Genome-wide association study provides insights into the genetic basis of Lewy body dementia
Ping Zhu, Zhengxin Jin, Shiyang Wu, Shan Gao, Yijie He, Shuyuan Hu, Fengzhen Liu, Yan Chen et al.. Molecular psychiatry, 2025-10-09
Topic: Genetics and APOE
Lewy body dementia (LBD) is the second most prevalent dementia, however most genetic risk remains uncharacterized. Here, we performed the largest LBD genome-wide association study (GWAS) meta-analysis including 4252 LBD cases and 189,290 controls. We confirmed four previously known risk loci APOE, GBA, BIN1, and SNCA-AS1, and highlighted a novel locus SYT16. We further integrated LBD GWAS with multi-omics datasets, and identified 85 LBD risk genes that were enriched in eight functional clusters including 51 statistically significant pathways (e.g., SYT16 was enriched in the phospholipid binding pathway). Drug-gene interaction analysis highlighted the potential clinical utility of these LBD risk genes, especially APOE, GBA, BIN1, SNCA, SYT16, and INO80E. Differential gene expression analysis further highlighted the significant dysregulation of these genes in LBD brain tissues (e.g., hippocampus) and brain cells (e.g., excitatory neurons). Using gene prioritization, we identified 20 candidate causal genes including five novel risk genes, one within the risk locus SYT16 and four outside known risk loci (INO80E, DOC2A, ASPHD1, and RITA1). Tissue and cell-type specific enrichment analyses showed significant enrichment in brain tissues (e.g., dorsolateral prefrontal cortex) and brain cells (e.g., astrocytes). Mendelian randomization analysis provided evidence for the causal effects of LBD on reduction in brain structures (e.g., hippocampus) and cognitive performance. Finally, genetic correlation analysis showed that LBD was significantly positively associated with Alzheimer's disease and Parkinson's disease. In summary, our findings provide insights into the genetic basis of LBD and identify novel targets for the molecular mechanisms underlying LBD.
Key findings
- We further integrated LBD GWAS with multi-omics datasets, and identified 85 LBD risk genes that were enriched in eight functional clusters including 51 statistically significant pathways (e.g., SYT16 was enriched in the phospholipid binding pathway).
- Differential gene expression analysis further highlighted the significant dysregulation of these genes in LBD brain tissues (e.g., hippocampus) and brain cells (e.g., excitatory neurons).
- Tissue and cell-type specific enrichment analyses showed significant enrichment in brain tissues (e.g., dorsolateral prefrontal cortex) and brain cells (e.g., astrocytes).
- Finally, genetic correlation analysis showed that LBD was significantly positively associated with Alzheimer's disease and Parkinson's disease.
- In summary, our findings provide insights into the genetic basis of LBD and identify novel targets for the molecular mechanisms underlying LBD.
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 75/100
Published in a leading specialty journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 42 of the 56 points we could judge it on, which is 75 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular psychiatry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41068259) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 42 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 42 of the 56 points we could judge it on is 75 out of 100. |
| Total | 75 / 100 | — |
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APA 7th
Zhu, P., Jin, Z., Wu, S., Gao, S., He, Y., Hu, S., et al. (2025). Genome-wide association study provides insights into the genetic basis of Lewy body dementia. Molecular psychiatry. https://doi.org/10.1038/s41380-025-03295-4
Vancouver
Zhu P, Jin Z, Wu S, Gao S, He Y, Hu S, et al. Genome-wide association study provides insights into the genetic basis of Lewy body dementia. Molecular psychiatry. 2025. doi:10.1038/s41380-025-03295-4. PMID: 41068259.
BibTeX
@article{zhu2025-41068259,
author = {Zhu, Ping and Jin, Zhengxin and Wu, Shiyang and Gao, Shan and He, Yijie and Hu, Shuyuan and Liu, Fengzhen and Chen, Yan and others},
title = {{Genome-wide association study provides insights into the genetic basis of Lewy body dementia}},
journal = {Molecular psychiatry},
year = {2025},
doi = {10.1038/s41380-025-03295-4},
pmid = {41068259},
url = {https://doi.org/10.1038/s41380-025-03295-4}
}
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