Table 1. Genes implicated as causal via identification of missense variants with high probability of driving the urate association signal.
Genes are included if they contain a missense variant with posterior probability of association of >50% or mapping into a small credible set (≤5 SNPs).
| Gene | SNP | #SNPs in set |
SNP PP |
Consequence | CADD | DHS | Gout meta- analysis P -value (EA) |
Brief summary of literature and gene function |
|---|---|---|---|---|---|---|---|---|
| ABCG2 | rs2231142 | 4 | 0.41 | p.Gln141Lys (NP_004818.2) |
18.2 | ENCODE epithelial | 1.21E-290 | Encodes a xenobiotic and high-capacity urate membrane transporter expressed in kidney, liver and gut. Causal variants have been reported for gout susceptibility (#138900) and the Junior Jr(a-) blood group phenotype (#614490). The locus was first identified in association with serum urate through GWAS (PMID:18834626) and confirmed in many studies since. The common causal variant Q141K has been experimentally confirmed (PMID:19506252) as a partial loss of function. |
| UNC5CL | rs742493 | 4 | 0.95 | p.Arg432Gly (NP_775832.2) (within Death domain) |
21.0 | ENCODE epithelial | 2.73E-01 | Encodes for the death-domain-containing Unc-5 Family C-Terminal-Like membrane-bound protein. Suggested as a candidate gene for mucosal diseases, with a role in epithelial inflammation and immunity (PMID:22158417). Experiments using human HEK293 cells showed that UNC5CL can transduce pro-inflammatory programs via activation of NF-κB, with the 432Gly variant less potent to do so than the 432Arg one (PMID:22158417). |
| HNF1A | rs1800574 | 2 | 0.92 | p.Ala98Val (NP_000536.5) | 23.4 | 1.83E-02 | Encodes a transcription factor with strong expression in liver, guts and kidney. Rare mutations cause autosomal-dominant MODY type III (#600496). Locus found in GWAS of T2D (PMID:22325160) and blood urea nitrogen (PMID:29403010). Together with HNF4-alpha, it was first recognized as master regulator of hepatocyte and islet transcription. Knockout mice show proximal tubular dysfunction (Fanconi syndrome). HNF1A enhanced promoter activity of PDZK1, URAT1, NPT4 and OAT4 in human renal proximal tubule cell-based assays (PMID:28724612), supporting a role in the coordinated expression of components of the urate “transportosome”. | |
| HNF4A | rs1800961 | 1 | 1.00 | p.Thr139Ile (NP_000448.3) | 24.7 | ENCODE pancreas | 7.43E-03 | Encodes another nuclear receptor and transcription factor that controls expression of many genes, including HNF1A and other overlapping target genes. Rare mutations cause autosomal-dominant MODY type I (#125850) and autosomal-dominant renal Fanconi syndrome 4 (# 616026). Shown to regulate expression of SLC2A9 and other members of the urate "transportosome" in cell-based assays (PMID 25209865, PMID:30124855). The GWAS locus has been reported for multiple cardio-metabolic traits and T2D (PMID:21874001). |
| CPS1 | rs1047891 | 84 | 0.84 | p.Thr1412Asn (NP_001116105.1) | 22.1 | 5.66E-02 | Encodes mitochondrial carbamoyl phosphate synthetase I, which catalyzes the first committed step of the urea cycle by synthesizing carbamoyl phosphate from ammonia, bicarbonate, and 2 molecules of ATP. Rare mutations cause autosomal-recessive carbamoylphosphate synthetase I deficiency (#237300). In addition to hyperammonemia, this disease features increased synthesis of glutamine, a precursor of purines. Elevated uric acid excretion has been reported in patients with hyperammonemia (PMID:6771064). GWAS locus for eGFR (PMID:26831199), homocysteine (PMID:23824729), urinary glycine concentrations (PMID: 26352407). | |
| GCKR | rs1260326 | 2 | 0.67 | p.Leu446Pro (NP_001477.2) | 0.1 | ENCODE kidney | 4.09E-41 | Encodes a regulatory protein prominently expressed in the liver that inhibits glucokinase. Identified in previous GWAS of urate (PMID:23263486) and multiple other cardio-metabolic traits. The 446L protein was shown to be less activated than 446Pro by physiological concentrations of fructose-6-phosphate, leading to reduced glucokinase inhibitory ability (PMID:19643913). |
Abbreviation: PP, posterior probability; DHS, DNase-I hypersensitivity site; CADD, Combined Annotation Dependent Depletion phred score; EA, European ancestry.
Gout meta-analysis P-values were two-sided (n = 763,813). Posterior probabilities were estimated from statistical fine-mapping using the Wakefield approach (Methods).