A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes
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.
Authors
- Douglas I. Katz (ORCID: https://orcid.org/0000-0002-7502-8505)
- Joseph Palmisano (ORCID: https://orcid.org/0000-0001-6000-3025)
- Robert C. Cantu (ORCID: https://orcid.org/0009-0002-4300-4063)
- Kurt Farrell (ORCID: https://orcid.org/0000-0001-6955-7278)
- Bertrand R. Huber (ORCID: https://orcid.org/0000-0002-5856-3477)
- Thor D. Stein (ORCID: https://orcid.org/0000-0001-6954-4477)
- Gyungah Jun (ORCID: https://orcid.org/0000-0002-3230-8697)
- Ann Carolyn McKee (ORCID: https://orcid.org/0000-0003-2961-7488)
- Adam Labadorf (ORCID: https://orcid.org/0000-0002-0753-8992)
- Jaeyoon Chung (ORCID: https://orcid.org/0000-0002-6431-9454)
- Lindsay A. Farrer (ORCID: https://orcid.org/0000-0001-5533-4225)
- Lee E. Goldstein (ORCID: https://orcid.org/0000-0001-8419-9800)
- Eric M. Reiman (ORCID: https://orcid.org/0000-0002-0705-3696)
- Bobak Abdolmohammadi
- Xudong Han (ORCID: https://orcid.org/0000-0001-7961-5179)
- Michael L. Alosco (ORCID: https://orcid.org/0000-0002-8113-8428)
- John F. Crary (ORCID: https://orcid.org/0000-0002-0556-293X)
- Daniel H. Daneshvar (ORCID: https://orcid.org/0000-0003-3691-9513)
- Robert A. Stern (ORCID: https://orcid.org/0000-0002-5008-077X)
- Brigid Dwyer (ORCID: https://orcid.org/0000-0002-6446-8054)
- Shruti Durape
- Richard Sherva (ORCID: https://orcid.org/0000-0003-2133-1493)
- Martha E. Shenton (ORCID: https://orcid.org/0000-0003-4235-7879)
- Kathryn L. Lunetta (ORCID: https://orcid.org/0000-0002-9268-810X)
- Brett Martin
- Yorghos Tripodis (ORCID: https://orcid.org/0000-0003-2190-7608)
- Jonathan D. Cherry (ORCID: https://orcid.org/0000-0002-1257-981X)
- Jesse Mez (ORCID: https://orcid.org/0000-0003-1438-5442)
- Jillian N Petrosky
- Sarah Bald
- Yichi Zhang (ORCID: https://orcid.org/0000-0003-4885-9028)
- Kristen Dams-O’Connor (ORCID: https://orcid.org/0000-0002-2506-0216)
- John J. Farrell (ORCID: https://orcid.org/0000-0001-6497-1090)
- Jeffrey L. Cummings
- Victor E. Alvarez
Institutions
- Boston University (US)
- Translational Genomics Research Institute (US)
- Allen Institute for Brain Science (US)
- University of Nevada, Las Vegas (US)
- Harvard University (US)
- University of Arizona (US)
- VA Boston Healthcare System (US)
- VA New England Healthcare System (US)
- Arizona State University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102084
- Citations
- 2
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.63