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

By James Boocock, Megan Leask, Yukinori Okada, Asian Genetic Epidemiology Network (AGEN) Consortium, Hirotaka Matsuo, Yusuke Kawamura, Yongyong Shi, Changgui Li, David B Mount, Asim K Mandal, Weiqing Wang, Murray Cadzow, Anna L Gosling, Tanya J Major, Julia A. Horsfield, Hyon K Choi, Tayaza Fadason, Justin O’Sullivan, Eli A Stahl, Tony R Merriman

Posted 22 Aug 2019
bioRxiv DOI: 10.1101/743864 (published DOI: 10.1093/hmg/ddaa013)

Serum urate is the end-product of purine metabolism. Elevated serum urate is causal of gout and a predictor of renal disease, cardiovascular disease and other metabolic conditions. 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 ten new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new loci. By cis- and trans-eQTL colocalization analysis we identified 24 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. Trans-ancestral functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that contained putative causal SNPs (posterior probability of causality > 0.8). This systematic analysis of serum urate GWAS loci has identified candidate causal genes at 19 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.

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