Network Interactions of Circulating FGF23, HRG-HMGB1, and Cardiac Disease in CKD

Background: Genome-wide association studies (GWAS) have identified numerous genetic loci associated with mineral metabolism markers but have exclusively focused on single-trait analysis. In this study, we performed a multi-trait analysis of GWAS (MTAG) of mineral metabolism, exploring overlapping genetic architecture between traits to identify novel genetic associations for fibroblast growth factor 23 (FGF23). Methods: We applied MTAG to variants common to GWAS of 5 genetically correlated mineral metabolism markers in European-ancestry participants. We integrated UK BioBank GWAS for blood levels for phosphate, 25-hydroxyvitamin D, and calcium (n=366,484) and CHARGE GWAS for parathyroid hormone (n=29,155) and FGF23 (n=13,716). We then used supervised and unsupervised deep machine learning to identify novel associations between genetic traits and FGF23. Results: MTAG increased the effective sample size for mineral metabolism 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 a functional genomics approach, we identified Histidine-rich glycoprotein ( HRG ) and high-mobility-group-box 1 ( HMGB1 ) as master regulators of downstream canonical pathways associated with circulating FGF23, and both genes were highly enriched in hypertrophied cardiac tissue of deceased hemodialysis patients. In addition, we found DNMT3A was associated with uremic toxin, 8-Hydroxy-2-deoxyguanosine, a biomarker of DNA damage. In silico gene perturbation analysis revealed DNMT3A is protective in patients with heart failure caused by hypertrophied or dilated cardiomyopathy. Conclusions: Our findings highlight the importance of MTAG analysis of mineral metabolism 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.