一种整合多背景的孟德尔随机化方法,用于鉴定人类组织中的风险基因。

An integrative multi-context Mendelian randomization method for identifying risk genes across human tissues.

机构信息

Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.

Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN, USA.

出版信息

Am J Hum Genet. 2024 Aug 8;111(8):1736-1749. doi: 10.1016/j.ajhg.2024.06.012. Epub 2024 Jul 24.

Abstract

Mendelian randomization (MR) provides valuable assessments of the causal effect of exposure on outcome, yet the application of conventional MR methods for mapping risk genes encounters new challenges. One of the issues is the limited availability of expression quantitative trait loci (eQTLs) as instrumental variables (IVs), hampering the estimation of sparse causal effects. Additionally, the often context- or tissue-specific eQTL effects challenge the MR assumption of consistent IV effects across eQTL and GWAS data. To address these challenges, we propose a multi-context multivariable integrative MR framework, mintMR, for mapping expression and molecular traits as joint exposures. It models the effects of molecular exposures across multiple tissues in each gene region, while simultaneously estimating across multiple gene regions. It uses eQTLs with consistent effects across more than one tissue type as IVs, improving IV consistency. A major innovation of mintMR involves employing multi-view learning methods to collectively model latent indicators of disease relevance across multiple tissues, molecular traits, and gene regions. The multi-view learning captures the major patterns of disease relevance and uses these patterns to update the estimated tissue relevance probabilities. The proposed mintMR iterates between performing a multi-tissue MR for each gene region and joint learning the disease-relevant tissue probabilities across gene regions, improving the estimation of sparse effects across genes. We apply mintMR to evaluate the causal effects of gene expression and DNA methylation for 35 complex traits using multi-tissue QTLs as IVs. The proposed mintMR controls genome-wide inflation and offers insights into disease mechanisms.

摘要

孟德尔随机化(MR)提供了对暴露对结果的因果效应的有价值的评估,然而,用于绘制风险基因的传统 MR 方法的应用面临着新的挑战。其中一个问题是作为工具变量(IVs)的表达数量性状基因座(eQTLs)的可用性有限,这阻碍了稀疏因果效应的估计。此外,eQTL 效应通常具有上下文或组织特异性,这挑战了 MR 假设即 IV 效应在 eQTL 和 GWAS 数据中是一致的。为了解决这些挑战,我们提出了一种多上下文多变量综合 MR 框架 mintMR,用于将表达和分子特征映射为联合暴露。它在每个基因区域中对多个组织中的分子暴露效应进行建模,同时在多个基因区域中进行估计。它使用在超过一种组织类型中具有一致效应的 eQTL 作为 IVs,从而提高 IV 一致性。mintMR 的一个主要创新在于采用多视图学习方法来共同对多个组织、分子特征和基因区域中的疾病相关性的潜在指标进行建模。多视图学习捕获了疾病相关性的主要模式,并使用这些模式来更新估计的组织相关性概率。所提出的 mintMR 在为每个基因区域执行多组织 MR 之间迭代,并联合学习基因区域之间的疾病相关组织概率,从而改善了基因之间的稀疏效应的估计。我们应用 mintMR 使用多组织 QTL 作为 IVs 来评估 35 种复杂特征的基因表达和 DNA 甲基化的因果效应。所提出的 mintMR 控制了全基因组膨胀,并提供了对疾病机制的深入了解。

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