{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:47:38Z","timestamp":1786135658513,"version":"build-2736575974"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","funder":[{"DOI":"10.13039\/100017618","name":"Division of Diabetes, Endocrinology, and Metabolic Diseases","doi-asserted-by":"crossref","award":["R01DK122075"],"award-info":[{"award-number":["R01DK122075"]}],"id":[{"id":"10.13039\/100017618","id-type":"DOI","asserted-by":"crossref"}]},{"name":"UCSF Gladstone Bioinformatics Core"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2025,10]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Multitrait analysis of genome-wide association study boosts the statistical power to identify novel genetic traits for fibroblast growth factor 23.<\/jats:p>\n <\/jats:list-item>\n \n A functional genomics approach aided network discovery to identify histidine-rich glycoprotein (HRG) and high-mobility group protein box 1 (HMGB1) as key regulators of cardiac disease in CKD.<\/jats:p>\n <\/jats:list-item>\n \n Integration of clinical and genetic data enhances the discovery power and is crucial for understanding the genetic underpinnings of mineral bone disorder related to CKD.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n 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 multitrait analysis of GWAS (MTAG) of mineral metabolism, exploring overlapping genetic architecture between traits to identify novel genetic associations for fibroblast growth factor 23 (FGF23).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We applied MTAG to variants common to GWAS of five genetically correlated mineral metabolism markers in participants of European ancestry. We integrated UK Biobank GWAS for blood levels for phosphate, 25-hydroxyvitamin D, and calcium (\n n<\/jats:italic>\n =366,484) and Cohorts for Heart and Aging Research in Genetic Epidemiology GWAS for parathyroid hormone (\n n<\/jats:italic>\n =29,155) and FGF23 (\n n<\/jats:italic>\n =13,716). We then used supervised and unsupervised deep machine learning to identify novel associations between genetic traits and FGF23.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n MTAG increased the effective sample size for mineral metabolism markers to\n n<\/jats:italic>\n =50,325 for FGF23. After clumping, MTAG identified independent genome-wide significant single-nucleotide polymorphisms 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 that\n DNMT3A<\/jats:italic>\n was associated with uremic toxin, 8-hydroxy-2-deoxyguanosine, a biomarker of DNA damage.\n In silico<\/jats:italic>\n gene perturbation analysis revealed that\n DNMT3A<\/jats:italic>\n is protective in patients with heart failure caused by hypertrophied or dilated cardiomyopathy.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n 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 and HMGB1 as key master regulators of FGF23 and cardiovascular disease in CKD.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000000710","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T12:00:26Z","timestamp":1744804826000},"page":"2008-2018","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":4,"title":["Network Interactions of Circulating FGF23, HRG-HMGB1, and Cardiac Disease in CKD"],"prefix":"10.1681","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7983-0127","authenticated-orcid":false,"given":"Farzana","family":"Perwad","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9572-9184","authenticated-orcid":false,"given":"Elvis A.","family":"Akwo","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arushi","family":"Singhal","sequence":"additional","affiliation":[{"name":"University of California Berkeley, Berkeley, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0324-8047","authenticated-orcid":false,"given":"Nicholas","family":"Vartanian","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-9757","authenticated-orcid":false,"given":"Larry J.","family":"Suva","sequence":"additional","affiliation":[{"name":"Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1905-1468","authenticated-orcid":false,"given":"Peter A.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4783-7046","authenticated-orcid":false,"given":"Cassianne","family":"Robinson-Cohen","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"issue":"1","key":"B1-20251121","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.kisu.2017.04.001","article-title":"KDIGO 2017 clinical practice guideline 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