Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
Acta Neuropathol. 2021 May;141(5):667-680. doi: 10.1007/s00401-021-02289-0. Epub 2021 Feb 26.
Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
进行性核上性麻痹（PSP）是仅次于帕金森病的第二常见神经退行性帕金森病，其特征为原发性 tau 病。利用与 PSP 相关的相当大的临床和神经病理学异质性，我们将 tau 神经病理学测量为定量特征，以在 PSP 内进行全基因组关联研究（GWAS），以鉴定潜在的 PSP 疾病过程的基因和生物学途径。在 882 例 PSP 病例中，从 18 个脑区记录了磷酸化 tau 免疫反应性卷曲体（CB）、神经纤维缠结（NFT）、丛生星形胶质细胞（TA）和 tau 丝的半定量评分，并使用 R ltm 包转换为潜在特征（LT）变量。LT 分析利用多变量回归模型将分类响应链接到未观察到的协变量，从而降低维度，生成一个单一的连续变量来解释评估的多个病变和脑区。我们首先测试了与 PSP LT 和 PSP GWAS 易感性位点的关联。在 rs242557（MAPT H1c 亚单倍型）与后脑 CB 和 rs1768208（MOBP）与前脑 tau 丝中发现了显著的 SNP/LT 关联。在 795 例 PSP 病例中，采用数字显微镜定量测定中脑脑桥和红核中的磷酸化 tau 负荷，并将 tau 负荷用作 GWAS 的定量表型。在 rs1768208 与中脑脑桥和红核 tau 负荷之间鉴定出最高关联。此外，我们在一个初始队列上进行了 PSP LT GWAS，在一个扩展队列上进行了后续 SNP 面板（37 个 SNP，P < 10），并进行了联合分析。在 SPTBN5/EHD4、SEC13/ATP2B2、EPHB1/PPP2R3A、TBC1D8、IFNGR1/OLIG3、ST6GAL1、HK1、CALB1 和 SGCZ 中的 SNP/LT 关联被鉴定为 SNPs 或附近的 SNPs。最后，使用全转录组和全基因组数据测试 SNP/转录本关联，在 rs3088159/SPTBN5/EHD4 和 rs154239/GHRL 处鉴定出显著的表达数量性状基因座。使用 LT 作为 GWAS 中的定量表型来模拟 tau 神经病理学异质性，可能会通过影响区域 tau 负荷，为 PSP 涉及的生物学途径提供实质性的见解。
Zotero 插件