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Revisiting tandem repeats in psychiatric disorders from perspectives of genetics, physiology, and brain evolution

Molecular Psychiatry volume 27, pages 466–475 (2022)Cite this article

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Abstract

Genome-wide association studies (GWASs) have revealed substantial genetic components comprised of single nucleotide polymorphisms (SNPs) in the heritable risk of psychiatric disorders. However, genetic risk factors not covered by GWAS also play pivotal roles in these illnesses. Tandem repeats, which are likely functional but frequently overlooked by GWAS, may account for an important proportion in the “missing heritability” of psychiatric disorders. Despite difficulties in characterizing and quantifying tandem repeats in the genome, studies have been carried out in an attempt to describe impact of tandem repeats on gene regulation and human phenotypes. In this review, we have introduced recent research progress regarding the genomic distribution and regulatory mechanisms of tandem repeats. We have also summarized the current knowledge of the genetic architecture and biological underpinnings of psychiatric disorders brought by studies of tandem repeats. These findings suggest that tandem repeats, in candidate psychiatric risk genes or in different levels of linkage disequilibrium (LD) with psychiatric GWAS SNPs and haplotypes, may modulate biological phenotypes related to psychiatric disorders (e.g., cognitive function and brain physiology) through regulating alternative splicing, promoter activity, enhancer activity and so on. In addition, many tandem repeats undergo tight natural selection in the human lineage, and likely exert crucial roles in human brain evolution. Taken together, the putative roles of tandem repeats in the pathogenesis of psychiatric disorders is strongly implicated, and using examples from previous literatures, we wish to call for further attention to tandem repeats in the post-GWAS era of psychiatric disorders.

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Fig. 1: Positions of tandem repeats in the genome and their functional effects.
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Acknowledgements

This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17), Yunnan Fundamental Research Projects (202101AW070020 to XX), National Natural Science Foundation of China (81971259 to ML, 31872778 to ZH), National Nature Science Foundation of China Key Project (81630030 and 81920108018 to TL), Special Foundation for Brain Research from Science and Technology Program of Guangdong (2018B030334001 to TL), Project for Hangzhou Medical Disciplines of Excellence and Key Project for Hangzhou Medical Disciplines (202004A11 to TL), the Western Light Innovative Research Team of Chinses Academy of Sciences, and the Innovative Research Team of Science and Technology department of Yunnan Province (2019HC004). Zhonghua Hu was also supported by Xiangya Hospital Start-up Research Grants, the innovative team program 2019RS1010 from Department of Science & Technology of Hunan Province, the innovation-driven team project 2020CX016 from Central South University, the Discipline Innovative Engineering Plan (111 Program) of China (B13036), a key laboratory grant from Hunan province (2016TP1006), and Hunan 100 Talents Program. We would like to apologize to those authors whose work were not cited or elaborately represented in this review due to space constraints.

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Author notes

  1. These authors contributed equally: Xiao Xiao, Chu-Yi Zhang.

Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Xiao Xiao, Chu-Yi Zhang & Ming Li

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China

    Chu-Yi Zhang

  3. Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhuohua Zhang & Zhonghua Hu

  4. Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China

    Zhuohua Zhang & Zhonghua Hu

  5. Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  6. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  7. Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  8. Eye Center of Xiangya Hospital and Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, Hunan, China

    Zhonghua Hu

  9. National Clinical Research Center on Mental Disorders, Changsha, Hunan, China

    Zhonghua Hu

  10. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Ming Li

  11. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Ming Li

  12. Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Tao Li

  13. Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China

    Tao Li

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  1. Xiao Xiao
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  2. Chu-Yi Zhang
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  3. Zhuohua Zhang
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  4. Zhonghua Hu
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Contributions

XX, CYZ, ZH, ML, and TL conceived and designed the study. ZZ, ML, and TL helped all aspects of manuscript written and results interpretation. XX, ML, CYZ, and ZH drafted the first version of the manuscript. All authors revised the manuscript critically and approved the final version.

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Correspondence to Zhonghua Hu, Ming Li or Tao Li.

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Xiao, X., Zhang, CY., Zhang, Z. et al. Revisiting tandem repeats in psychiatric disorders from perspectives of genetics, physiology, and brain evolution. Mol Psychiatry 27, 466–475 (2022). https://doi.org/10.1038/s41380-021-01329-1

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