用介导表达评分回归量化基因调控表达对复杂性状的介导作用的稳健性。

IF 2.5 Q3 BIOCHEMICAL RESEARCH METHODS Biology Methods and Protocols Pub Date : 2023-10-17 eCollection Date: 2023-01-01 DOI:10.1093/biomethods/bpad024
Chen Lin, Wei Liu, Wei Jiang, Hongyu Zhao
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引用次数: 0

摘要

通过全基因组关联研究(GWAS),遗传关联信号大多在非编码区发现,表明基因表达调控在人类疾病和性状中的作用。然而,将表达数量性状基因座(eQTL)与疾病相关变异共定位的成功率有限。介导表达得分回归(MESC)是最近提出的一种量化由遗传调控基因表达介导的性状遗传力比例的方法。将MESC应用于GWAS结果,对许多性状的介导遗传力估计较低。由于MESC依赖于顺式eQTL效应、基因效应和非介导SNP效应之间的严格独立性假设,它可能无法表征这些效应大小之间的真实关系,从而导致有偏差的结果。在这里,我们考虑了MESC的稳健性,以研究由MESC推断的介导遗传力的低部分是否反映了复杂性状的生物学现实,或者是由模型错误指定引起的低估。我们的结果表明,MESC可能导致介导遗传力的估计有偏差,基因注释的错误指定导致低估,而SNP注释的错误标记可能导致高估。此外,eQTL效应估计的错误可能导致对介导遗传力的低估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Robustness of quantifying mediating effects of genetically regulated expression on complex traits with mediated expression score regression.

Genetic association signals have been mostly found in noncoding regions through genome-wide association studies (GWAS), suggesting the roles of gene expression regulation in human diseases and traits. However, there has been limited success in colocalizing expression quantitative trait locus (eQTL) with disease-associated variants. Mediated expression score regression (MESC) is a recently proposed method to quantify the proportion of trait heritability mediated by genetically regulated gene expressions (GReX). Applications of MESC to GWAS results have yielded low estimation of mediated heritability for many traits. As MESC relies on stringent independence assumptions between cis-eQTL effects, gene effects, and nonmediated SNP effects, it may fail to characterize the true relationships between those effect sizes, which leads to biased results. Here, we consider the robustness of MESC to investigate whether the low fraction of mediated heritability inferred by MESC reflects biological reality for complex traits or is an underestimation caused by model misspecifications. Our results suggest that MESC may lead to biased estimates of mediated heritability with misspecification of gene annotations leading to underestimation, whereas misspecification of SNP annotations may lead to overestimation. Furthermore, errors in eQTL effect estimates may lead to underestimation of mediated heritability.

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来源期刊
Biology Methods and Protocols
Biology Methods and Protocols Agricultural and Biological Sciences-Agricultural and Biological Sciences (all)
CiteScore
3.80
自引率
2.80%
发文量
28
审稿时长
19 weeks
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