17q21.31微管相关蛋白tau（MAPT）区域的一种结构单倍型与慢性创伤性脑病内表型风险增加相关。

A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes.

作者信息

Han Xudong, Zhang Yichi, Petrosky Jillian N, Bald Sarah, Sherva Richard M, Labadorf Adam, Cherry Jonathan D, Chung Jaeyoon, Farrell Kurt, Abdolmohammadi Bobak, Durape Shruti, Martin Brett M, Palmisano Joseph N, Farrell John J, Alvarez Victor E, Huber Bertrand R, Dwyer Brigid, Daneshvar Daniel H, Dams-O'Connor Kristen, Jun Gyungah R, Lunetta Kathryn L, Goldstein Lee E, Katz Douglas I, Cantu Robert C, Shenton Martha E, Cummings Jeffrey L, Reiman Eric M, Stern Robert A, Alosco Michael L, Tripodis Yorghos, Farrer Lindsay A, Stein Thor D, Crary John F, McKee Ann C, Mez Jesse

机构信息

Bioinformatics Graduate Program, Boston University, Boston, MA, USA; Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.

Bioinformatics Graduate Program, Boston University, Boston, MA, USA.

出版信息

Cell Rep Med. 2025 May 20;6(5):102084. doi: 10.1016/j.xcrm.2025.102084. Epub 2025 Apr 15.

DOI:10.1016/j.xcrm.2025.102084

PMID:40239644

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12147854/

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.

摘要

慢性创伤性脑病（CTE）是一种与重复性头部撞击（RHI）暴露相关的神经退行性tau蛋白病。包含微管相关蛋白tau（MAPT）的17q21.31区域的基因变异与tau蛋白病有关，但尚未在CTE中进行研究。该区域包括一个长达百万碱基的倒位（H1/H2）和拷贝数变异，包括α、β和γ片段，可被表征为九种分离的结构单倍型。我们利用17q21.31区域的阵列SNP数据和一个参考面板来推断结构单倍型，并在447名有RHI暴露的欧洲血统脑供体中测试它们与CTE内表型的关联。H1β1γ1单倍型与CTE中常见受影响的多个皮质和内侧颞叶区域的痴呆和半定量tau蛋白负担显著相关。在背外侧前额叶皮质中进行的H1β1γ1差异表达分析涉及顺式作用基因和炎症途径。综上所述，H1β1γ1单倍型可能有助于解释在具有相似RHI暴露的人群中CTE的异质性。