Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Division of Biomedical Statistics and Informatics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Acta Neuropathol Commun. 2020 Dec 7;8(1):218. doi: 10.1186/s40478-020-01097-z.
The microtubule-associated protein tau (MAPT) H1 haplotype is the strongest genetic risk factor for corticobasal degeneration (CBD). However, the specific H1 subhaplotype association is not well defined, and it is not clear whether any MAPT haplotypes influence severity of tau pathology or clinical presentation in CBD. Therefore, in the current study we examined 230 neuropathologically confirmed CBD cases and 1312 controls in order to assess associations of MAPT haplotypes with risk of CBD, severity of tau pathology (measured as semi-quantitative scores for coiled bodies, neurofibrillary tangles, astrocytic plaques, and neuropil threads), age of CBD onset, and disease duration. After correcting for multiple testing (P < 0.0026 considered as significant), we confirmed the strong association between the MAPT H2 haplotype and decreased risk of CBD (Odds ratio = 0.26, P = 2 × 10), and also observed a novel association between the H1d subhaplotype and an increased CBD risk (Odds ratio = 1.76, P = 0.002). Additionally, although not statistically significant after correcting for multiple testing, the H1c haplotype was associated with a higher risk of CBD (Odds ratio = 1.49, P = 0.009). No MAPT haplotypes were significantly associated with any tau pathology measures, age of CBD onset, or disease duration. Though replication will be important and there is potential that population stratification could have influenced our findings, these results suggest that several MAPT H1 subhaplotypes are primarily responsible for the strong association between MAPT H1 and risk of CBD, but that H1 subhaplotypes are unlikely to play a major role in driving tau pathology or clinical features. Our findings also indicate that similarities in MAPT haplotype risk-factor profile exist between CBD and the related tauopathy progressive supranuclear palsy, with H2, H1d, and H1c displaying associations with both diseases.
微管相关蛋白 tau（MAPT）H1 单倍型是皮质基底节变性（CBD）最强的遗传风险因素。然而，特定的 H1 亚单倍型关联尚不清楚，也不清楚任何 MAPT 单倍型是否会影响 CBD 中的 tau 病理学严重程度或临床表型。因此，在目前的研究中，我们检查了 230 例经神经病理学证实的 CBD 病例和 1312 例对照，以评估 MAPT 单倍型与 CBD 风险、tau 病理学严重程度（通过螺旋体、神经纤维缠结、星形胶质细胞斑块和神经丝的半定量评分来衡量）、CBD 发病年龄和疾病持续时间的关联。在对多次测试进行校正后（校正后 P<0.0026 被认为具有显著意义），我们证实了 MAPT H2 单倍型与 CBD 风险降低之间的强烈关联（优势比=0.26，P=2×10），并且还观察到 H1d 亚单倍型与 CBD 风险增加之间的新关联（优势比=1.76，P=0.002）。此外，尽管在对多次测试进行校正后没有统计学意义，但 H1c 单倍型与 CBD 风险增加相关（优势比=1.49，P=0.009）。没有 MAPT 单倍型与任何 tau 病理学测量、CBD 发病年龄或疾病持续时间显著相关。尽管复制将很重要，并且存在人群分层可能影响我们发现的可能性，但这些结果表明，几个 MAPT H1 亚单倍型主要负责 MAPT H1 与 CBD 风险之间的强烈关联，但 H1 亚单倍型不太可能在驱动 tau 病理学或临床特征方面发挥主要作用。我们的研究结果还表明，MAPT 单倍型风险因素谱在 CBD 和相关的 tau 病进行性核上性麻痹之间存在相似之处，H2、H1d 和 H1c 与这两种疾病都有关联。
