MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, EH9 3FL, UK.
Sci Rep. 2018 Mar 21;8(1):4982. doi: 10.1038/s41598-018-23307-4.
We propose a novel approach to analyze genomic data that incorporates haplotype information for detecting rare variants within a regional heritability mapping framework. The performance of our approach was tested in a simulation study based on human genotypes. The phenotypes were simulated by generating regional variance using either SNP(s) or haplotype(s). Regional genomic relationship matrices, constructed with either a SNP-based or a haplotype-based estimator, were employed to estimate the regional variance. The results from the study show that haplotype heritability mapping captures the regional effect, with its relative performance decreasing with increasing analysis window size. The SNP-based regional mapping approach often misses the effect of causal haplotype(s); however, it has a greater power to detect simulated SNP-based-variants. Heritability estimates suggest that the haplotype heritability mapping estimates the simulated regional heritability accurately for all phenotypes and analysis windows. However, the SNP-based analysis overestimates the regional heritability and performs less well than our haplotype-based approach for the simulated rare haplotype-based-variant. We conclude that haplotype heritability mapping is a useful tool to capture the effect of rare variants, and explain a proportion of the missing heritability.
我们提出了一种新的方法来分析基因组数据，该方法结合了单倍型信息，用于在区域遗传性作图框架内检测罕见变异。我们的方法的性能在基于人类基因型的模拟研究中进行了测试。通过使用 SNP 或单倍型生成区域方差来模拟表型。使用基于 SNP 或基于单倍型的估计量构建区域基因组关系矩阵，以估计区域方差。研究结果表明，单倍型遗传制图捕获了区域效应，其相对性能随分析窗口大小的增加而降低。基于 SNP 的区域映射方法经常会错过因果单倍型的影响；但是，它具有检测模拟 SNP 变体的更大能力。遗传力估计表明，对于所有表型和分析窗口，单倍型遗传制图都能准确估计模拟的区域遗传力。但是，基于 SNP 的分析高估了区域遗传力，并且在模拟的罕见单倍型变体方面的性能不如我们基于单倍型的方法。我们得出的结论是，单倍型遗传制图是一种有用的工具，可以捕获罕见变异的影响，并解释一部分缺失的遗传力。
