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Cited by 20Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

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

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Li, Yu, Xu, Min, Xiang, Bo-Lin, Li, Xiao, Zhang, Deng-Feng, Zhao, Hui, Bi, Rui, Yao, Yong-Gang·2023·Neuropsychopharmacology
DOI 10.1038/s41386-023-01542-2PMC PMC10516988
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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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Cited by

Sorted by citations

Authors
Li, Y., Xu, M., Xiang, B.-L., Li, X., Zhang, D.-F., Zhao, H., Bi, R., & Yao, Y.-G.
Affiliations
  • Kunming Institute of Zoology (CN)
  • Chinese University of Hong Kong (HK)
Corresponding author
  • Bi, Rui
  • Yao, Yong-Gang
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2023-02-04
Volume
48
Issue
11
Pages
1555-1566
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-023-01542-2
PMC
PMC10516988
OpenAlex
W4319228134
Cited by
20
References
9
Citations by year
2026: 5 · 2025: 6 · 2024: 8 · 2023: 1
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (31730037, 31970560)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, cathepsin H, protective genetic variants, causal variants, transcription factor binding, gene expression, microglia, amyloid-beta phagocytosis, genetic susceptibility, Han Chinese
MeSH terms
Alzheimer Disease, Animals, Humans, Neurodegenerative Diseases, Genetic Predisposition to Disease, Genomics, Genome-Wide Association Study, Cathepsin H

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