Bao Michelle M, Kars Meltem Ece, Zhang David, Gettler Kyle, Rader Daniel, Snapper Scott, Itan Yuval, Cho Judy H
Division of Pediatric Gastroenterology, Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
J Crohns Colitis. 2025 Jul 3;19(7). doi: 10.1093/ecco-jcc/jjaf098.
Monogenic forms of inflammatory bowel disease (IBD) are driven by variants in genes critical to pathways in intestinal homeostasis and immunity. We investigated gene- and variant-level effects of these genes with IBD and phenome-wide association, leveraging large-scale whole exome sequencing data across 4 diverse cohorts: BioMe Biobank (Regeneron and Sema4), Penn Med Biobank, and UK Biobank.
Predicted loss- and gain-of function variants were extracted from 102 monogenic genes. Gene- and variant-level association tests for binary traits were performed across 4 cohorts grouped based on genetic similarity in European, African, and Admixed American populations.
From 11 546 variants extracted, over two-thirds were predicted as loss-of-function (LOF), with 93% classified as ultra-rare and 1172 Goldilocks variants (not ultra-rare) enriched at least 10-fold in African populations. Gene-level IBD association testing demonstrated numerous replicated associations in European cohorts, reflecting well-powered independent cohorts. Twenty monogenic genes overlap with genome-wide IBD loci, fifteen of which displayed gene-level association trends. Heterozygous carriage of African-predominant LOF alleles in NPC1 (intracellular cholesterol transport) and ADA/ADA2 (purine metabolism), were associated with IBD. These variants also showed replicated associations with phenotypes related to cardiac conduction, infection, and lipid metabolism.
We define overlap between monogenic and genome-wide IBD loci and reveal population-specific allelic heterogeneity of IBD risk genes. We uncover novel phenotype associations suggesting pleiotropic effects of monogenic IBD genes. African-predominant variants revealed allelic associations absent in European cohorts, and of potential clinical significance, underscoring the importance of increasing diversity in genetic studies.
单基因形式的炎症性肠病（IBD）由对肠道内稳态和免疫途径至关重要的基因变异驱动。我们利用来自4个不同队列（BioMe生物银行（再生元和Sema4）、宾夕法尼亚大学医学部生物银行和英国生物银行）的大规模全外显子测序数据，研究了这些基因在基因和变异水平上对IBD的影响以及表型全基因组关联。
从102个单基因中提取预测的功能丧失和功能获得变异。对欧洲、非洲和混合裔美国人群中基于遗传相似性分组的4个队列进行了二元性状的基因和变异水平关联测试。
在提取的11546个变异中，超过三分之二被预测为功能丧失（LOF），其中93%被分类为超罕见变异，1172个“金发姑娘”变异（非超罕见）在非洲人群中富集至少10倍。基因水平的IBD关联测试在欧洲队列中显示了许多重复的关联，这反映了有充分统计学效力的独立队列。20个单基因与全基因组IBD位点重叠，其中15个显示出基因水平的关联趋势。NPC1（细胞内胆固醇转运）和ADA/ADA2（嘌呤代谢）中以非洲人群为主的LOF等位基因的杂合携带与IBD相关。这些变异还显示出与心脏传导、感染和脂质代谢相关表型的重复关联。
我们定义了单基因IBD位点与全基因组IBD位点之间的重叠，并揭示了IBD风险基因的人群特异性等位基因异质性。我们发现了新的表型关联，提示单基因IBD基因具有多效性。以非洲人群为主的变异揭示了欧洲队列中不存在的等位基因关联，且具有潜在的临床意义，强调了在基因研究中增加多样性的重要性。
