Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control. (27th January 2020)

• Record Type: Journal Article
• Authors: Boocock, James; Leask, Megan; Okada, Yukinori; Matsuo, Hirotaka; Kawamura, Yusuke; Shi, Yongyong; Li, Changgui; Mount, David B; Mandal, Asim K; Wang, Weiqing; Cadzow, Murray; Gosling, Anna L; Major, Tanya J; Horsfield, Julia A; Choi, Hyon K; Fadason, Tayaza; O'Sullivan, Justin; Stahl, Eli A; Merriman, Tony R
• Is Part Of: Human molecular genetics. Volume 29:Number 6(2020)
• Page Start: 923
• Page End: 943
• Publication Date: 2020-01-27
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddaa013
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: 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.