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在校正全基因组关联研究中的志愿者偏差后,单核苷酸多态性效应大小和遗传力估计值会增加。

Correcting for volunteer bias in GWAS increases SNP effect sizes and heritability estimates.

作者信息

van Alten Sjoerd, Domingue Benjamin W, Faul Jessica, Galama Titus, Marees Andries T

机构信息

Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Tinbergen Institute, Amsterdam, Netherlands.

出版信息

Nat Commun. 2025 Apr 15;16(1):3578. doi: 10.1038/s41467-025-58684-8.

Abstract

Selection bias in genome-wide association studies (GWASs) due to volunteer-based sampling (volunteer bias) is poorly understood. The UK Biobank (UKB), one of the largest and most widely used cohorts, is highly selected. Using inverse probability (IP) weights we estimate inverse probability weighted GWAS (WGWAS) to correct GWAS summary statistics in the UKB for volunteer bias. Our IP weights were estimated using UK Census data - the largest source of population-representative data - made representative of the UKB's sampling population. These weights have a substantial SNP-based heritability of 4.8% (s.e. 0.8%), suggesting they capture volunteer bias in GWAS. Across ten phenotypes, WGWAS yields larger SNP effect sizes, larger heritability estimates, and altered gene-set tissue expression, despite decreasing the effective sample size by 62% on average, compared to GWAS. The impact of volunteer bias on GWAS results varies by phenotype. Traits related to disease, health behaviors, and socioeconomic status are most affected. We recommend that GWAS consortia provide population weights for their data sets, or use population-representative samples.

摘要

全基因组关联研究(GWAS)中由于基于志愿者的抽样(志愿者偏差)导致的选择偏差目前了解甚少。英国生物银行(UKB)是最大且使用最广泛的队列之一,其样本具有高度选择性。我们使用逆概率(IP)权重估计逆概率加权GWAS(WGWAS),以校正UKB中GWAS汇总统计数据的志愿者偏差。我们的IP权重是使用英国人口普查数据估计的——这是人口代表性数据的最大来源——使其能够代表UKB的抽样人群。这些权重具有基于单核苷酸多态性(SNP)的显著遗传力,为4.8%(标准误0.8%),这表明它们捕捉到了GWAS中的志愿者偏差。在十种表型中,与GWAS相比,尽管有效样本量平均减少了62%,但WGWAS产生了更大的SNP效应大小、更高的遗传力估计值,并且改变了基因集组织表达。志愿者偏差对GWAS结果的影响因表型而异。与疾病、健康行为和社会经济地位相关的性状受影响最大。我们建议GWAS联盟为其数据集提供人群权重,或使用具有人群代表性的样本。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7df/12000612/c326c842cfa1/41467_2025_58684_Fig1_HTML.jpg

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