A population-specific low-frequency variant of SLC22A12 (p.W258*) explains nearby genome-wide association signals for serum uric acid concentrations among Koreans

Abstract

Prolonged hyperuricemia is a cause of gout and an independent risk factor for chronic health conditions including diabetes and chronic kidney diseases. Genome-wide association studies (GWASs) for serum uric acid (SUA) concentrations have repeatedly confirmed genetic loci including those encoding uric acid transporters such as ABCG2 and SLC9A2. However, many single nucleotide polymorphisms (SNPs) found in GWASs have been common variants with small effects and unknown functions. In addition, there is still much heritability to be explained. To identify the causative genetic variants for SUA concentrations in Korean subjects, we conducted a GWAS (1902 males) and validation study (2912 males and females) and found four genetic loci reaching genome-wide significance on chromosomes 4 (ABCG2) and 11 (FRMD8, EIF1AD and SLC22A12-NRXN2). Three loci on chromosome 11 were distributed within a distance of 1.3 megabases and they were in weak or moderate linkage disequilibrium (LD) states (r 2 = 0.02-0.68). In a subsequent association analysis on the GWAS loci of chromosome 11 using closely positioned markers derived from whole genome sequencing data, the most significant variant to be linked with the nearby GWAS signal was rs121907892 (c.774G>A, p.W258*) of the SLC22A12 gene. This variant, and each of the three GWAS SNPs, were in LD (r 2 = 0.06-0.32). The strength of association of SNPs with SUA concentration (negative logarithm of P-values) and the genetic distance (r 2 of LD) between rs121907892 and the surrounding SNPs showed a quantitative correlation. This variant has been found only in Korean and Japanese subjects and is known to lower the SUA concentration in the general population. Thus, this low-frequency variant, rs121907892, known to regulate SUA concentrations in previous studies, is responsible for the nearby GWAS signals.

A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants

“…Using a population-specific genotyping array and a population-matching imputation panel, we were able to obtain highly accurate genotypes which led to the discovery of several novel GWAS variants, especially at low AF. Finding low-frequency coding variants with large effects has recently been a concern of GWAS, and some successful cases have been reported ( 45 – 48 ). Protein-altering variants affecting certain phenotypes are crucial in understanding pathophysiology and can be directly linked to treatment ( 26 , 49 ).…”

Genetic Basis of the Epidemiological Features and Clinical Significance of Renal Hypouricemia

“…Interestingly, the same mutant URAT1 allele (W258X) was found in studies of individuals with hypouricemia in Korea and this was also the most prevalent (57%) mutant URAT1 allele in the Korean population [ 26 ]. Haplotype analysis of the W258X mutant allele was also performed in the Korean population [ 28 ], and this showed that the mutant W258X allele was associated with the same haplotype in Korea as in Japan. However, it cannot be concluded that the origin of the W258X allele is common to Japan and Korea because different sets of genetic markers were used in the studies in Japan and Korea.…”