细胞类型解决的遗传变异影响炎症性肠病的风险
威康桑格研究所Carl A. Anderson小组宣布他们研究出细胞类型解决的遗传变异影响炎症性肠病的风险。相关论文于2026年6月3日发表于国际顶尖学术期刊《自然》杂志上。
在这里，课题组人员绘制了来自421人（包括125名炎症性肠病（IBD）患者）的220万个单细胞肠道活检和血液中的顺式表达数量性状位点（eQTLs）。细胞型水平的eQTLs更远于转录起始位点，富含增强子，不太可能调节最近的基因，并且与全基因组关联研究（GWASs）中检测到的IBD位点共定位的可能性比组织水平分辨率检测到的eQTLs高3.5倍以上。
该团队在超过一半的已知IBD基因座中发现了效应基因，包括髓细胞中的MAML2、PSEN2和ZMIZ1，暗示了肠道免疫功能障碍中Notch信号的减少。小组还在上皮干细胞和祖细胞中发现了Wnt调控基因，包括MYC，这表明受损的更新有助于屏障的破坏。他们的研究结果提供了一个将IBD的遗传风险与特定基因和细胞类型联系起来的机制图谱，以及一个解释复杂疾病中疾病相关组织的GWAS位点主题单细胞eQTL图谱的广义框架。
据介绍，与复杂疾病相关的大多数遗传变异位于非编码区，这使识别效应基因和相关细胞类型的工作复杂化。
附：英文原文
Title: Cell-type-resolved genetic variation shapes inflammatory bowel disease risk
Author: Alegbe, Tobi, Harris, Bradley T., Fachal, Laura, Ramirez-Navarro, Lucia, Tutert, Marcus, Krzak, Monika, Ghouraba, Mennatallah, Strickland, Michelle, Ozols, Matiss, Cohen, Celeste E., Khullar, Saniya, Khabirova, Eleonora, Panousis, Nikolaos I., Ochoa, David, Wana, Noor, Hu, May Xueqi, Skelton, Jason, Ostermayer, Jasmin, Cheam, Kimberly Ai Xian, Leland Taylor, D., Gu, Yong, Dawson, Claire, Thompson, Tina, Arestang, Kenneth, Nishad, Nilanga, Brezina, Biljana, Caballes, Charry Queen, Garri, Wendy, Leonard, Steven, Iyer, Vivek, Parkes, Miles, Wallace, Chris, McIntyre, Rebecca E., Martin, Cristina Cotobal, Jones, Gareth-Rhys, Raine, Tim, Anderson, Carl A.
Issue&Volume: 2026-06-03
Abstract: Most genetic variants associated with complex diseases lie in non-coding regions1, complicating efforts to identify effector genes and relevant cell types. Here we map cis-expression quantitative trait loci (eQTLs) across 2.2 million single cells using intestinal biopsies and blood from 421 individuals, including 125 with inflammatory bowel disease (IBD). Cell-type-level eQTLs were more distal to transcription start sites, enriched in enhancers, less likely to regulate the nearest gene, and more than 3.5-fold more likely to colocalize with IBD loci detected in genome-wide association studies (GWASs) than eQTLs detected at tissue-level resolution. We nominate effector genes at more than half of known IBD loci, including MAML2, PSEN2 and ZMIZ1 in myeloid cells, implicating reduced Notch signalling in intestinal immune dysfunction. We also identify Wnt-regulated genes, including MYC, in epithelial stem and progenitor cells, suggesting that impaired renewal contributes to barrier breakdown. Our results provide a mechanistic map that links genetic risk to specific genes and cell types in IBD, and a generalized framework for interpretation of GWAS loci using single-cell eQTL mapping of disease-relevant tissues in complex diseases.
DOI: 10.1038/s41586-026-10627-z
Source: https://www.nature.com/articles/s41586-026-10627-z
期刊信息
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
投稿链接：http://www.nature.com/authors/submit_manuscript.html
