Multi-trait Analysis of GWAS for circulating FGF23 Identifies Novel Network Interactions Between HRG-HMGB1 and Cardiac Disease in CKD.
Multi-trait Analysis of GWAS for circulating FGF23 Identifies Novel Network Interactions Between HRG-HMGB1 and Cardiac Disease in CKD.
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对循环 FGF23 的 GWAS 多特征分析确定了 HRG-HMGB1 与 CKD 心脏病之间的新型网络相互作用。
DOI：
10.1101/2024.03.04.24303051
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Robinson-Cohen,Cassianne
中科院分区：
文献类型：
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作者：
Perwad,Farzana;Akwo,ElvisA;Vartanian,Nicholas;Suva,LarrryJ;Friedman,PeterA;Robinson-Cohen,Cassianne
背景全基因组关联研究（GWAS）已经确定了许多与矿物质代谢（MM）标记相关的遗传位点，但只集中在单性状分析上。在这项研究中，我们进行了一个多性状分析的GWAS（MTAG）的MM，探索性状之间的重叠遗传结构，以确定新的遗传协会成纤维细胞生长因子23（FGF 23）。（钙、磷、FGF 23、25-羟基维生素D（25（OH）D）和甲状旁腺激素（PTH））。我们整合了来自UKBioBank GWAS的磷酸盐、25（OH）D和钙（n= 366，484）血液水平信息，以及CHARGE GWAS的PTH（n= 29，155）和FGF 23（n= 16，624）信息。然后，我们使用功能基因组学模型的互动和动态的网络，以确定新的遗传性状和循环FGF 23之间的关联。结果MTAG增加了有效的样本量为所有MM标志物的n=50,325 FGF 23。聚类后，MTAG鉴定了所有性状的独立全基因组显著SNP，包括FGF 23的62个位点。这些位点中的许多以前没有在单性状分析中报道过。通过功能基因组学，我们确定了富含组氨酸的糖蛋白（HRG）和高迁移率族蛋白1（HMGB 1）基因作为与FGF 23相关的下游经典途径的主要调节因子。HRG-HMGB 1网络的相互作用也高度富集在左心室心脏组织的一个队列的死亡hemodialystpatients.ConclusionOur研究结果突出了MTAG分析MM标记物的重要性，以提高基因组范围内的显着位点的数量FGF 23，以确定新的遗传性状。功能基因组学揭示了告知独特细胞功能的新网络，并将HRG-HMGB 1确定为CKD中FGF 23和心血管疾病的关键主调节因子。未来的研究将更深入地了解与FGF 23相关的遗传特征及其在健康和疾病中的作用。
BackgroundGenome-wide association studies (GWAS) have identified numerous genetic loci associated with mineral metabolism (MM) markers but have exclusively focused on single-trait analysis. In this study, we performed a multi-trait analysis of GWAS (MTAG) of MM, exploring overlapping genetic architecture between traits, to identify novel genetic associations for fibroblast growth factor 23 (FGF23).MethodsWe applied MTAG to genetic variants common to GWAS of 5 genetically correlated MM markers (calcium, phosphorus, FGF23, 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH)) in European-ancestry subjects. We integrated information from UKBioBank GWAS for blood levels for phosphate, 25(OH)D and calcium (n=366,484), and CHARGE GWAS for PTH (n=29,155) and FGF23 (n=16,624). We then used functional genomics to model interactive and dynamic networks to identify novel associations between genetic traits and circulating FGF23.ResultsMTAG increased the effective sample size for all MM markers to n=50,325 for FGF23. After clumping, MTAG identified independent genome-wide significant SNPs for all traits, including 62 loci for FGF23. Many of these loci have not been previously reported in single-trait analyses. Through functional genomics we identified Histidine-rich glycoprotein (HRG) and high mobility group box 1(HMGB1) genes as master regulators of downstream canonical pathways associated with FGF23. HRG-HMGB1 network interactions were also highly enriched in left ventricular heart tissue of a cohort of deceased hemodialysis patients.ConclusionOur findings highlight the importance of MTAG analysis of MM markers to boost the number of genome-wide significant loci for FGF23 to identify novel genetic traits. Functional genomics revealed novel networks that inform unique cellular functions and identified HRG-HMGB1 as key master regulators of FGF23 and cardiovascular disease in CKD. Future studies will provide a deeper understanding of genetic signatures associated with FGF23 and its role in health and disease.