不平衡的样本量给全基因组杂合性分析带来了虚假的相关性。

IF 1.1 4区 生物学 Q4 GENETICS & HEREDITY Human Heredity Pub Date : 2019-01-01 Epub Date: 2020-06-15 DOI:10.1159/000507576
Li Liu, Richard J Caselli
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引用次数: 2

摘要

过度杂合度(H)是一个广泛使用的衡量群体遗传多样性的指标。随着高通量测序和基因分型数据变得容易获得,它已被应用于研究全基因组遗传多样性与人类疾病和性状的关系。然而,这些研究经常报告相互矛盾的结果。在本文中,我们对五项全外显子组研究进行了荟萃分析,以检验H评分与阿尔茨海默病的关系。我们表明,一个组的平均H值与疾病状态无关,但它与样本量有关。在所有五项研究中,样本较多的组的H分数明显低于样本较少的组。为了消除经验数据集中潜在的混杂因素,我们执行计算机模拟来创建人工基因组,以控制多态性位点的数量、样本量和等位基因频率。对这些模拟数据的分析证实了样本量与H分数之间的负相关关系。此外,我们发现具有大量罕见变异的基因组也具有过高的H值。这些偏见会导致基因多样性和感兴趣的表型之间的虚假联系。基于这些发现,我们主张研究在使用全基因组H评分评估不同人群遗传多样性时,应平衡样本量,这有助于提高未来研究的可重复性。
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Unbalanced Sample Size Introduces Spurious Correlations to Genome-Wide Heterozygosity Analyses.

Excess of heterozygosity (H) is a widely used measure of genetic diversity of a population. As high-throughput sequencing and genotyping data become readily available, it has been applied to investigating the associations of genome-wide genetic diversity with human diseases and traits. However, these studies often report contradictory results. In this paper, we present a meta-analysis of five whole-exome studies to examine the association of H scores with Alzheimer's disease. We show that the mean H score of a group is not associated with the disease status, but ot is associated with the sample size. Across all five studies, the group with more samples has a significantly lower H score than the group with fewer samples. To remove potential confounders in empirical data sets, we perform computer simulations to create artificial genomes controlled for the number of polymorphic loci, the sample size, and the allele frequency. Analyses of these simulated data confirm the negative correlation between the sample size and the H score. Furthermore, we find that genomes with a large number of rare variants also have inflated H scores. These biases altogether can lead to spurious associations between genetic diversity and the phenotype of interest. Based on these findings, we advocate that studies shall balance the sample sizes when using genome-wide H scores to assess genetic diversities of different populations, which helps improve the reproducibility of future research.

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来源期刊
Human Heredity
Human Heredity 生物-遗传学
CiteScore
2.50
自引率
0.00%
发文量
12
审稿时长
>12 weeks
期刊介绍: Gathering original research reports and short communications from all over the world, ''Human Heredity'' is devoted to methodological and applied research on the genetics of human populations, association and linkage analysis, genetic mechanisms of disease, and new methods for statistical genetics, for example, analysis of rare variants and results from next generation sequencing. The value of this information to many branches of medicine is shown by the number of citations the journal receives in fields ranging from immunology and hematology to epidemiology and public health planning, and the fact that at least 50% of all ''Human Heredity'' papers are still cited more than 8 years after publication (according to ISI Journal Citation Reports). Special issues on methodological topics (such as ‘Consanguinity and Genomics’ in 2014; ‘Analyzing Rare Variants in Complex Diseases’ in 2012) or reviews of advances in particular fields (‘Genetic Diversity in European Populations: Evolutionary Evidence and Medical Implications’ in 2014; ‘Genes and the Environment in Obesity’ in 2013) are published every year. Renowned experts in the field are invited to contribute to these special issues.
期刊最新文献
Place of concordance-discordance model in evaluating NGS performance. Implications of the Co-Dominance Model for Hardy-Weinberg Testing in Genetic Association Studies. Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer. Investigation of Recessive Effects of Coding Variants on Common Clinical Phenotypes in Exome-Sequenced UK Biobank Participants. comorbidPGS: An R Package Assessing Shared Predisposition between Phenotypes Using Polygenic Scores.
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