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This study aimed to discover variants associated with early\u2010onset gout.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted whole\u2010genome sequencing in a discovery adolescent\u2010onset gout cohort of 905 individuals (gout onset 12 to 19 years) to discover common and low\u2010frequency single\u2010nucleotide variants (SNVs) associated with gout. Candidate common SNVs were genotyped in an early\u2010onset gout cohort of 2,834 individuals (gout onset \u226430 years old), and meta\u2010analysis was performed with the discovery and replication cohorts to identify loci associated with early\u2010onset gout. Transcriptome and epigenomic analyses, quantitative real\u2010time polymerase chain reaction and RNA sequencing in human peripheral blood leukocytes, and knock\u2010down experiments in human THP\u20101 macrophage cells investigated the regulation and function of candidate gene <jats:italic>RCOR1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In addition to <jats:italic>ABCG2<\/jats:italic>, a urate transporter previously linked to pediatric\u2010onset and early\u2010onset gout, we identified two novel loci (<jats:italic>P<\/jats:italic><jats:sub>meta<\/jats:sub> &lt; 5.0 \u00d7 10<jats:sup>\u22128<\/jats:sup>): rs12887440 (<jats:italic>RCOR1<\/jats:italic>) and rs35213808 (<jats:italic>FSTL5<\/jats:italic>\u2010<jats:italic>MIR4454<\/jats:italic>). Additionally, we found associations at <jats:italic>ABCG2<\/jats:italic> and <jats:italic>SLC22A12<\/jats:italic> that were driven by low\u2010frequency SNVs. SNVs in <jats:italic>RCOR1<\/jats:italic> were linked to elevated blood leukocyte messenger RNA levels. THP\u20101 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This is the first comprehensive genetic characterization of adolescent\u2010onset gout. The identified risk loci of early\u2010onset gout mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent\u2010onset gout.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42969","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T01:48:46Z","timestamp":1723168126000},"page":"107-115","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel Genetic Loci in Early\u2010Onset Gout Derived From Whole\u2010Genome Sequencing of an Adolescent Gout Cohort"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3726-6844","authenticated-orcid":false,"given":"Aichang","family":"Ji","sequence":"first","affiliation":[{"name":"Affiliated Hospital of Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sui","sequence":"additional","affiliation":[{"name":"China National Center for Bioinformation, Beijing Institute of 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