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

Area of Science:

• Neurogenetics
• Molecular Biology
• Alzheimer's Disease Research

Background:

• Alzheimer's disease (AD) is a leading cause of neurodegeneration with high heritability.
• Genome-wide association studies (GWASs) have linked the Cathepsin H (CTSH) gene to AD risk.
• The precise functional variants and regulatory mechanisms of CTSH in AD remain unclear.

Purpose of the Study:

• To comprehensively investigate the role of CTSH variants in Alzheimer's disease pathogenesis.
• To identify functional genetic variants within CTSH associated with AD.
• To elucidate the molecular mechanisms by which CTSH influences AD development.

Main Methods:

• Utilized genetic association studies in European and Han Chinese populations.
• Analyzed CTSH mRNA expression levels in AD patients and animal models.
• Investigated the impact of the protective allele on transcription factor binding and CTSH expression.
• Performed CRISPR-Cas9 mediated knockout of CTSH in human microglia cells.

Main Results:

• Identified rs2289702 in CTSH as a significant functional variant conferring protection against AD.
• Validated the association of rs2289702 with AD in independent cohorts.
• Observed significantly increased CTSH mRNA levels in AD patients and models.
• Demonstrated that the protective allele T of rs2289702 decreases CTSH expression by disrupting transcription factor binding.
• Showed that CTSH knockout in microglia enhances Aβ peptide phagocytosis.

Conclusions:

• CTSH is implicated in Alzheimer's disease genetic susceptibility.
• Discovered a genetic regulatory mechanism for CTSH in AD pathogenesis involving rs2289702.
• CTSH variants influence AD risk by modulating microglia's Aβ clearance function.