We conducted genome sequencing to search for rare variation contributing to early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 435 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than one in 10,000 or private), computational prediction of deleteriousness (CADD) (10 or 15 thresholds), and molecular function (protein loss-of-function [LoF] only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Replication analysis was conducted on 16,434 independent cases and 15,587 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p = 4.6 × 10-8, genome-wide corrected p = 0.0026). Most of these variants were canonical LoF or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of Alzheimer's disease (AD) and FTD (replication only p = 0.0029). The combined analysis odds ratio was 2.3 (95% confidence interval [CI] 1.6-3.4) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 3.7 (95% CI 1.7-9.4). For LoF variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.1 (95% CI 1.9-5.2). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.

中文翻译：

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TET2 中的非编码和功能丧失编码变体与多种神经退行性疾病相关。


我们进行了基因组测序，以寻找导致早发性阿尔茨海默病 (EOAD) 和额颞叶痴呆 (FTD) 的罕见变异。对欧洲血统的 435 例病例和 671 例对照进行了发现分析。使用基于变异稀有性（小于万分之一或私人）、有害性计算预测 (CADD)（10 或 15 个阈值）和分子功能（蛋白质功能丧失）的过滤器对与疾病相关的罕见变异进行负担测试仅[LoF]，仅编码改变，或实验预测的调控区域中的编码加非编码变体）。对 16,434 个独立病例和 15,587 个独立对照进行了复制分析。 TET2 中的罕见变异在 EOAD 和 FTD 联合发现的队列中得到富集（p = 4.6 × 10-8，全基因组校正 p = 0.0026）。大多数这些变体是规范的 LoF 或预测调控区域中的非编码变体。这种富集在阿尔茨海默病 (AD) 和 FTD 的多个队列中得到复制（仅复制 p = 0.0029）。 AD 和 FTD 的综合分析优势比为 2.3（95% 置信区间 [CI] 1.6-3.4）。独立于编码变体考虑的合格非编码变体的比值比为 3.7 (95% CI 1.7-9.4)。对于 LoF 变异，合并优势比（AD、FTD 和肌萎缩侧索硬化症，其临床病理学与 FTD 重叠）为 3.1 (95% CI 1.9-5.2)。 TET2 催化 DNA 去甲基化。鉴于衰老过程中 DNA 甲基化发生明确的变化，TET2 的罕见变化可能会通过改变关键衰老相关过程的稳态而带来神经退行性变的风险。此外，我们的研究强调了非编码变异在复杂疾病遗传研究中的相关性。