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A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes
Xudong Han, Yichi Zhang, Jillian N Petrosky, Sarah Bald, Richard Sherva, Adam Thomas Labadorf, Jonathan D. Cherry, Jaeyoon Chung et al.. Cell Reports Medicine, 2025-04-15
Topic: Brain proteins, microglia and lab models
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. Genetic variation in the 17q21.31 region, containing microtubule-associated protein tau ( MAPT ), has been implicated in tauopathies but has not been investigated in CTE. The region includes a megabase-long inversion (H1/H2) and copy-number variations, including α, β, and γ segments, which can be characterized as nine segregating structural haplotypes. We leveraged array SNP data and a reference panel across the 17q21.31 region to impute structural haplotypes and test their association with CTE endophenotypes in 447 European ancestry brain donors with RHI exposure. The H1β1γ1 haplotype was significantly associated with dementia and semi-quantitative tau burden in multiple cortical and medial temporal regions commonly affected in CTE. H1β1γ1 differential expression analyses in dorsolateral frontal cortex implicated cis -acting genes and inflammatory pathways. Taken together, the H1β1γ1 haplotype may help explain CTE heterogeneity among those with similar RHI exposure. • 17q21.31 structural haplotypes include a 1 Mb inversion (H) and duplications (α, β, γ) • H1β1γ1 was associated with CTE neuropathological and clinical endophenotypes • Among football players, H1β1γ1 effect was similar to effect of playing 9.6 years • In DGE analysis, H1β1γ1 showed up-regulation of immune-related genes and pathways Han et al. identify H1β1γ1, a structural haplotype in the 17q21.31 region that contains MAPT , as a genetic risk factor for CTE neuropathological and clinical endophenotypes. H1β1γ1 DGE analyses in the dorsolateral frontal cortex implicate cis -acting genes and inflammatory pathways. H1β1γ1 may help explain CTE risk beyond repetitive head impact exposure.
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APA 7th
Han, X., Zhang, Y., Petrosky, J. N., Bald, S., Sherva, R., Labadorf, A. T., et al. (2025). A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes. Cell Reports Medicine. https://doi.org/10.1016/j.xcrm.2025.102084
Vancouver
Han X, Zhang Y, Petrosky JN, Bald S, Sherva R, Labadorf AT, et al. A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes. Cell Reports Medicine. 2025. doi:10.1016/j.xcrm.2025.102084. PMID: 40239644.
BibTeX
@article{han2025-40239644,
author = {Han, Xudong and Zhang, Yichi and Petrosky, Jillian N and Bald, Sarah and Sherva, Richard and Labadorf, Adam Thomas and Cherry, Jonathan D. and Chung, Jaeyoon and others},
title = {{A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes}},
journal = {Cell Reports Medicine},
year = {2025},
doi = {10.1016/j.xcrm.2025.102084},
pmid = {40239644},
url = {https://doi.org/10.1016/j.xcrm.2025.102084}
}
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Key findings
- Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure.
- The H1β1γ1 haplotype was significantly associated with dementia and semi-quantitative tau burden in multiple cortical and medial temporal regions commonly affected in CTE.
- Taken together, the H1β1γ1 haplotype may help explain CTE heterogeneity among those with similar RHI exposure. • 17q21.31 structural haplotypes include a 1 Mb inversion (H) and duplications (α, β, γ) • H1β1γ1 was associated with CTE neuropathological and clinical endophenotypes • Among football players, H1β1γ1 effect was similar to effect of playing 9.6 years • In DGE analysis, H1β1γ1 showed up-regulation of immune-related genes and pathways Han et al. identify H1β1γ1, a structural haplotype in the 17q21.31 region that contains MAPT , as a genetic risk factor for CTE neuropathological and clinical endophenotypes.
Why it matters
Among 447 brain donors with repetitive head impact exposure, a specific structural haplotype in the MAPT region was linked to dementia and greater tau burden in brain areas affected in CTE. This identifies a possible genetic factor behind why some people with similar head impact exposure develop CTE, but it does not provide a treatment or cure.
Study details
- Evidence strengthLow
How this study scored 41/100
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 (Cell Reports Medicine) |
| Journal's citation record | 1 / 4 | Cell Reports Medicine: journal h-index 104 (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 | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.5× 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 | 1 / 4 | Cited 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Jesse Mez: h-index 59 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40239644) |
| Free to read | 2 / 2 | Free to read |
| Total | 41 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/j.xcrm.2025.102084
- PubMed: 40239644
- Original source →
- Free full text: Cell Reports Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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