In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation. We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci.

中文翻译：

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迟发性阿尔茨海默病大脑染色质可及性景观的性别依赖性神经胶质特异性变化

在后 GWAS 时代，解码迟发性阿尔茨海默病 (LOAD) 的基本遗传病因并将关联转化为因果关系的需求尚未得到满足。我们使用来自 40 个冷冻脑组织的 NeuN 分选核进行 ATAC-seq 分析，以确定细胞类型特定方式染色质可及性景观的负载特定变化。我们在神经元核中鉴定了 211 个负载特异性差异染色质可及位点，其中四个与负载-GWAS 区域重叠（±100 kb SNP）。虽然非神经元细胞核没有显示 LOAD 特异性差异，但按性别分层确定了女性中 842 个 LOAD 特异性染色质可及位点。非神经元样本中的这些性别依赖位点中有 7 个与 LOAD-GWAS 区域重叠，包括 APOE。LOAD 基因座使用单核 RNA-seq 数据集进行了功能验证。使用大脑分选核可以识别染色质结构中性别依赖性细胞类型特异性负载变化。这些发现增强了对 LOAD-GWAS 发现的解释，提供了潜在的病理机制，并提出了新的 LOAD-基因座。