美国加州大学尔湾分校Wei Li等研究人员合作发现，多组学定量性状基因位点将串联重复序列大小变异与人类大脑基因调控联系起来。相关论文于2025年1月14日发表于国际顶尖学术期刊《自然—遗传学》杂志上。

研究人员基于来自1597名捐赠者的4412个多组学样本（其中1586个为新测序样本），量化了串联重复序列（TR）大小变异对大脑基因调控的影响，并跨越不同的分子表型。研究人员识别了约220万个TR分子定量性状基因位点（TR-xQTL），将约139000个独特的TR与邻近的分子表型联系起来，其中包括许多已知的疾病风险TR，如与肌萎缩侧索硬化症相关的C9orf72中的G2C4扩增。精细定位分析揭示了约18700个TR作为潜在的致病变异。

体外实验进一步确认了三种TR的致病和独立调控效应。额外的共定位分析表明，TR变异可能在与大脑相关的表型中起到致病作用，突出了NUDT14中的3?-UTR TR与大脑皮层面积的关联，以及PLEKHA1中的TG重复与阿尔茨海默病的关联。

据介绍，TR大小变异与约50种神经系统疾病有关，但其对人脑基因调控的影响在很大程度上仍然未知。

附：英文原文

Title: Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain

Author: Cui, Ya, Arnold, Frederick J., Li, Jason Sheng, Wu, Jie, Wang, Dan, Philippe, Julien, Colwin, Michael R., Michels, Sebastian, Chen, Chaorong, Sallam, Tamer, Thompson, Leslie M., La Spada, Albert R., Li, Wei

Issue&Volume: 2025-01-14

Abstract: Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease.

DOI: 10.1038/s41588-024-02057-2

Source: https://www.nature.com/articles/s41588-024-02057-2