Genetic Colocalization of Expression Quantitative Trait Loci (eQTL) Mapping and GWAS in a multiethnic brain bank: An Insight into ancestry‐specific Regulatory Architecture in Alzheimer's disease
Vivek Ruhela, Basilio Cieza, Richard P Mayeux, Dolly Reyes‐Dumeyer, Andrew F. Teich, Giuseppe Tosto. Alzheimer s & Dementia, 2025-12-01
Topic: Brain proteins, microglia and lab models
In the colocalization of cis-eQTL and GWAS signals for Hispanics, we observed a high posterior probability (posterior prob = 0.9947) for the upstream gene variant rs755980338 on chromosome 11, which locally regulates EHD1 gene (GWAS p-value = 0.009, cis-eQTL p-value = 0.0041). Similarly, in trans-eQTL analysis of NHW brains, we identified strong colocalization for the upstream gene variant rs7840855 on chromosome 8 (posterior prob = 0.7, GWAS p-value = 3.4e-06), regulating both TMEM68 (trans-eQTL p-value = 5.36e-06) and DEFA10P (trans-eQTL p-value = 9.52e-06). This study highlights the importance of population-stratified eQTL and colocalization analysis in identifying genetic regulatory mechanisms underlying complex diseases such as AD. The high colocalization probabilities indicate shared causal variants, supporting the functional relevance of these genes in AD risk. Our findings suggest that EHD1, TMEM68, and DEFA10P may play an ancestry-specific role in AD. For example, EHD1 gene is involved in neuronal BACE1 transcytosis which is highly relevant for AD. Similarly, TMEM68 was colocalized with chromosome 8 in brain prefrontal cortex and hypothalamus in GTEx panel. These insights contribute to a better understanding of AD genetic architecture, with potential implications for precision medicine approaches across populations. Results can be visualized via our newly-developed BRAINscape (Figure 1) an interactive Shiny-based interface for seamless data visualization to facilitate the integrative analysis of multi-omics data.
Key findings
- In the colocalization of cis-eQTL and GWAS signals for Hispanics, we observed a high posterior probability (posterior prob = 0.9947) for the upstream gene variant rs755980338 on chromosome 11, which locally regulates EHD1 gene (GWAS p-value = 0.009, cis-eQTL p-value = 0.0041).
- Similarly, in trans-eQTL analysis of NHW brains, we identified strong colocalization for the upstream gene variant rs7840855 on chromosome 8 (posterior prob = 0.7, GWAS p-value = 3.4e-06), regulating both TMEM68 (trans-eQTL p-value = 5.36e-06) and DEFA10P (trans-eQTL p-value = 9.52e-06).
- This study highlights the importance of population-stratified eQTL and colocalization analysis in identifying genetic regulatory mechanisms underlying complex diseases such as AD.
- The high colocalization probabilities indicate shared causal variants, supporting the functional relevance of these genes in AD risk.
- Our findings suggest that EHD1, TMEM68, and DEFA10P may play an ancestry-specific role in AD.
Why it matters
This genetic study found ancestry-specific colocalization signals linking variants regulating EHD1, TMEM68, and DEFA10P to Alzheimer's disease risk in Hispanic and non-Hispanic white brain samples. It suggests these genes may play an ancestry-specific role in Alzheimer's disease, with potential implications for precision medicine, but no treatment is tested.
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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 randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer s & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 0 / 6 | Cited 0.0× 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 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Giuseppe Tosto: h-index 32 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Columbia University: institution h-index 1,824 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41447294) |
| Free to read | 2 / 2 | Free to read |
| Total | 33 / 100 | — |
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Read the original
- DOI: 10.1002/alz70855_107199
- PubMed: 41447294
- Original source →
- Free full text: Alzheimer s & Dementia →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Ruhela, V., Cieza, B., Mayeux, R. P., Reyes‐Dumeyer, D., Teich, A. F., & Tosto, G. (2025). Genetic Colocalization of Expression Quantitative Trait Loci (eQTL) Mapping and GWAS in a multiethnic brain bank: An Insight into ancestry‐specific Regulatory Architecture in Alzheimer's disease. Alzheimer s & Dementia. https://doi.org/10.1002/alz70855_107199
Vancouver
Ruhela V, Cieza B, Mayeux RP, Reyes‐Dumeyer D, Teich AF, Tosto G. Genetic Colocalization of Expression Quantitative Trait Loci (eQTL) Mapping and GWAS in a multiethnic brain bank: An Insight into ancestry‐specific Regulatory Architecture in Alzheimer's disease. Alzheimer s & Dementia. 2025. doi:10.1002/alz70855_107199. PMID: 41447294.
BibTeX
@article{ruhela2025-41447294,
author = {Ruhela, Vivek and Cieza, Basilio and Mayeux, Richard P and Reyes‐Dumeyer, Dolly and Teich, Andrew F. and Tosto, Giuseppe},
title = {{Genetic Colocalization of Expression Quantitative Trait Loci (eQTL) Mapping and GWAS in a multiethnic brain bank: An Insight into ancestry‐specific Regulatory Architecture in Alzheimer's disease}},
journal = {Alzheimer s \& Dementia},
year = {2025},
doi = {10.1002/alz70855_107199},
pmid = {41447294},
url = {https://doi.org/10.1002/alz70855_107199}
}
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