The role of admixture in the rare variant contribution to inflammatory bowel disease.
The role of admixture in the rare variant contribution to inflammatory bowel disease.
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DOI：
10.1186/s13073-023-01244-w
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发表时间：
2023-11-15
期刊：
影响因子：
12.3
通讯作者：
Gibson, Greg
中科院分区：
文献类型：
--
作者：
Astore, Courtney;Sharma, Shivam;Nagpal, Sini;Cutler, David J.;Rioux, John D.;Cho, Judy H.;Mcgovern, Dermot P. B.;Brant, Steven R.;Kugathasan, Subra;Jordan, I. King;Gibson, Greg
随着全外显子组/基因组测序关联研究的引入，涉及克罗恩病（CD）等复杂多基因疾病的罕见变异的鉴定加速了。罕见变异可用于诊断和治疗评估;然而，由于它们可能仅限于特定的祖先群体，因此需要在发现人群之外评估它们对风险评估的贡献。先前的研究表明，NOD 2中三种已知的罕见变异在西非和亚洲人群中不存在，仅通过混合物在非洲裔美国人中起作用。来自3418名非裔美国人，1774例炎症性肠病（IBD）病例和1644例对照的全基因组测序（WGS）数据用于评估比值比和等位基因频率（AF），以及在一项大型外显子组关联研究中发现的欧洲来源的CD变体的单倍型特异性祖先起源。进行了当地和全球血统分析，以评估混合物对IBD的贡献，对比欧洲和非洲裔美国人队列。欧洲发现队列中与CD相关的25种罕见变异在非裔美国人中的频率通常低5倍。相应地，在可以进行比较的情况下，与欧洲个体相比，发现罕见变异体在非洲裔美国人中IBD的预测负担降低了四倍。几乎所有罕见的CD欧洲变异体都是在非裔美国人队列的欧洲单倍型上发现的，这意味着它们主要由于最近的混合物而导致非裔美国人的疾病风险。此外，欧洲血统的比例与每个非裔美国人携带的罕见CD欧洲变体的数量以及他们的多基因疾病风险相关。在影响其他10种常见复杂疾病的23种突变中也观察到了类似的发现，这些罕见变异是在欧洲队列中发现的。欧洲来源的克罗恩病罕见变异在非洲裔美国人中更为罕见，主要由于混合物而导致疾病风险，在进行跨祖先遗传评估时需要考虑到这一点。在线版本包含补充材料，可通过10.1186/s13073-023-01244-w获得。
Identification of rare variants involved in complex, polygenic diseases like Crohn’s disease (CD) has accelerated with the introduction of whole exome/genome sequencing association studies. Rare variants can be used in both diagnostic and therapeutic assessments; however, since they are likely to be restricted to specific ancestry groups, their contributions to risk assessment need to be evaluated outside the discovery population. Prior studies implied that the three known rare variants in NOD2 are absent in West African and Asian populations and only contribute in African Americans via admixture. Whole genome sequencing (WGS) data from 3418 African American individuals, 1774 inflammatory bowel disease (IBD) cases, and 1644 controls were used to assess odds ratios and allele frequencies (AF), as well as haplotype-specific ancestral origins of European-derived CD variants discovered in a large exome-wide association study. Local and global ancestry was performed to assess the contribution of admixture to IBD contrasting European and African American cohorts. Twenty-five rare variants associated with CD in European discovery cohorts are typically five-fold lower frequency in African Americans. Correspondingly, where comparisons could be made, the rare variants were found to have a predicted four-fold reduced burden for IBD in African Americans, when compared to European individuals. Almost all of the rare CD European variants were found on European haplotypes in the African American cohort, implying that they contribute to disease risk in African Americans primarily due to recent admixture. In addition, proportion of European ancestry correlates the number of rare CD European variants each African American individual carry, as well as their polygenic risk of disease. Similar findings were observed for 23 mutations affecting 10 other common complex diseases for which the rare variants were discovered in European cohorts. European-derived Crohn’s disease rare variants are even more rare in African Americans and contribute to disease risk mainly due to admixture, which needs to be accounted for when performing cross-ancestry genetic assessments. The online version contains supplementary material available at 10.1186/s13073-023-01244-w.
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影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
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作者：
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通讯作者：
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8
作者：
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Hugot, Jean-Pierre