Novel genetic loci in adolescent-onset gout derived from whole genome sequencing of a Chinese cohort

Abstract

BackgroundGout 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.MethodsWe 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.FindingsIn 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), andFSTL5–MIR4454(rs35213808, Pmeta= 4.02 × 10-8; ORmeta= 1.49). Additionally, we found association atABCG2andSLC22A12that was driven by low frequency SNVs. Furthermore, eight uncommon SNVs and three indels in the exome were predicted to be harmful. SNVs inRCOR1were linked to heightened blood leukocyte mRNA levels. THP–1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation.InterpretationPerforming 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.