A cross-tissue transcriptome-wide association study identifies WDPCP as a potential susceptibility gene for coronary atherosclerosis

IF 1.4 Q3 PERIPHERAL VASCULAR DISEASE

Atherosclerosis plus Pub Date : 2024-12-01 DOI:10.1016/j.athplu.2024.11.002

Xinyue Hu , Guanglei Chen , Xiaofang Yang , Jin Cui , Ning Zhang

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引用次数: 0

Abstract

Background

Coronary atherosclerosis (CAS) is a complex chronic inflammatory disease with significant genetic and environmental contributions. While genome-wide association studies (GWAS) have pinpointed many risk loci, over 75 % are in non-coding regions, complicating functional analysis and understanding gene-disease mechanisms.

Methods

We conducted a cross-tissue transcriptome-wide association study (TWAS) using data from the GWAS Catalog (16,041 cases, 440,307 controls) and the Genotype-Tissue Expression (GTEx) v8 eQTL dataset. Initially, we used the Unified Test for Molecular Signatures (UTMOST) for analysis, followed by validation with Functional Summary-based Imputation (FUSION) and conditional and joint (COJO) analyses. Candidate genes were further refined using Multi-marker Analysis of Genomic Annotation (MAGMA). Causal relationships were assessed through Summary Data-Based Mendelian Randomization (SMR), colocalization analysis (COLOC), and Mendelian Randomization (MR). GeneMANIA was used to identify interacting genes, and Phenome-Wide Association Study (PheWAS) was employed to enhance the results.

Results

UTMOST identified 33 susceptibility genes for CAS. Out of these, 17 met stringent criteria in both UTMOST and FUSION analyses. Combining results from UTMOST, FUSION, and MAGMA, we identified four critical candidate genes. WDPCP was the only gene to pass SMR, COLOC, and MR analyses, confirming its causal role in CAS. GeneMANIA revealed additional interacting genes, and PheWAS validated WDPCP's role as a susceptibility gene.

Conclusion

WDPCP is a potential novel susceptibility gene for CAS, influencing endothelial function, lipid metabolism, and coronary artery development. This study extends GWAS findings, highlighting WDPCP's potential as a therapeutic target and its consistent expression across different tissues. Further validation studies are warranted.

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一项跨组织转录组关联研究确定WDPCP是冠状动脉粥样硬化的潜在易感基因

背景：冠状动脉粥样硬化（CAS）是一种复杂的慢性炎症性疾病，具有重要的遗传和环境因素。虽然全基因组关联研究（GWAS）已经确定了许多风险位点，但超过75%的位点位于非编码区，这使功能分析和理解基因-疾病机制变得复杂。方法利用GWAS目录（16,041例，440,307例对照）和基因型-组织表达（GTEx） v8 eQTL数据集进行跨组织转录组关联研究（TWAS）。最初，我们使用分子特征统一测试（maximum）进行分析，然后使用基于功能摘要的Imputation （FUSION）和条件和联合（COJO）分析进行验证。候选基因进一步细化使用多标记分析基因组注释（MAGMA）。通过基于汇总数据的孟德尔随机化（SMR）、共定位分析（COLOC）和孟德尔随机化（MR）评估因果关系。利用GeneMANIA鉴定互作基因，并利用全现象关联研究（PheWAS）对结果进行强化。结果most检测到33个CAS易感基因。其中17例在极限分析和融合分析中均符合严格的标准。结合ultimate， FUSION和MAGMA的结果，我们确定了四个关键的候选基因。WDPCP是唯一通过SMR、COLOC和MR分析的基因，证实了其在CAS中的因果作用。GeneMANIA发现了其他相互作用的基因，PheWAS证实了WDPCP作为易感基因的作用。结论wdpcp是一种潜在的新型CAS易感基因，影响内皮功能、脂质代谢和冠状动脉发育。这项研究扩展了GWAS的发现，强调了WDPCP作为治疗靶点的潜力及其在不同组织中的一致表达。进一步的验证研究是必要的。

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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