Astrocyte-enriched and cilia-related genetic signatures in dementia: A whole-exome sequencing study

Alzheimer's disease (AD), the most prevalent form of dementia, is highly heritable, yet much of its genetic basis remains unexplained. Most genetic studies have focused on European populations, with limited data from under-represented groups. Whole-exome sequencing (WES) in the Han Chinese population may help identify novel rare variants and population-specific genetic risk factors.

This study aims to use WES to identify potential candidate genes associated with dementia and AD in the Han Chinese population.

In this exploratory pilot study, we performed WES in 63 Han Chinese patients with dementia, including 43 with AD and 20 with non-AD dementia (including one with dementia with Lewy bodies, one with Parkinson's dementia, four with frontotemporal dementia and 14 with mixed dementia), to identify rare coding variants. Gene-based case-control burden analyses using public gnomAD controls were conducted in the overall dementia cohort and the AD subgroup. Protein-protein interaction, functional enrichment, weighted gene coexpression network analysis (WGCNA) and gene set variation analysis (GSVA) using single-nucleus RNA sequencing (snRNA-seq) datasets were performed to evaluate biological relevance and cell-type-specific activity. Cell-type marker enrichment analysis was used to identify relevant neuronal subtypes. Multilevel evidence was integrated to prioritise candidate risk genes.

We identified suggestive rare variant signals in genes involved in cilia-related pathways, with stronger signals in the AD subgroup. These candidate genes were enriched in WGCNA modules associated with ageing, microtubule organisation and dementia pathology. GSVA showed increased activity of candidate genes in astrocytes using the snRNA-seq dataset. Cell-type marker analysis revealed strong enrichment in Ex6 excitatory neurons. Finally, integration of multilevel evidence prioritised 10 candidate genes.

This pilot study provides preliminary evidence that cilia-related pathways may be involved in dementia, especially AD susceptibility in the Han Chinese population. Further validation in larger independent cohorts with ancestry-matched controls and in functional experiments is required. Larger sample sizes for each dementia subtype will improve the detection of both dementia-shared and subtype-specific signals.