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Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study
Acta Neuropathologica Communications ( IF 6.2 ) Pub Date : 2021-09-15 , DOI: 10.1186/s40478-021-01250-2
Adam J Dugan 1 , Peter T Nelson 2, 3 , Yuriko Katsumata 1, 2 , Lincoln M P Shade 1 , Kevin L Boehme 4 , Merilee A Teylan 5 , Matthew D Cykowski 6 , Shubhabrata Mukherjee 7 , John S K Kauwe 4, 7 , Timothy J Hohman 8 , Julie A Schneider 9 , , David W Fardo 1, 2
Affiliation  

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.

中文翻译:

与 LATE-NC 和海马硬化风险相关的基因(TMEM106B、GRN、ABCC9、KCNMB2 和 APOE)分析提供了发病机制见解:一项回顾性遗传关联研究

边缘系统为主的年龄相关性 TDP-43 脑病神经病理学改变 (LATE-NC) 是 TDP-43 蛋白病最普遍的亚型,影响多达 1/3 的老年人。LATE-NC 通常与海马硬化 (HS) 病理同时发生。目前尚不清楚为什么一些患有 LATE-NC 的人会发展为 HS 而其他人则不会,但遗传可能发挥了作用。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 n = 631 名受试者)和宗教秩序研究与记忆和急速衰老项目(ROSMAP;包括 n = 780 名)的研究参与者的基因组和尸检测量数据. 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。测试了 TMEM106B、GRN、ABCC9、KCNMB2 和 APOE 10 kb 以内的单核苷酸变异 (SNV) 与 HS 和 LATE-NC 的关联,并分别测试了阿尔茨海默病的病理,即淀粉样斑块和神经原纤维缠结。确定了显着相关的 SNV。当对结果进行荟萃分析时,TMEM106B、GRN 和 APOE 与 LATE 和 HS 均具有显着的基于基因的关联,而 ABCC9 仅与 HS 具有显着的关联。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,在调整 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氏症类型的病理学无关。总之,使用未包含在 LATE 或 HS 基因组学先前研究中的数据,我们复制了几个先前报告的基于基因的关联,并发现了特定风险等位基因可以差异影响 LATE-NC 和 HS 的新证据。除了 APOE 之外,这些基因似乎都与阿尔茨海默氏症类型的病理学无关。总之,使用未包含在 LATE 或 HS 基因组学先前研究中的数据,我们复制了几个先前报告的基于基因的关联,并发现了特定风险等位基因可以差异影响 LATE-NC 和 HS 的新证据。除了 APOE 之外,这些基因似乎都与阿尔茨海默氏症类型的病理学无关。总之,使用未包含在 LATE 或 HS 基因组学先前研究中的数据,我们复制了几个先前报告的基于基因的关联,并发现了特定风险等位基因可以对 LATE-NC 和 HS 产生不同影响的新证据。
更新日期:2021-09-15
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