Bellomo Tiffany R, Bone William P, Chen Brian Y, Gawronski Katerina A B, Zhang David, Park Joseph, Levin Michael, Tsao Noah, Klarin Derek, Lynch Julie, Assimes Themistocles L, Gaziano J Michael, Wilson Peter W, Cho Kelly, Vujkovic Marijana, O'Donnell Christopher J, Chang Kyong-Mi, Tsao Philip S, Rader Daniel J, Ritchie Marylyn D, Damrauer Scott M, Voight Benjamin F
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Front Genet. 2022 Feb 2;12:787545. doi: 10.3389/fgene.2021.787545. eCollection 2021.
Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the locus affects splicing in human liver tissue and induced pluripotent derived hepatocyte-like cells. These results show that joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. The signal at represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.
尽管影响不同的动脉区域，但相关的动脉粥样硬化性血管疾病——冠状动脉疾病（CAD）和外周动脉疾病（PAD）具有相似的风险因素且病理生物学过程相同。为了识别与动脉粥样硬化相关的新的多效性基因座，我们对它们共同的遗传结构以及常见风险因素的遗传结构进行了联合分析。利用来自9种已知的动脉粥样硬化（CAD、PAD）和动脉粥样硬化风险因素（体重指数、开始吸烟、2型糖尿病、低密度脂蛋白、高密度脂蛋白、总胆固醇和甘油三酯）的全基因组关联研究的汇总统计数据，我们进行了15项独立的多性状遗传关联扫描，结果发现了25个新的多效性基因座，这些基因座在各自性状方面尚未被报道为全基因组显著。与单组织eQTL的共定位在14个检测信号处鉴定出了候选因果基因。值得注意的是，PAD和LDL-C在 基因座处的信号影响人类肝脏组织和诱导多能干细胞衍生的肝细胞样细胞中的 剪接。这些结果表明，对相关动脉粥样硬化疾病性状及其风险因素进行联合分析能够识别出统一的生物学机制，这可能为治疗干预提供机会。 处的信号代表了可能的共同因果生物学机制，现有抑制剂可能能够被用于新的治疗方法。
