Background Gout is a polygenetic inflammatory disease. Although hundreds of genetic variants associated with gout and serum urate levels have been identified in studies of adults, the pathogenesis of adolescent–onset gout remains unclear. To better characterize the genetic landscape of adolescent–onset gout, a whole genome sequencing study was done in a large Chinese adolescent–onset gout cohort. Methods We conducted whole genome sequencing in a discovery adolescent–onset gout cohort of 905 individuals (gout onset 12–19 years) to discover common SNVs, uncommon SNVs, and indels associated with gout. Candidate common SNVs were replicated in an early–onset gout cohort of 2834 individuals (gout onset ≤ 30 years old). Loci associated with early–onset gout (P < 5.0 × 10-8) were identified after meta–analysis with the discovery and replication cohorts. Transcriptome and epigenomic analyses, RT–qPCR and RNA–seq in human peripheral blood leukocytes, and knock–down experiments in human THP–1 macrophage cells investigated regulation and functions of candidate gene RCOR1. Findings In addition to ABCG2, a urate transporter previously linked to pediatric–onset and early–onset gout, we identified four novel loci: VPRBP (rs868933181, Pmeta = 6.27 × 10-9; ORmeta = 1.66), NKILA–MIR4532 (rs72626599, Pmeta = 6.48 × 10-9; ORmeta = 1.58), RCOR1 (rs12887440, Pmeta = 3.37 × 10-8; ORmeta = 1.48), and FSTL5–MIR4454 (rs35213808, Pmeta = 4.02 × 10-8; ORmeta = 1.49). Additionally, we found association at ABCG2 and SLC22A12 that was driven by low frequency SNVs. Furthermore, eight uncommon SNVs and three indels in the exome were predicted to be harmful. SNVs in RCOR1 were linked to heightened blood leukocyte mRNA levels. THP–1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. Interpretation Performing the first comprehensive characterization of adolescent–onset gout genomes identified risk loci of early–onset gout. Loci 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.

The authors have declared no competing interest.

The National Natural Science Foundation of China and the National Key R&D Program of China.

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This study was reviewed and approved by the ethics committee of the Affiliated Hospital of Qingdao University (QYFYKYLL923011921) and Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation (2015H023).

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Adolescent gout GWAS summary statistics and the genotype data can be made available on request to the corresponding author.