Integrative Prioritization of Causal Genes for Coronary Artery Disease.
Integrative Prioritization of Causal Genes for Coronary Artery Disease.
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DOI：
10.1161/circgen.121.003365
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Kovacic JC
中科院分区：
文献类型：
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作者：
Hao K;Ermel R;Sukhavasi K;Cheng H;Ma L;Li L;Amadori L;Koplev S;Franzén O;d'Escamard V;Chandel N;Wolhuter K;Bryce NS;Venkata VRM;Miller CL;Ruusalepp A;Schunkert H;Björkegren JLM;Kovacic JC
通过全基因组关联研究（GWAS），数百个候选基因与冠状动脉疾病（CAD）相关。然而，一直缺乏一种系统的方法来理解这些基因的因果机制，以及一种方法来优先考虑它们进行进一步的研究。这代表了为CAD患者开发新的疾病和基因特异性疗法的主要障碍。最近，已经出现了强大的整合基因组学分析（伊加）管道，通过将组织/细胞特异性基因表达数据与GWAS数据集整合来识别和优先考虑候选致病基因。我们的目标是为CAD开发一个全面的伊加管道，并提供一个因果CAD基因的优先列表。为此，我们利用了几种互补的信息学方法，将来自CAD GWAS（来自UK Biobank和CARDIoGRAMplusC 4D）的汇总统计数据与STARNET研究中9种心脏代谢组织/细胞类型的转录组和表达定量性状基因座数据整合在一起。我们确定了162个独特的候选致病CAD基因，这些基因从一种到七种疾病相关组织/细胞类型中发挥作用，包括动脉壁，血液，肝脏，骨骼肌，脂肪，泡沫细胞和巨噬细胞。当对它们的因果效应进行排序时，最佳候选的因果CAD基因是CDKN 2B（与9p21.3风险位点相关）和PHACTR 1;两者都在动脉壁中发挥因果效应。大多数候选致病基因在与CAD相关的跨组织基因调控共表达网络中有代表性，其中22/162是这些网络中的关键驱动因素。我们鉴定了候选的因果CAD基因并对其进行了优先排序，还定位了它们的因果效应组织。这些结果应该作为一种资源，并促进有针对性的研究，以确定顶级致病CAD基因的功能影响。
Hundreds of candidate genes have been associated with coronary artery disease (CAD) through genome-wide association studies (GWAS). However, a systematic way to understand the causal mechanism(s) of these genes, and a means to prioritize them for further study, has been lacking. This represents a major roadblock for developing novel disease- and gene-specific therapies for CAD patients. Recently, powerful integrative genomics analyses (IGA) pipelines have emerged to identify and prioritize candidate causal genes by integrating tissue/cell-specific gene expression data with GWAS datasets. We aimed to develop a comprehensive IGA pipeline for CAD and to provide a prioritized list of causal CAD genes. To this end, we leveraged several complimentary informatics approaches to integrate summary statistics from CAD GWAS (from UK Biobank and CARDIoGRAMplusC4D) with transcriptomic and expression quantitative trait loci data from nine cardiometabolic tissue/cell types in the STARNET study. We identified 162 unique candidate causal CAD genes, which exerted their effect from between one and up to seven disease-relevant tissues/cell types, including the arterial wall, blood, liver, skeletal muscle, adipose, foam cells and macrophages. When their causal effect was ranked, the top candidate causal CAD genes were CDKN2B (associated with the 9p21.3 risk locus) and PHACTR1; both exerting their causal effect in the arterial wall. A majority of candidate causal genes were represented in cross-tissue gene regulatory co-expression networks that are involved with CAD, with 22/162 being key drivers in those networks. We identified and prioritized candidate causal CAD genes, also localizing their tissue(s) of causal effect. These results should serve as a resource and facilitate targeted studies to identify the functional impact of top causal CAD genes.