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

IF 31.7 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2025-01-14 DOI:10.1038/s41588-024-02057-2

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

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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 ~2.2 million 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 3ʹ-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease. Mapping of multi-omic molecular quantitative trait loci associated with tandem repeat size variation in up to 4,412 human brain samples from 1,597 donors offers insights into how these variants affect gene regulation and mediate disease risk.

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多组学定量性状位点将串联重复大小变异与人脑基因调控联系起来

串联重复序列（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。在本研究中，我们基于来自1,597个供体的4,412个多组学样本，包括1,586个新测序的样本，量化了TR大小变化对不同分子表型的脑基因调控的影响。我们确定了约220万个TR分子数量性状位点（TR- xqtl），将约139,000个独特的TR与附近的分子表型联系起来，包括许多已知的疾病风险TR，例如与肌萎缩性侧索硬化症相关的C9orf72中的G2C4扩增。精细映射显示约18,700个tr是潜在的因果变异。我们的体外实验进一步证实了三种TRs的因果关系和独立的调节作用。另外的共定位分析表明，TR变异在脑相关表型中的潜在因果作用，突出表现为NUDT14中与皮质表面积相关的3′-UTR TR和与阿尔茨海默病相关的PLEKHA1中的TG重复。

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来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution