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 ten 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, 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.

中文翻译：

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43个血清尿酸盐相关位点的基因组解剖为尿酸盐控制的分子机制提供了多种见解。

高血清尿酸盐是痛风的先决条件，并与代谢性疾病有关。全基因组关联研究（GWAS）报告了数十个与血清尿酸盐控制相关的基因座，但是在了解相关基因座的分子基础方面进展甚微。在这里，我们使用欧洲和东亚人群的数据进行了祖先荟萃分析，以识别出十个新的血清尿酸水平位点。全基因组共定位与顺式表达数量性状基因座（eQTL）确定了另外五个新的候选基因座。通过顺式和反式eQTL共定位分析，我们分别鉴定了34个和20个基因，其中因果eQTL变体极有可能与血清尿酸盐相关基因座共享。确定的一个新基因座是SLC22A9，它编码有机阴离子转运蛋白7（OAT7）。我们证明了OAT7是一种非常弱的尿酸盐-丁酸盐交换剂。在eQTL分析中鉴定出的新的牵连基因包括编码构成肌营养不良蛋白复合物的蛋白质的基因，肌营养不良蛋白复合物是在细胞膜上传递信号蛋白和转运蛋白的支架。MLXIP，与先前确定的MLXIPL一样，是可以通过戊糖-磷酸途径调节血清尿酸的转录因子；以及编码线粒体功能所需蛋白的MRPS7和IDH2。功能精细映射确定了六个基因座（RREB1，INHBC，HLF，UBE2Q2，SFMBT1，HNF4G）与包含推定的因果SNP的共定位eQTL。对血清尿酸GWAS基因座进行的系统分析确定了24个基因座的候选因果基因，以及一个可能与控制血清尿酸水平有关的以前未确认的基因网络，