Gilbody Joe, Borges Maria Carolina, Davey Smith George, Sanderson Eleanor
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, University of Bristol, Bristol, UK.
Genet Epidemiol. 2025 Jan;49(1):e22606. doi: 10.1002/gepi.22606.
Genome-wide association studies (GWAS) are hypothesis-free studies that estimate the association between polymorphisms across the genome with a trait of interest. To increase power and to estimate the direct effects of these single-nucleotide polymorphisms (SNPs) on a trait GWAS are often conditioned on a covariate (such as body mass index or smoking status). This adjustment can introduce bias in the estimated effect of the SNP on the trait. Two-sample Mendelian randomisation (MR) studies use summary statistics from GWAS estimate the causal effect of a risk factor (or exposure) on an outcome. Covariate adjustment in GWAS can bias the effect estimates obtained from MR studies conducted using covariate adjusted GWAS data. Multivariable MR (MVMR) is an extension of MR that includes multiple traits as exposures. Here we propose the use of MVMR to correct the bias in MR studies from covariate adjustment. We show how MVMR can recover unbiased estimates of the direct effect of the exposure of interest by including the covariate used to adjust the GWAS within the analysis. We apply this method to estimate the effect of systolic blood pressure on type-2 diabetes and the effect of waist circumference on systolic blood pressure. Our analytical and simulation results show that MVMR provides unbiased effect estimates for the exposure when either the exposure or outcome of interest has been adjusted for a covariate. Our results also highlight the parameters that determine when MR will be biased by GWAS covariate adjustment. The results from the applied analysis mirror these results, with equivalent results seen in the MVMR with and without adjusted GWAS. When GWAS results have been adjusted for a covariate, biasing MR effect estimates, direct effect estimates of an exposure on an outcome can be obtained by including that covariate as an additional exposure in an MVMR estimation. However, the estimated effect of the covariate obtained from the MVMR estimation is biased.
全基因组关联研究(GWAS)是无假设研究,用于估计全基因组多态性与感兴趣性状之间的关联。为了提高效能并估计这些单核苷酸多态性(SNP)对性状的直接影响,GWAS通常以协变量(如体重指数或吸烟状况)为条件。这种调整可能会在SNP对性状的估计效应中引入偏差。两样本孟德尔随机化(MR)研究使用GWAS的汇总统计量来估计风险因素(或暴露)对结局的因果效应。GWAS中的协变量调整可能会使使用协变量调整后的GWAS数据进行的MR研究获得的效应估计产生偏差。多变量MR(MVMR)是MR的扩展,它将多个性状作为暴露因素。在此,我们建议使用MVMR来纠正协变量调整导致的MR研究中的偏差。我们展示了MVMR如何通过在分析中纳入用于调整GWAS的协变量来恢复感兴趣暴露因素直接效应的无偏估计。我们应用此方法来估计收缩压对2型糖尿病的影响以及腰围对收缩压的影响。我们的分析和模拟结果表明,当感兴趣的暴露因素或结局针对协变量进行了调整时,MVMR可为暴露因素提供无偏效应估计。我们的结果还突出了决定MR何时会因GWAS协变量调整而产生偏差的参数。应用分析的结果反映了这些结果,在使用和未使用调整后GWAS的MVMR中都能看到等效结果。当GWAS结果针对协变量进行了调整从而使MR效应估计产生偏差时,通过在MVMR估计中将该协变量作为额外的暴露因素纳入,可以获得暴露因素对结局的直接效应估计。然而,从MVMR估计中获得的协变量估计效应是有偏差的。
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