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Identifying potential drug targets for cerebral amyloid angiopathy: A Mendelian randomization study based on the druggable genes
Jiuchang Zhang, Anmu Xie, Zhongrui Yan. Medicine, 2025-10-31
Topic: Amyloid, tau and blood-test diagnosis
Cerebral amyloid angiopathy (CAA), which is prevalent among older adults, constitutes a major cause of brain hemorrhage, dementia, and cognitive decline. Currently, no effective treatments for alleviating the disease of CAA exist. Hence, the discovery of novel drug targets for CAA is of utmost significance. Cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium and genome-wide association study of CAA from FinnGen database were used to screen for drug-usable genes causally associated with CAA. Robustness was assessed using colocalization analysis and heterogeneity in dependent instruments (HEIDI) tests. Significant findings were further validated using summary-data-based Mendelian randomization (SMR) with blood and arterial tissue eQTL data from eQTLGen and GTEx. Potential drugs targeting prioritized genes were screened using the DSigDB database, and binding interactions were evaluated via molecular docking. Mendelian randomization analysis identified 10 druggable genes significantly associated with CAA risk (false discovery rate 0.75) that dipeptidyl peptidase 9 (DPP9) and CAA share a causal genetic variant. DPP9 is a member of the dipeptidyl peptidase IV family and participates in cellular energy metabolism. SMR with HEIDI test confirmed the causal relationship between genetically predicted DPP9 expression and increased CAA risk in both blood (P_SMR 0.05) and arterial tissues (P_SMR 0.05). Drug screening identified sitagliptin and zoledronic acid as potential DPP9-targeting compounds. Molecular docking demonstrated a highly favorable binding interaction between sitagliptin and DPP9 (binding energy = -9.0 kcal/mol). This study provides genetic evidence identifying DPP9 as a potential drug target for CAA. The antidiabetic drug sitagliptin, predicted to bind DPP9 with high affinity, represents a promising candidate for therapeutic repurposing in CAA.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Zhang, J., Xie, A., & Yan, Z. (2025). Identifying potential drug targets for cerebral amyloid angiopathy: A Mendelian randomization study based on the druggable genes. Medicine. https://doi.org/10.1097/md.0000000000045643
Vancouver
Zhang J, Xie A, Yan Z. Identifying potential drug targets for cerebral amyloid angiopathy: A Mendelian randomization study based on the druggable genes. Medicine. 2025. doi:10.1097/md.0000000000045643. PMID: 41261637.
BibTeX
@article{zhang2025-41261637,
author = {Zhang, Jiuchang and Xie, Anmu and Yan, Zhongrui},
title = {{Identifying potential drug targets for cerebral amyloid angiopathy: A Mendelian randomization study based on the druggable genes}},
journal = {Medicine},
year = {2025},
doi = {10.1097/md.0000000000045643},
pmid = {41261637},
url = {https://doi.org/10.1097/md.0000000000045643}
}
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Key findings
- Cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium and genome-wide association study of CAA from FinnGen database were used to screen for drug-usable genes causally associated with CAA.
- Significant findings were further validated using summary-data-based Mendelian randomization (SMR) with blood and arterial tissue eQTL data from eQTLGen and GTEx.
- Mendelian randomization analysis identified 10 druggable genes significantly associated with CAA risk (false discovery rate 0.75) that dipeptidyl peptidase 9 (DPP9) and CAA share a causal genetic variant.
- Molecular docking demonstrated a highly favorable binding interaction between sitagliptin and DPP9 (binding energy = -9.0 kcal/mol).
Why it matters
Using Mendelian randomization on druggable genes, this study identified 10 genes significantly associated with cerebral amyloid angiopathy risk and found that DPP9 shares a causal genetic variant with CAA. It is a genetic drug-target discovery study and no treatment, cure or prevention is tested in patients.
Study details
- Evidence strengthLow
How this study scored 33/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 32 of the 96 points we could judge it on, which is 33 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Medicine) |
| Journal's citation record | 3 / 4 | Medicine: journal h-index 285 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 1 / 6 | Cited 0.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 0 / 3 | Affiliated Hospital of Qingdao University: institution h-index 237 (OpenAlex) |
| Multicenter collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41261637) |
| Free to read | 2 / 2 | Free to read |
| Points | 32 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 32 of the 96 points we could judge it on is 33 out of 100. |
| Total | 33 / 100 | — |
What each of these 20 components measures, and what this score is not →
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