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Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease
Su WM, Gu XJ, Dou M, Duan QQ, Jiang Z, Yin KF, Cai WC, Cao B et al.. Journal of neurology, neurosurgery, and psychiatry, 2023-06-22
Topic: Amyloid, tau and blood-test diagnosis
Background Alzheimer's disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for AD and analyse their pathophysiological mechanisms and potential side effects. Methods A two-sample MR integrating the identified druggable genes was performed to estimate the causal effects of blood and brain druggable expression quantitative trait loci (eQTLs) on AD. A repeat study was conducted using different blood and brain eQTL data sources to validate the identified genes. Using AD markers with available genome-wide association studies data, we evaluated the causal relationship between established AD markers to explore possible mechanisms. Finally, the potential side effects of the druggable genes for AD treatment were assessed using a phenome-wide MR. Results Overall, 5883 unique druggable genes were aggregated; 33 unique potential druggable genes for AD were identified in at least one dataset (brain or blood), and 5 were validated in a different dataset. Among them, three prior druggable genes (epoxide hydrolase 2 ( EPHX2 ), SERPINB1 and SIGLEC11 ) reached significant levels in both blood and brain tissues. EPHX2 may mediate the pathogenesis of AD by affecting the entire hippocampal volume. Further phenome-wide MR analysis revealed no potential side effects of treatments targeting EPHX2 , SERPINB1 or SIGLEC11 . Conclusions This study provides genetic evidence supporting the potential therapeutic benefits of targeting the three druggable genes for AD treatment, which will be useful for prioritising AD drug development.
Key findings
- Results Overall, 5883 unique druggable genes were aggregated; 33 unique potential druggable genes for AD were identified in at least one dataset (brain or blood), and 5 were validated in a different dataset.
- Among them, three prior druggable genes (epoxide hydrolase 2 ( EPHX2 ), SERPINB1 and SIGLEC11 ) reached significant levels in both blood and brain tissues.
- Further phenome-wide MR analysis revealed no potential side effects of treatments targeting EPHX2 , SERPINB1 or SIGLEC11 .
Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded 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 and multi-centre collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of neurology, neurosurgery, and psychiatry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 3 / 5 | 2023 — within 6 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 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| 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 37349091) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
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APA 7th
Su, W. M., Gu, X. J., Dou, M., Duan, Q. Q., Jiang, Z., Yin, K. F., et al. (2023). Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease. Journal of neurology, neurosurgery, and psychiatry. https://doi.org/10.1136/jnnp-2023-331142
Vancouver
Su WM, Gu XJ, Dou M, Duan QQ, Jiang Z, Yin KF, et al. Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease. Journal of neurology, neurosurgery, and psychiatry. 2023. doi:10.1136/jnnp-2023-331142. PMID: 37349091.
BibTeX
@article{su2023-37349091,
author = {Su, W. M. and Gu, X. J. and Dou, M. and Duan, Q. Q. and Jiang, Z. and Yin, K. F. and Cai, W. C. and Cao, B. and others},
title = {{Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease}},
journal = {Journal of neurology, neurosurgery, and psychiatry},
year = {2023},
doi = {10.1136/jnnp-2023-331142},
pmid = {37349091},
url = {https://doi.org/10.1136/jnnp-2023-331142}
}
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