Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries

Abstract

Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.Inflammatory bowel diseases (IBDs) are a group of chronic, debilitating disorders of the gastrointestinal tract with the peak onset in adolescence and early adulthood 1 . As of 2017, there were 6.8 million people diagnosed with IBD globally 2 , with increasing incidence and prevalence worldwide, especially in recently industrialized countries, likely due to the modernization and westernization of the populations 2,3 . IBDs have the following two etiologically related subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWAS) have discovered over 240 genetic loci associated with IBD 4 . However, to date, most IBD genetic associations have been derived using individuals of European (EUR) ancestries 4,5 , with only a few studies of much smaller sample sizes in non-EUR populations [6][7][8] . For example, the largest IBD GWAS in African 9 and Asian 7 populations included 2,345 and 3,195 cases, respectively, only about 10% of the number in the largest EUR IBD GWAS (29,336) 4 . Among the ImmunoChip samples, a cohort that was uniformly processed and drove several large-scale IBD genetics studies 6,10-12 , 87% of patients were of EUR ancestries, with the remaining 13% from Asian (7%), Indian (4%) and Iranian (2%) ancestries, respectively. This strong bias toward EUR severely limits our

Susceptibility gene profiling elucidates the pathogenesis of inflammatory bowel disease and provides precision medicine

“…They identified 16 new genetic loci just across EAS ancestries. Variance explained for these IBD EAS loci across EUR and EAS was mainly by higher minor allele frequencies (MAFs) in EAS instead of similar effect sizes (average MAF 0.25 versus 0.17, two‐sided paired t ‐test p = .015) (Figure 1), suggesting the importance of including global ancestries in genetic studies to ensure the relevance of the genetic findings 5 . Furthermore, Liu et al.…”

“…Recently in Nat Genet, Liu et al are the first to clarify the genetic architectures associated with human IBD using the largest samples from EAS ancestries including Chinese IBD patients. 5 They identified 16 new genetic loci just across EAS ancestries. Variance explained for these IBD EAS loci across EUR and EAS was mainly by higher minor allele frequencies (MAFs) in EAS instead of similar effect sizes (average MAF 0.25 versus 0.17, two-sided paired t-test p = .015) (Figure 1), suggesting the importance of including global ancestries in genetic studies to ensure the relevance of the genetic findings.…”

“…Variance explained for these IBD EAS loci across EUR and EAS was mainly by higher minor allele frequencies (MAFs) in EAS instead of similar effect sizes (average MAF 0.25 versus 0.17, two-sided paired t-test p = .015) (Figure 1), suggesting the importance of including global ancestries in genetic studies to ensure the relevance of the genetic findings. 5 Furthermore, Liu et al identified 81 new genetic loci associated with IBD across both EAS and EUR ancestries, thus increasing the number of IBD-associated genetic loci to 320 by comparing with 45 106 IBD cases and 353 562 healthy donors from East Asian countries (China, Korea and Japan), the International IBD Genetics Union (IIBDGC) and FinnGen. 5 Variance explained by IBD-associated loci differs across EAS ancestries and EUR ancestries, which is, to a greater degree, driven by MAFs but less by the effect sizes (32% of IBD associations have different MAFs, and 22% have different odds ratios).…”

“…Recently in Nat Genet , Liu et al. are the first to clarify the genetic architectures associated with human IBD using the largest samples from EAS ancestries including Chinese IBD patients 5 . They identified 16 new genetic loci just across EAS ancestries.…”

“…To some extent, the accuracy of predicting an individual's risk of CD or UC could be improved by jointly modeling EAS and EUR populations. Accordingly, the genetic diversity of the population plays a major role in GWAS for the equitable deployment of PRS in clinical settings 5 …”