美国马萨诸塞州总医院计算与综合生物学中心Ramnik J. Xavier小组的一项最新研究探明了群体规模的免疫多组图谱揭示了调节性疾病机制。2026年9月30日出版的《自然》发表了这项成果。

大多数疾病相关遗传变异位于非编码区，然而由于缺乏表征调控变异分子后果的实证框架，机制性见解受到限制。单细胞分子数量性状位点（QTL）定位将变异与基因调控联系起来，但缺乏追踪从染色质到表达机制的能力和同时测量。在此，研究人员表明，对免疫细胞中染色质可及性和基因表达的群体规模同时分析，揭示了将变异与疾病联系起来的调控架构。通过对1,108名芬兰个体中1000万例外周血单个核细胞进行配对的单核转座酶可及染色质测序（snATAC–seq）和单核RNA测序（snRNA-seq）分析，研究人员鉴定出20,829个基因的51,083个顺式表达QTL、210,584个峰的338,100个顺式染色质可及性QTL、119,094个推定因果变异和593,765个峰-基因连接。完成染色质到表达级联的变异，其疾病共定位是仅染色质效应的两倍，大规模平行报告基因检测验证了10,428个精细定位的分子QTL。在演化上受约束的基因中，研究人员鉴定出多层调控缓冲，其中染色质可及性变化以正常效应大小发生，但向表达的传递通过更弱、更多的增强子-基因连接而减弱。这解释了为什么疾病变异优先靶向受约束的基因，尽管表达QTL看似减少。使用大规模平行报告基因检测的分析证实，这种缓冲作用于调控元件下游，约束作用于染色质到表达的界面，而非内在的顺式调控活性。该图谱为超过一半的免疫疾病关联提供了可检验的假说，自身免疫位点（TICAM1和RHOH）和芬兰富集变异（TNRC18和IL21R）的级联即为示例。

附：英文原文

Title: Population-scale immune multiome atlas reveals regulatory disease mechanisms

Author: Kanai, Masahiro, Delorey, Toni M., Honkanen, Jarno, Rodosthenous, Rodosthenis S., Juvila, Julianna, Murphy, Shane, Teixeira-Soldano, Isabella, Hwang, Hee Seung, Karjalainen, Juha, Halonen, Jussi, Panagiotaropoulou, Georgia, Zhang, Yuanxiang, McCabe, Cristin, Chen, Eric, Nanki, Kosaku, Yoshida, Toshimi, Liu, Kai, Glean, Marla, Mehrotra, Nitya, Finan, Emily P., Chafamo, Daniel, Zhu, Yixiao, Arvas, Mikko, Ruotsalainen, Sanni, Zheng, Zhili, Tomofuji, Yoshihiko, Tokuyasu, Daiki, Namba, Shinichi, Sonehara, Kyuto, Okada, Yukinori, Reeve, Mary Pat, Kurki, Mitja, Porter, Caroline B. M., Ashenberg, Orr, Zhou, Wei, Pitknen, Kimmo, Partanen, Jukka, Palotie, Aarno, Graham, Daniel B., Daly, Mark J., Xavier, Ramnik J.

Issue&Volume: 2026-09-30

Abstract: Most disease-associated genetic variants lie in non-coding regions1,2, yet mechanistic insights are limited by the lack of an empirical framework for characterizing the molecular consequences of regulatory variation. Single-cell molecular quantitative trait locus (QTL) mapping3,4 connects variants to gene regulation but lacks the power and simultaneous measurements to trace mechanisms from chromatin to expression5. Here we show that population-scale simultaneous profiling of chromatin accessibility and gene expression across immune cells reveals regulatory architectures connecting variants to disease. From paired single-nucleus assay for transposase-accessible chromatin-sequencing (snATAC–seq) and single-nucleus RNA-sequencing (snRNA-seq) analysis of 10million peripheral blood mononuclear cells in 1,108 Finnish individuals6, we identify 51,083 cis-expression QTLs for 20,829 genes, 338,100 cis-chromatin accessibility QTLs for 210,584 peaks, 119,094 putative causal variants and 593,765 peak–gene links. Variants completing chromatin-to-expression cascades show twice the disease colocalization of chromatin-only effects, with massively parallel reporter assays7 validating 10,428 fine-mapped molecular QTLs. At evolutionarily constrained genes, we identify multilayered regulatory buffering, in which chromatin accessibility changes occur with normal effect sizes, but transmission to expression is attenuated through weaker, more numerous enhancer–gene links. This reconciles why disease variants preferentially target constrained genes despite apparent expression QTL depletion8,9,10,11. Analysis using a massively parallel reporter assay7 confirms that this buffering acts downstream of the regulatory element, with constraint operating at the chromatin-to-expression interface rather than on intrinsic cis-regulatory activity. Our atlas provides testable hypotheses for over half of immune disease associations, illustrated by cascades at autoimmune loci (TICAM1 and RHOH) and Finnish-enriched variants (TNRC18 and IL21R).

DOI: 10.1038/s41586-026-11078-2

Source: https://www.nature.com/articles/s41586-026-11078-2