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

Ya Cui^#¹, Frederick J Arnold^#², Jason Sheng Li³, Jie Wu⁴, Dan Wang⁵, Julien Philippe², Michael R Colwin², Sebastian Michels^{2

6}, Chaorong Chen³, Tamer Sallam⁵, Leslie M Thompson⁷, Albert R La Spada^{8

9}, Wei Li¹⁰

Affiliations

¹ Division of Computational Biomedicine, Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. yac7@uci.edu.
² Departments of Pathology & Laboratory Medicine, Neurology, Biological Chemistry, and Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
³ Division of Computational Biomedicine, Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
⁴ Departments of Psychiatry and Human Behavior, Neurobiology and Behavior, and Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
⁵ Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Neurology, University of Ulm, Oberer Eselsberg, Ulm, Germany.
⁷ Departments of Psychiatry and Human Behavior, Neurobiology and Behavior, and Biological Chemistry, University of California, Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
⁸ Departments of Pathology & Laboratory Medicine, Neurology, Biological Chemistry, and Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA. alaspada@uci.edu.
⁹ UCI Center for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA. alaspada@uci.edu.
¹⁰ Division of Computational Biomedicine, Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. wei.li@uci.edu.

^# Contributed equally.

PMID: 39809899
DOI: 10.1038/s41588-024-02057-2

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

Ya Cui et al. Nat Genet. 2025 Feb.

. 2025 Feb;57(2):369-378.

doi: 10.1038/s41588-024-02057-2. Epub 2025 Jan 14.

Authors

Affiliations

¹ Division of Computational Biomedicine, Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. yac7@uci.edu.
² Departments of Pathology & Laboratory Medicine, Neurology, Biological Chemistry, and Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
³ Division of Computational Biomedicine, Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
⁴ Departments of Psychiatry and Human Behavior, Neurobiology and Behavior, and Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
⁵ Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Neurology, University of Ulm, Oberer Eselsberg, Ulm, Germany.
⁷ Departments of Psychiatry and Human Behavior, Neurobiology and Behavior, and Biological Chemistry, University of California, Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
⁸ Departments of Pathology & Laboratory Medicine, Neurology, Biological Chemistry, and Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA. alaspada@uci.edu.
⁹ UCI Center for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA. alaspada@uci.edu.
¹⁰ Division of Computational Biomedicine, Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. wei.li@uci.edu.

^# Contributed equally.

PMID: 39809899
DOI: 10.1038/s41588-024-02057-2

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 3'-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer's disease.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. Hannan, A. J. Tandem repeats mediating genetic plasticity in health and disease. Nat. Rev. Genet. 19, 286–298 (2018). - PubMed - DOI
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Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain

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

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