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Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
Cyril P. Pottier, Fahri Küçükali, Matt C. Baker, Anthony Batzler, Gregory D. Jenkins, Marka van Blitterswijk, Cristina T. Vicente, Wouter De Coster et al.. Nature Communications, 2025-04-25
Topic: Brain proteins, microglia and lab models
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications. Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.
Key findings
- We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor.
- In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes.
- Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder.
Why it matters
This genetic study of FTLD-TDP, a fatal neurodegenerative disorder distinct from Alzheimer's disease, confirmed UNC13A and identified TNIP1 as risk factors and found subtype-specific risk genes. These findings have potential diagnostic and therapeutic implications but do not yet provide a treatment or cure.
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Study details
- Study designmeta-analysis
- Participants985
- 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 effect reported because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature Communications) |
| Journal's citation record | 4 / 4 | Nature Communications: journal h-index 747 (OpenAlex, 2026-10-29) |
| 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 | 2 / 4 | 985 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| Times cited | 3 / 7 | Cited 25 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 8.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 14.1× 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 | 2 / 4 | Cited 25 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Edward B. Lee: h-index 79 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 52 institution(s) in 8 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40280976) |
| Free to read | 2 / 2 | Free to read |
| Total | 75 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41467-025-59216-0
- PubMed: 40280976
- Original source →
- Free full text: Nature Communications →
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
Pottier, C. P., Küçükali, F., Baker, M. C., Batzler, A., Jenkins, G. D., van Blitterswijk, M., et al. (2025). Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing. Nature Communications. https://doi.org/10.1038/s41467-025-59216-0
Vancouver
Pottier CP, Küçükali F, Baker MC, Batzler A, Jenkins GD, van Blitterswijk M, et al. Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing. Nature Communications. 2025. doi:10.1038/s41467-025-59216-0. PMID: 40280976.
BibTeX
@article{pottier2025-40280976,
author = {Pottier, Cyril P. and Küçükali, Fahri and Baker, Matt C. and Batzler, Anthony and Jenkins, Gregory D. and van Blitterswijk, Marka and Vicente, Cristina T. and De Coster, Wouter and others},
title = {{Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing}},
journal = {Nature Communications},
year = {2025},
doi = {10.1038/s41467-025-59216-0},
pmid = {40280976},
url = {https://doi.org/10.1038/s41467-025-59216-0}
}
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