增强罕见变异关联研究的实力,通过使用大规模人口测序来进行推算
Jinglan Dai1, Yixin Zhang1, Yuan Gao1
1Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Genomics, proteomics & bioinformatics
|September 19, 2025
概括
假定遗传数据,特别是TOPMed的数据,与罕见变异关联研究的全基因组测序 (WGS) 非常接近. 更大的样本大小和归算数据显著增加了检测罕见变异的能力,有助于复杂的特征遗传性研究.
科学领域:
- 基因组学就是基因组学.
- 人口遗传学 人口遗传学
- 统计遗传学 统计遗传学
背景情况:
- 种群规模的全基因组测序 (WGS) 能够精确捕获罕见变异,这对于理解复杂特征遗传性至关重要,通常被传统的全基因组关联研究 (GWAS) 遗漏.
- 假定遗传数据与WGS对于罕见变异关联研究的实用性仍然是一个开放的问题.
研究的目的:
- 评估SNP数组数据与WGS对比的统一性和性能,用于罕见变异检测.
- 评估各种特征和样本大小的关联研究中计入数据的力量.
主要方法:
- 利用英国生物银行提供的WGS数据 (n=150,119) 作为基础真相.
- 对于使用R平方和克莱默V的罕见变体,评估了归算质量 (TOPMed,HRC+UK10K).
- 对45个特征进行了关联测试,比较WGS和不同样本大小的归算数据.
- 使用SNP阵列和WGS数据对肺癌和卵巢癌进行了元分析.
主要成果:
- 即使对于极其罕见的变异 (小等位基数≤5) 实现了优质的TOPM归算 (R-平方>0.6).
- 跨种族的TOPMed输入数据显示了与WGS (克莱默V>0.75) 的更高一致性.
- 在相同的样本大小下,归算数据没有超过WGS,但TOPMed-归算数据结果更一致.
- 随着TOPMed输入数据的样本规模增加到488,377个,罕见变种检测率提高了27.71% (定量) 和10倍 (二进制).
- 分析发现了更多的变体和基因,而不是仅WGS的结果.
结论:
- 从大型测序队列中输入的罕见变异可以增强关联测试的功率,特别是当WGS样本大小有限时.
- TOPMed输入数据为罕见变异关联研究提供了宝贵的资源,接近WGS质量并通过规模提高发现能力.
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