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Multi-Ancestry Transcriptome-Wide Association Studies of Cognitive Function, White Matter Hyperintensity, and Alzheimer’s Disease
Dima Chaar, Zheng Li, Lulu Shang, Scott M. Ratliff, Thomas H. Mosley, Sharon L. R. Kardia, Wei Zhao, Xiang Zhou et al.. International Journal of Molecular Sciences, 2025-03-09
Topic: Amyloid, tau and blood-test diagnosis
Genetic variants increase the risk of neurocognitive disorders in later life, including vascular dementia (VaD) and Alzheimer’s disease (AD), but the precise relationships between genetic risk factors and underlying disease etiologies are not well understood. Transcriptome-wide association studies (TWASs) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWASs on VaD and AD have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European ancestry (EA) and African ancestry (AA) samples to identify genes associated with general cognitive function, white matter hyperintensity (WMH), and AD. Regions were fine-mapped using Fine-mapping Of CaUsal gene Sets (FOCUS). We identified 266, 23, 69, and 2 genes associated with general cognitive function, WMH, AD (using EA GWAS summary statistics), and AD (using AA GWAS), respectively (Bonferroni-corrected alpha = p < 2.9 × 10−6), some of which had been previously identified. Enrichment analysis showed that many of the identified genes were in pathways related to innate immunity, vascular dysfunction, and neuroinflammation. Further, the downregulation of ICA1L was associated with a higher WMH and with AD, indicating its potential contribution to overlapping AD and VaD neuropathology. To our knowledge, our study is the first TWAS on cognitive function and neurocognitive disorders that used expression mapping studies for multiple ancestries. This work may expand the benefits of TWASs beyond a single ancestry group and help to identify gene targets for pharmaceuticals or preventative treatments for dementia.
Key findings
- Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European ancestry (EA) and African ancestry (AA) samples to identify genes associated with general cognitive function, white matter hyperintensity (WMH), and AD.
- We identified 266, 23, 69, and 2 genes associated with general cognitive function, WMH, AD (using EA GWAS summary statistics), and AD (using AA GWAS), respectively (Bonferroni-corrected alpha = p < 2.9 × 10−6), some of which had been previously identified.
- Enrichment analysis showed that many of the identified genes were in pathways related to innate immunity, vascular dysfunction, and neuroinflammation.
- Further, the downregulation of ICA1L was associated with a higher WMH and with AD, indicating its potential contribution to overlapping AD and VaD neuropathology.
Why it matters
This genetic study identified many genes associated with cognitive function, white matter hyperintensity, and Alzheimer's disease across European and African ancestry samples. It highlights biological pathways such as innate immunity and vascular dysfunction, but does not test any treatment or prevention.
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (International Journal of Molecular Sciences) |
| Journal's citation record | 3 / 4 | International Journal of Molecular Sciences: journal h-index 426 (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 | 2 / 7 | Cited 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Jennifer A. Smith: h-index 99 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Michigan: institution h-index 2,240 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40141087) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.3390/ijms26062443
- PubMed: 40141087
- Original source →
- Free full text: International Journal of Molecular Sciences →
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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Chaar, D., Li, Z., Shang, L., Ratliff, S. M., Mosley, T. H., Kardia, S. L. R., et al. (2025). Multi-Ancestry Transcriptome-Wide Association Studies of Cognitive Function, White Matter Hyperintensity, and Alzheimer’s Disease. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms26062443
Vancouver
Chaar D, Li Z, Shang L, Ratliff SM, Mosley TH, Kardia SLR, et al. Multi-Ancestry Transcriptome-Wide Association Studies of Cognitive Function, White Matter Hyperintensity, and Alzheimer’s Disease. International Journal of Molecular Sciences. 2025. doi:10.3390/ijms26062443. PMID: 40141087.
BibTeX
@article{chaar2025-40141087,
author = {Chaar, Dima and Li, Zheng and Shang, Lulu and Ratliff, Scott M. and Mosley, Thomas H. and Kardia, Sharon L. R. and Zhao, Wei and Zhou, Xiang and others},
title = {{Multi-Ancestry Transcriptome-Wide Association Studies of Cognitive Function, White Matter Hyperintensity, and Alzheimer’s Disease}},
journal = {International Journal of Molecular Sciences},
year = {2025},
doi = {10.3390/ijms26062443},
pmid = {40141087},
url = {https://doi.org/10.3390/ijms26062443}
}
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