与阿尔茨海默病相关的结构变异以及其他常见的与年龄相关的临床和神经病理特征
Ricardo A Vialle1, Katia de Paiva Lopes1, Yan Li1
1Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
medRxiv : the preprint server for health sciences
|August 26, 2024
概括
结构变异 (SVs) 可能解释了缺失的阿尔茨海默病 (AD) 遗传性. 这项研究发现了与AD/ADRD特征相关的SV,包括与认知性和病理相关的TMEM106B中删除.
科学领域:
- 遗传学 是一个遗传学.
- 神经科学是一个神经科学.
- 基因组学就是基因组学.
背景情况:
- 阿尔茨海默氏病 (AD) 的遗传性并不能完全由单核酸多态 (SNP) 和小的indels.解释.
- 大规模的基因组重组,称为结构变异 (SV),是AD缺失遗传性的潜在贡献者.
- 了解SVs在AD病变发生中的作用对于推进诊断和治疗策略至关重要.
研究的目的:
- 调查常见结构变异 (SVs) 与阿尔茨海默病及相关疾病 (AD/ADRD) 临床和病理特征的关联.
- 通过基于SNP的分析无法检测到的AD/ADRD的新遗传风险位点.
- 探索已识别的SVs对基因表达和AD相关表型的功能影响.
主要方法:
- 使用全基因组测序 (WGS) 数据对大约20,000种常见的SV进行全基因组关联分析,这些数据来自ROS/MAP研究中的1088名参与者.
- 检查SVs与一系列AD/ADRD临床和病理特征之间的关联.
- 链接不平衡 (LD) 分析,以评估 SV 和已知的 AD GWAS 领先变体之间的关系.
主要成果:
- 由于样本规模有限,没有发现全基因组显著的关联,但22个SV显示名义关联 (P <0.05) 与AD/ADRD表型,并与GWAS变体在LD中.
- 在TMEM106B中删除一个Alu元素与纠密度,TDP-43,认知弹性和减少TMEM106B蛋白质密度密切相关.
- 确定了七种新的SV,不在SNP的LD中,包括与认知障碍和弹性相关的C1orf186中的重复.
结论:
- 常见的结构变异在阿尔茨海默病和相关疾病的发病过程中发挥着潜在的作用.
- SVs,特别是那些与SNP没有链接不平衡的SVs,可能代表新的AD/ADRD风险位置.
- 需要在独立队列中进行进一步的验证,以确认已识别的SV关联及其功能意义.
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