On Genetic Correlation Estimation With Summary Statistics From Genome-Wide Association Studies.
On Genetic Correlation Estimation With Summary Statistics From Genome-Wide Association Studies.
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DOI：
10.1080/01621459.2021.1906684
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发表时间：
2022
影响因子：
3.7
通讯作者：
Zhu, Hongtu
中科院分区：
文献类型：
--
作者：
Zhao, Bingxin;Zhu, Hongtu
跨性状多基因风险评分（PRS）方法已得到普及，用于评估复杂性状的遗传相关性，使用生物库规模的全基因组关联研究（GWAS）的汇总统计量。然而，经验证据显示了一种常见的偏差现象，即高度显著的跨性状PRS在独立测试GWAS中只能解释非常少量的遗传方差（R2可以< 1%）。本文的目的是调查和解决跨性状PRS在众多GWAS应用中的偏差现象。我们发现，估计的遗传相关性可以渐近偏向于零。一个一致的跨特质PRS估计，然后提出了纠正这种渐近偏差。此外，我们研究了通过GWAS p值进行SNP筛选是否可以改善估计，并显示GWAS之间重叠样本的影响。我们分析了GWAS在儿科成像、神经认知和遗传学研究中测量的反应时间和基于脑结构磁共振成像的特征的汇总统计量。我们发现，原始的跨性状PRS估计严重低估了认知功能和人脑结构之间的遗传相似性（平均R2 = 1.32%），而偏差校正估计揭示了这些密切相关的遗传性状之间的遗传重叠程度适中（平均R2 = 22.42%）。本文的补充材料，包括可用于复制作品的材料的标准化描述，可作为在线补充。
Cross-trait polygenic risk score (PRS) method has gained popularity for assessing genetic correlation of complex traits using summary statistics from biobank-scale genome-wide association studies (GWAS). However, empirical evidence has shown a common bias phenomenon that highly significant cross-trait PRS can only account for a very small amount of genetic variance (R2 can be < 1%) in independent testing GWAS. The aim of this paper is to investigate and address the bias phenomenon of cross-trait PRS in numerous GWAS applications. We show that the estimated genetic correlation can be asymptotically biased toward zero. A consistent cross-trait PRS estimator is then proposed to correct such asymptotic bias. In addition, we investigate whether or not SNP screening by GWAS p-values can lead to improved estimation and show the effect of overlapping samples among GWAS. We analyze GWAS summary statistics of reaction time and brain structural magnetic resonance imaging-based features measured in the Pediatric Imaging, Neurocognition, and Genetics study. We find that the raw cross-trait PRS estimators heavily underestimate the genetic similarity between cognitive function and human brain structures (mean R2 = 1.32%), whereas the bias-corrected estimators uncover the moderate degree of genetic overlap between these closely related heritable traits (mean R2 = 22.42%). Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.
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