加州大学Thomas S. Wingo课题组宣布他们开发出21种神经和精神疾病的多祖先脑pQTL精细定位和全基因组关联研究整合。这一研究成果于2025年9月8日发表在国际顶尖学术期刊《自然—遗传学》上。

为理解大脑蛋白表达的共享及祖先特异性遗传调控及其对疾病的影响，我们绘制了1362份来自非裔美国人、西班牙裔/拉丁美洲人和非西班牙裔白人多族裔人群脑蛋白组的蛋白数量性状基因座（pQTLs）图谱。通过多族裔精细定位MESuSiE技术确认为特定人群推定因果pQTLs的位点中，绝大多数在三个研究人群间存在共享（称为多族裔因果pQTLs），这些位点显著富集于外显子和启动子区域。

为探究其对疾病的影响，我们采用孟德尔随机化方法将858个多族裔因果pQTLs作为工具变量，结合神经精神和神经系统疾病的全基因组关联研究结果（欧洲血统参与者21个特征，非洲血统参与者10个特征，西班牙裔参与者4个特征）进行分析。最终发现119个多族裔pQTL-蛋白对与这些疾病的因果关联具有一致性。值得注意的是，这些基因对中29%的多族裔pQTLs为编码变异。该研究为建立适用于不同遗传背景个体的神经精神疾病新分子模型奠定了重要基础。

附：英文原文

Title: Multiancestry brain pQTL fine-mapping and integration with genome-wide association studies of 21 neurologic and psychiatric conditions

Author: Wingo, Aliza P., Liu, Yue, Vattathil, Selina M., Gerasimov, Ekaterina S., Mei, Zhen, Ravindran, Suda Parimala, Liu, Jiaqi, Shantaraman, Ananth, Seifar, Fatemeh, Wang, Erming, Zhang, Bin, Reddy, Joseph, Allen, Mariet, Ertekin-Taner, Nilfer, De Jager, Philip L., Fox, Edward J., Duong, Duc M., Epstein, Michael P., Cutler, David J., Levey, Allan I., Bennett, David A., Seyfried, Nicholas T., Wingo, Thomas S., Wingo, Aliza P., Liu, Yue, Vattathil, Selina M., Gerasimov, Ekaterina S., Mei, Zhen, Ravindran, Suda Parimala, Liu, Jiaqi, Shantaraman, Ananth, Seifar, Fatemeh, Wang, Erming, Zhang, Bin, Reddy, Joseph, Allen, Mariet, Ertekin-Taner, Nilfer, De Jager, Philip L., Fox, Edward J., Duong, Duc M., Epstein, Michael P., Cutler, David J., Levey, Allan I., Bennett, David A., Seyfried, Nicholas T., Wingo, Thomas S.

Issue&Volume: 2025-09-08

Abstract: To understand shared and ancestry-specific genetic control of brain protein expression and its ramifications for disease, we mapped protein quantitative trait loci (pQTLs) in 1,362 brain proteomes from African American, Hispanic/Latin American and non-Hispanic white donors. Among the pQTLs that multiancestry fine-mapping MESuSiE confidently assigned as putative causal pQTLs in a specific population, most were shared across the three studied populations and are referred to as multiancestry causal pQTLs. These multiancestry causal pQTLs were enriched for exonic and promoter regions. To investigate their effects on disease, we modeled the 858 multiancestry causal pQTLs as instrumental variables using Mendelian randomization and genome-wide association study results for neurologic and psychiatric conditions (21 traits in participants with European ancestry, 10 in those with African ancestry and 4 in Hispanic participants). We identified 119 multiancestry pQTL–protein pairs consistent with a causal role in these conditions. Remarkably, 29% of the multiancestry pQTLs in these pairs were coding variants. These results lay an important foundation for the creation of new molecular models of neurologic and psychiatric conditions that are likely to be relevant to individuals across different genetic ancestries.

DOI: 10.1038/s41588-025-02291-2

Source: https://www.nature.com/articles/s41588-025-02291-2