ArticleCell reports. Medicine2025
A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes.
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Article in Cell reports. Medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3citing papers in PubMed
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Who cites it
3 citing papers in PubMed.
- Chronic traumatic encephalopathy: A devastating legacy of repetitive concussion.Neurobiology of disease · 2026Review
- Genome-wide analysis of subcortical aging identifies a spatially structured pattern of genetic associations.GeroScience · 2026Article
- Advancing biomarker development for chronic traumatic encephalopathy: Summary and recommendations from the 2025 Leon Thal Summit.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
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Authors and funding
36 authors.
Xudong HanBioinformatics Graduate Program, Boston University, Boston, MA, USA; Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Yichi ZhangBioinformatics Graduate Program, Boston University, Boston, MA, USA.
Jillian N PetroskyBioinformatics Graduate Program, Boston University, Boston, MA, USA.
Sarah BaldBioinformatics Graduate Program, Boston University, Boston, MA, USA.
Richard M ShervaSection of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Adam LabadorfBioinformatics Graduate Program, Boston University, Boston, MA, USA; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA.
Jonathan D CherryBoston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Jaeyoon ChungSection of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Kurt FarrellDepartments of Pathology, Neuroscience, and Artificial Intelligence & Human Health, Neuropathology Brain Bank & Research CoRE, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Bobak AbdolmohammadiDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA.
Shruti DurapeDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA.
Brett M MartinBoston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA.
Joseph N PalmisanoBoston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA.
John J FarrellSection of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Victor E AlvarezBoston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Bedford VA Healthcare System, Bedford, MA, USA.
Bertrand R HuberDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Bedford VA Healthcare System, Bedford, MA, USA.
Brigid DwyerDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Braintree Rehabilitation Hospital, Braintree, MA, USA.
Daniel H DaneshvarDepartment of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA.
Kristen Dams-O'ConnorDepartment of Rehabilitation and Human Performance, Brain Injury Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Gyungah R JunSection of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Kathryn L LunettaDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Lee E GoldsteinBoston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Departments of Biomedical, Electrical & Computer Engineering, Boston University College of Engineering, Boston, MA, USA; Departments of Radiology and Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Douglas I KatzDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Braintree Rehabilitation Hospital, Braintree, MA, USA.
Robert C CantuBoston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Neurosurgery, Emerson Hospital, Concord, MA, USA.
Martha E ShentonBoston VA Healthcare System, Boston, MA, USA; Psychiatry Neuroimaging Laboratory, Departments of Psychiatry and Radiology, Brigham and Women's Hospital, Boston, MA, USA.
Jeffrey L CummingsChambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.
Eric M ReimanBanner Alzheimer's Institute, University of Arizona, Arizona State University, Translational Genomics Research Institute, and Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Robert A SternDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, USA.
DIAGNOSE CTE Research Project Investigators
Michael L AloscoDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA.
Yorghos TripodisBoston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Lindsay A FarrerSection of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Thor D SteinBoston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Bedford VA Healthcare System, Bedford, MA, USA.
John F CraryDepartments of Pathology, Neuroscience, and Artificial Intelligence & Human Health, Neuropathology Brain Bank & Research CoRE, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ann C McKeeDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Bedford VA Healthcare System, Bedford, MA, USA.
Jesse MezDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA. Electronic address: jessemez@bu.edu.
Funding
FRAMINGHAM HEART STUDY - YEAR 5 EXAM75N92019D00031 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · 2019 to 2024
$29.8MNeuropathology CoreP30AG013846 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI KOWALL, NEIL W. · 1996 to 2020
$29.1MRenewal of Centers of Biomedical Research Excellence (COBRE) (Phase 2) CNTN - ResubmissionP20GM109025 · NIGMS · CLEVELAND CLINIC FOUNDATION · PI Robert J. Fox, Jefferson Kinney · 2015 to 2026
$22.8MChronic Traumatic Encephalopathy: Detection, Diagnosis, Course, and Risk FactorsU01NS093334 · NINDS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI CUMMINGS, JEFFREY L., REIMAN, ERIC MICHAEL · 2016 to 2022
$17.0MTraumatic Brain Injury and Repetitive Head Impacts: Contributions to AD/ADRD and CTE Neuropathology and Resulting Clinical SyndromesU54NS115266 · NINDS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI STEIN, THOR · 2019 to 2023
$10.3MCTE and Posttraumatic Neurodegeneration: Neuropathology and Ex Vivo ImagingU01NS086659 · NINDS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI MCKEE, ANN C. · 2014 to 2017
$6.1MLeveraging Existing Aging Research Networks to investigate TBI and AD/ADRD risk (LEARN TBI & AD)R01AG061028 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI DAMS-O'CONNOR, KRISTEN, MEZ, JESSE BENJAMIN · 2019 to 2023
$5.9MChronic Traumatic Encephalopathy: Clinical Presentation and BiomarkersR01NS078337 · NINDS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI STERN, ROBERT A · 2011 to 2013
$2.0MAlzheimer's Disease and Related Dementias Innovation Incubator (InnovaTor)R25AG083721 · NIA · UNIVERSITY OF NEVADA LAS VEGAS · PI JEFFREY L. CUMMINGS, Xue K Zhong · 2023 to 2026
$1.0MRepetitive Head Impact Exposure and Later-Life White Matter Signal Abnormalities: An Investigation in Former NFL Players, Subjects with Alzheimer's Disease, and Cognitively Normal ControlsK23NS102399 · NINDS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI ALOSCO, MICHAEL · 2018 to 2022
$793kChronic Traumatic Encephalopathy: Clinical Presentation and BiomarkersR56NS078337 · NINDS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI STERN, ROBERT A · 2014 to 2014
$786kGenetic and Neuropsychological Heterogeneity in Alzheimer's DiseaseK23AG046377 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI MEZ, JESSE BENJAMIN · 2014 to 2018
$639kBLRD VA I01 BX005933CSRD VA I01 CX001135NHLBI NIH HHS 75N92019D00031NIA NIH HHS K23 AG046377NIA NIH HHS P30 AG013846NIA NIH HHS R01 AG061028NIA NIH HHS R25 AG083721NICHD NIH HHS R21 HD089088NIGMS NIH HHS P20 GM109025NINDS NIH HHS F32 NS096803NINDS NIH HHS K23 NS102399NINDS NIH HHS R01 NS078337NINDS NIH HHS R56 NS078337NINDS NIH HHS U01 NS086659NINDS NIH HHS U01 NS093334NINDS NIH HHS U01 NS137483NINDS NIH HHS U54 NS115266
Abstract
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.
Indexed as
Chromosomes, Human, Pair 17Chronic Traumatic EncephalopathyEndophenotypesGenetic Predisposition to DiseaseHaplotypestau ProteinsAdultAgedFemaleHumansMaleMiddle AgedPolymorphism, Single NucleotideRisk FactorsMAPT protein, humantau Proteins17q21.31chronic traumatic encephalopathydementiadifferential gene expressionimmune systemMAPTrepetitive head impactsstructural haplotypestauopathytraumatic brain injury
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