Astrocyte-enriched and cilia-related genetic signatures in dementia: A whole-exome sequencing study.
- 1Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering Shanghai Jiao Tong University Shanghai China.
- 2School of Biomedical Sciences, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong China.
- 3Shanghai Key Laboratory of Mental Disorders Translational Research Shanghai China.
Abstract
Background
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.Aims
This study aims to use WES to identify potential candidate genes associated with dementia and AD in the Han Chinese population.Methods
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.Results
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.Conclusions
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.
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BibTeX
@article{deng2026astrocyteenriched,
title = {{Astrocyte-enriched and cilia-related genetic signatures in dementia: A whole-exome sequencing study.}},
author = {Miaohan Deng and Yucan Chen and Lu Zhao and Weichen Song and Qi Qiu and Lin Sun and Xiang Lin and Weidi Wang and Guan Ning Lin and Xia Li},
journal = {General psychiatry},
year = {2026},
month = oct,
doi = {10.1002/gps3.70062},
url = {https://europepmc.org/article/MED/42910247},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Astrocyte-enriched and cilia-related genetic signatures in dementia: A whole-exome sequencing study.
AU - Miaohan Deng
AU - Yucan Chen
AU - Lu Zhao
AU - Weichen Song
AU - Qi Qiu
AU - Lin Sun
AU - Xiang Lin
AU - Weidi Wang
AU - Guan Ning Lin
AU - Xia Li
PY - 2026
DA - 2026/10/21
JO - General psychiatry
DO - 10.1002/gps3.70062
UR - https://europepmc.org/article/MED/42910247
AB - Background 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.Aims This study aims to use WES to identify potential candidate genes associated with dementia and AD in the Han Chinese population.Methods 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.Results 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.Conclusions 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.
SN - 2517-729X
ER -