Department of Biostatistics, College of Public Health, University of Kentucky, 201 Multidisciplinary Science Building, 725 Rose Street, Lexington, KY, 40536-0082, USA.
Sanders-Brown Center On Aging and Alzheimer's Disease Research Center, University of Kentucky, Lexington, KY, 40536, USA.
Acta Neuropathol Commun. 2021 Sep 15;9(1):152. doi: 10.1186/s40478-021-01250-2.
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer's Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer's pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer's-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.
边缘为主的与年龄相关的 TDP-43 蛋白病性脑病的神经病理学改变（LATE-NC）是 TDP-43 蛋白病最常见的亚型，影响多达三分之一的老年人。LATE-NC 常与海马硬化（HS）病理学共存。目前尚不清楚为什么一些 LATE-NC 患者会发展为 HS，而另一些则不会，但遗传可能起作用。先前的研究发现 LATE-NC 表型与特定基因之间存在关联：TMEM106B、GRN、ABCC9、KCNMB2 和 APOE。本研究分析了来自国家阿尔茨海默病协调中心（NACC；包括 631 名研究参与者的基因组和尸检测量）和宗教秩序研究与记忆和拉什衰老项目（ROSMAP；包括 780 名参与者）的研究参与者的数据。我们的目标是使用新收集的数据重新评估与疾病相关的遗传变异，并询问特定的基因型/表型关联是否可以为疾病驱动途径提供新的见解。先前 LATE/HS 全基因组关联研究（GWAS）中包含的研究对象被排除在外。TMEM106B、GRN、ABCC9、KCNMB2 和 APOE 基因 10 kb 内的单核苷酸变异（SNVs）被测试与 HS 和 LATE-NC 相关，并分别与阿尔茨海默病的病理相关，即淀粉样斑块和神经纤维缠结。确定了具有显著关联的 SNVs。当对结果进行荟萃分析时，TMEM106B、GRN 和 APOE 与 LATE 和 HS 具有显著的基因关联，而 ABCC9 仅与 HS 具有显著关联。在仅限于 LATE-NC+病例的敏感性分析中，ABCC9 变体再次与 HS 相关。相比之下，当调整 TDP-43 蛋白病时，TMEM106B、GRN 和 APOE 与 HS 的关联减弱，表明这些基因可能主要与 TDP-43 蛋白病相关。除了 APOE 之外，这些基因似乎都与阿尔茨海默病型病理无关。总之，使用先前未包含在 LATE 或 HS 基因组学研究中的数据，我们复制了几个先前报道的基于基因的关联，并发现了新的证据，即特定的风险等位基因可以不同地影响 LATE-NC 和 HS。
