, NOD2 and IL23R genes implicated in Crohn's disease in individuals of European descent did not show significant ties to the condition in the African American participants.

When they focused on rare variants, meanwhile, the researchers saw enrichment in the calcium-binding neuro-immunomodulator gene CALB2 in individuals with ulcerative colitis. That set included variants that appear to be specific to individuals with African ancestry, though the authors noted that "this finding needs to be interpreted with caution because of the lack of replication in an independent cohort or functional validation."

"Further research into the mechanisms responsible for ancestry-specific effects is warranted, including evaluation of the influences of linked rare variants, cumulative genetic background modifiers, and genotype-by-environment interactions," the authors concluded.

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