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在全基因组关联研究中,LD评分回归作为混杂因素和遗传相关性估计方法的准确性。

The accuracy of LD Score regression as an estimator of confounding and genetic correlations in genome-wide association studies.

作者信息

Lee James J, McGue Matt, Iacono William G, Chow Carson C

机构信息

Department of Psychology, University of Minnesota Twin Cities, Minneapolis, Minnesota.

Mathematical Biology Section, Laboratory of Biological Modeling, NIDDK, National Institutes of Health, Bethesda, Maryland.

出版信息

Genet Epidemiol. 2018 Dec;42(8):783-795. doi: 10.1002/gepi.22161. Epub 2018 Sep 24.


DOI:10.1002/gepi.22161
PMID:30251275
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6758917/
Abstract

To infer that a single-nucleotide polymorphism (SNP) either affects a phenotype or is linkage disequilibrium with a causal site, we must have some assurance that any SNP-phenotype correlation is not the result of confounding with environmental variables that also affect the trait. In this study, we study the properties of linkage disequilibrium (LD) Score regression, a recently developed method for using summary statistics from genome-wide association studies to ensure that confounding does not inflate the number of false positives. We do not treat the effects of genetic variation as a random variable and thus are able to obtain results about the unbiasedness of this method. We demonstrate that LD Score regression can produce estimates of confounding at null SNPs that are unbiased or conservative under fairly general conditions. This robustness holds in the case of the parent genotype affecting the offspring phenotype through some environmental mechanism, despite the resulting correlation over SNPs between LD Scores and the degree of confounding. Additionally, we demonstrate that LD Score regression can produce reasonably robust estimates of the genetic correlation, even when its estimates of the genetic covariance and the two univariate heritabilities are substantially biased.

摘要

为了推断单核苷酸多态性(SNP)要么影响一种表型,要么与一个因果位点处于连锁不平衡状态,我们必须确保任何SNP与表型的相关性不是与也影响该性状的环境变量混淆的结果。在本研究中,我们研究了连锁不平衡(LD)评分回归的特性,这是一种最近开发的方法,用于利用全基因组关联研究的汇总统计数据,以确保混淆不会使假阳性数量膨胀。我们不将遗传变异的影响视为随机变量,因此能够获得关于该方法无偏性的结果。我们证明,在相当一般的条件下,LD评分回归可以产生在无效SNP处的混淆估计值,这些估计值是无偏的或保守的。尽管LD评分与混淆程度之间在SNP之间存在相关性,但在亲本基因型通过某种环境机制影响后代表型的情况下,这种稳健性依然成立。此外,我们证明,即使LD评分回归对遗传协方差和两个单变量遗传力的估计存在很大偏差,它也能产生相当稳健的遗传相关性估计值。

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本文引用的文献

[1]
Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Nat Genet. 2018-7-23

[2]
Genetic analysis of social-class mobility in five longitudinal studies.

Proc Natl Acad Sci U S A. 2018-7-9

[3]
Mixed-model association for biobank-scale datasets.

Nat Genet. 2018-7

[4]
The Nature of Nurture: Using a Virtual-Parent Design to Test Parenting Effects on Children's Educational Attainment in Genotyped Families.

Twin Res Hum Genet. 2018-4

[5]
The nature of nurture: Effects of parental genotypes.

Science. 2018-1-26

[6]
Local Genetic Correlation Gives Insights into the Shared Genetic Architecture of Complex Traits.

Am J Hum Genet. 2017-11-2

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Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection.

Nat Genet. 2017-10

[8]
Meta-GWAS Accuracy and Power (MetaGAP) Calculator Shows that Hiding Heritability Is Partially Due to Imperfect Genetic Correlations across Studies.

PLoS Genet. 2017-1-17

[9]
Molecular Genetic Contributions to Social Deprivation and Household Income in UK Biobank.

Curr Biol. 2016-11-21

[10]
Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

Nat Genet. 2016-12

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