改进的多祖先精细图谱识别出分子特征和疾病风险背后的顺式调控变异，这一成果由南加州大学Nicholas Mancuso研究小组经过不懈努力而取得。相关论文于2025年7月21日发表在《自然—遗传学》杂志上。

在这里，该研究组提出了共享单一效应和（SuShiE）模型，该模型利用连锁不平衡异质性来提高精细映射精度，推断跨祖先效应大小相关性并估计祖先特异性表达预测权重。通过大量的模拟，该研究团队发现SuShiE始终优于现有的方法。课题组将SuShiE应用于TOPMed-MESA和GENOA研究中来自不同祖先个体的36907种分子表型，包括mRNA表达和蛋白质水平。与现有方法相比，SuShiE精细定位顺式molQTLs的基因数量增加了18.2%，同时优先考虑更少的变异，并显示出更高的功能富集。

虽然SuShiE推断出祖先之间高度一致的顺式molQTL结构，但它发现了预测功能丧失不耐受基因异质性的证据。最后，研究人员利用sushi衍生的顺式molQTL效应大小，对All of Us生物库中的6个白细胞相关性状进行了转录组和蛋白质组范围的关联研究，与现有方法相比，鉴定出的基因增加了25.4%。总的来说，SuShiE为分子性状的顺式遗传结构提供了新的见解。

据了解，顺式分子数量性状位点（cis-molQTL）的多祖先统计精细定位旨在提高从标记变异中区分同源顺式分子数量性状位点的精度。

附：英文原文

Title: Improved multiancestry fine-mapping identifies cis-regulatory variants underlying molecular traits and disease risk

Author: Lu, Zeyun, Wang, Xinran, Carr, Matthew, Kim, Artem, Gazal, Steven, Mohammadi, Pejman, Wu, Lang, Pirruccello, James, Kachuri, Linda, Gusev, Alexander, Mancuso, Nicholas

Issue&Volume: 2025-07-21

Abstract: Multiancestry statistical fine-mapping of cis-molecular quantitative trait loci (cis-molQTL) aims to improve the precision of distinguishing causal cis-molQTLs from tagging variants. Here we present the sum of shared single effects (SuShiE) model, which leverages linkage disequilibrium heterogeneity to improve fine-mapping precision, infer cross-ancestry effect size correlations and estimate ancestry-specific expression prediction weights. Through extensive simulations, we find that SuShiE consistently outperforms existing methods. We apply SuShiE to 36,907 molecular phenotypes including mRNA expression and protein levels from individuals of diverse ancestries in the TOPMed-MESA and GENOA studies. SuShiE fine-maps cis-molQTLs for 18.2% more genes compared with existing methods while prioritizing fewer variants and exhibiting greater functional enrichment. While SuShiE infers highly consistent cis-molQTL architectures across ancestries, it finds evidence of heterogeneity at genes with predicted loss-of-function intolerance. Lastly, using SuShiE-derived cis-molQTL effect sizes, we perform transcriptome- and proteome-wide association studies on six white blood cell-related traits in the All of Us biobank and identify 25.4% more genes compared with existing methods. Overall, SuShiE provides new insights into the cis-genetic architecture of molecular traits.

DOI: 10.1038/s41588-025-02262-7

Source: https://www.nature.com/articles/s41588-025-02262-7