Novel Genetic Loci in Early‐Onset Gout Derived From Whole‐Genome Sequencing of an Adolescent Gout Cohort

Objective Mechanisms underlying the adolescent‐onset and early‐onset gout are unclear. This study aimed to discover variants associated with early‐onset gout. Methods We conducted whole‐genome sequencing in a discovery adolescent‐onset gout cohort of 905 individuals (gout onset 12 to 19 years) to discover common and low‐frequency single‐nucleotide variants (SNVs) associated with gout. Candidate common SNVs were genotyped in an early‐onset gout cohort of 2,834 individuals (gout onset ≤30 years old), and meta‐analysis was performed with the discovery and replication cohorts to identify loci associated with early‐onset gout. Transcriptome and epigenomic analyses, quantitative real‐time polymerase chain reaction and RNA sequencing in human peripheral blood leukocytes, and knock‐down experiments in human THP‐1 macrophage cells investigated the regulation and function of candidate gene RCOR1 . Results In addition to ABCG2 , a urate transporter previously linked to pediatric‐onset and early‐onset gout, we identified two novel loci ( P meta < 5.0 × 10 −8 ): rs12887440 ( RCOR1 ) and rs35213808 ( FSTL5 ‐ MIR4454 ). Additionally, we found associations at ABCG2 and SLC22A12 that were driven by low‐frequency SNVs. SNVs in RCOR1 were linked to elevated blood leukocyte messenger RNA levels. THP‐1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. Conclusion This is the first comprehensive genetic characterization of adolescent‐onset gout. The identified risk loci of early‐onset gout mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent‐onset gout.