Cell-type-specific genetic associations in Lewy body dementia identified using single-cell eQTL-based Mendelian...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Lewy body dementia (LBD) is a neurodegenerative disease characterized by alpha-synuclein aggregation and cognitive/motor impairments.
• Genetic risk factors for LBD are known, but cellular mechanisms linking genetic variations to disease susceptibility are unclear.

Purpose of the Study:

• To investigate cell-type-specific genetic associations with Lewy body dementia risk.
• To identify potential molecular targets for LBD by integrating genetic data with cell-specific gene expression.

Main Methods:

• Single-cell transcriptome-wide Mendelian randomization was performed across eight major brain cell types.
• Bayesian colocalization analysis and replication in independent LBD cohorts were used to validate findings.
• Phenome-wide association analysis assessed cross-trait associations.

Main Results:

• ANKRD65 gene expression in excitatory neurons was significantly associated with reduced LBD risk (OR=0.65, p=0.00013).
• This association showed strong colocalization (PP=0.93) and consistent effect direction across APOE ε4 subgroups.
• No significant associations were found with non-neurological traits.

Conclusions:

• A genetically supported, cell-type-specific link between ANKRD65 expression in excitatory neurons and LBD risk was identified.
• This study underscores the utility of cell-resolved transcriptomic regulation and genetic inference for pinpointing therapeutic targets in neurodegenerative diseases.