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Functional genomics identify causal variant underlying the protective CTSH locus for Alzheimer’s disease

Neuropsychopharmacology (2023)Cite this article

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Abstract

Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disease, which has a high heritability of up to 79%. Exploring the genetic basis is essential for understanding the pathogenic mechanisms underlying AD development. Recent genome-wide association studies (GWASs) reported an AD-associated signal in the Cathepsin H (CTSH) gene in European populations. However, the exact functional/causal variant(s), and the genetic regulating mechanism of CTSH in AD remain to be determined. In this study, we carried out a comprehensive study to characterize the role of CTSH variants in the pathogenesis of AD. We identified rs2289702 in CTSH as the most significant functional variant that is associated with a protective effect against AD. The genetic association between rs2289702 and AD was validated in independent cohorts of the Han Chinese population. The CTSH mRNA expression level was significantly increased in AD patients and AD animal models, and the protective allele T of rs2289702 was associated with a decreased expression level of CTSH through the disruption of the binding affinity of transcription factors. Human microglia cells with CTSH knockout showed a significantly increased phagocytosis of Aβ peptides. Our study identified CTSH as being involved in AD genetic susceptibility and uncovered the genetic regulating mechanism of CTSH in pathogenesis of AD.

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Fig. 1: Functional genomics analysis identifies rs2289702 as a functional variant in the CTSH gene.
Fig. 2: SNP rs2289702 affects the binding affinity of transcription factors.
Fig. 3: Alterations of the CTSH mRNA level in the brain tissues of AD patients and AD mouse models.
Fig. 4: Knockout of the CTSH gene in human microglial cells alters gene expression pattern and increases phagocytosis of Aβ42.

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Acknowledgements

We thank Dr. Ian Logan for his helpful comments and language editing. We would like to thank the Institutional Center for Shared Technologies and Facilities of Kunming Institute of Zoology, Chinese Academy of Sciences for providing us with confocal microscopy image acquisition and flow cytometric analysis. We are grateful to Cong Li for his technical support.

Funding

This study was supported by the National Natural Science Foundation of China (32230021, 31970560, and 31730037), The STI2030-Major Projects (2021ZD0200900), Yunnan Province (202003AD150009, 2019FA027, and 202101AT070285), and Strategic Priority Research Program (B) of the Chinese Academy of Sciences (CAS) (XDB32020200), the International Partnership Program of Chinese Academy of Sciences (152453KYSB20170031), the Bureau of Frontier Sciences and Education, CAS (QYZDJ-SSW-SMC005) and the Youth Innovation Promotion Association of CAS (2020000017).

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  1. These authors contributed equally: Yu Li, Min Xu.

Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, Yunnan, China

    Yu Li, Min Xu, Bo-Lin Xiang, Xiao Li, Deng-Feng Zhang, Rui Bi & Yong-Gang Yao

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, Yunnan, China

    Yu Li, Min Xu, Bo-Lin Xiang, Xiao Li, Deng-Feng Zhang, Rui Bi & Yong-Gang Yao

  3. KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, 650204, Kunming, China

    Hui Zhao & Yong-Gang Yao

  4. Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

    Hui Zhao

  5. Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics, The Chinese University of Hong Kong, Hong Kong SAR, China

    Hui Zhao

  6. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Rui Bi & Yong-Gang Yao

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Contributions

YL, YGY, and RB conceived and designed the study. YL, YGY, and RB compiled the figures and wrote the manuscript with help and input from all authors. YL, RB, BLX, MX and XL performed experiments. MX, DFZ, and RB performed the data processing and analysis. HZ revised the draft. All authors revised the manuscript and approved the publication.

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Correspondence to Rui Bi or Yong-Gang Yao.

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Li, Y., Xu, M., Xiang, BL. et al. Functional genomics identify causal variant underlying the protective CTSH locus for Alzheimer’s disease. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01542-2

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