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High serum urate is a prerequisite for gout and associated with metabolic disease. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control; however, there has been little progress in understanding the molecular basis of the associated loci. Here, we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify 10 new loci for serum urate levels. Genome-wide colocalization with  cis -expression quantitative trait loci (eQTL) identified a further five new candidate loci. By  cis-  and  trans -eQTL colocalization analysis, we identified 34 and 20 genes, respectively, where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was  SLC22A9  that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane;  MLXIP  that, with the previously identified  MLXIPL , is a transcription factor that may regulate serum urate via the pentose–phosphate pathway and  MRPS7  and  IDH2  that encode proteins necessary for mitochondrial function. Functional fine mapping identified six loci ( RREB1, INHBC, HLF, UBE2Q2, SFMBT1  and  HNF4G ) with colocalized eQTL containing putative causal SNPs. This systematic analysis of serum urate GWAS loci identified candidate causal genes at 24 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control