Multi-trait Analysis of GWAS for circulating FGF23 Identifies Novel Network Interactions Between HRG-HMGB1 and Cardiac Disease in CKD

medRxiv - Nephrology Pub Date : 2024-03-06 DOI:10.1101/2024.03.04.24303051

Farzana Perwad, Elvis Akwo, Nicholas Vartanian, Larry J Suva, Peter Friedman, Cassiane Robinson-Cohen

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Abstract

Background: Genome-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). Methods: We 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. Results: MTAG 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. Conclusion: Our 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.

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循环 FGF23 的 GWAS 多性状分析发现了 HRG-HMGB1 与慢性肾脏病心脏病之间的新型网络交互作用

背景：全基因组关联研究（GWAS）发现了许多与矿物质代谢（MM）标记相关的遗传位点，但这些研究只侧重于单性状分析。在本研究中，我们对矿物质代谢的全基因组关联研究（GWAS）进行了多性状分析（MTAG），探索性状间重叠的遗传结构，以确定成纤维细胞生长因子 23（FGF23）的新遗传关联：我们将 MTAG 应用于欧洲血统受试者中 5 个与遗传相关的 MM 标志物（钙、磷、FGF23、25-羟基维生素 D (25(OH)D) 和甲状旁腺激素 (PTH)）的 GWAS 中常见的遗传变异。我们整合了英国生物库（UKBioBank）关于血液中磷酸盐、25（OH）D 和钙（366 484 人）水平的 GWAS 信息，以及 CHARGE 关于 PTH（29 155 人）和 FGF23（16 624 人）的 GWAS 信息。然后，我们利用功能基因组学建立了交互式动态网络模型，以确定遗传特征与循环 FGF23 之间的新关联：MTAG将所有MM标记物的有效样本量增加到FGF23的50,325个样本。经过聚类后，MTAG 发现了所有性状的独立全基因组显著 SNPs，包括 FGF23 的 62 个位点。其中许多位点以前在单性状分析中从未报道过。通过功能基因组学研究，我们发现富组氨酸糖蛋白（HRG）和高迁移率组盒 1（HMGB1）基因是与 FGF23 相关的下游典型通路的主调控因子。在一组已故血液透析患者的左心室心脏组织中，HRG-HMGB1 网络相互作用也高度富集。结论我们的研究结果突显了 MM 标记的 MTAG 分析对于增加 FGF23 的全基因组重要位点数量以鉴定新的遗传特征的重要性。功能基因组学揭示了新的网络，为独特的细胞功能提供了信息，并确定了 HRG-HMGB1 是 FGF23 和 CKD 心血管疾病的关键主调控因子。未来的研究将使人们更深入地了解与 FGF23 相关的遗传特征及其在健康和疾病中的作用。

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medRxiv - Nephrology

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