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

PLoS One. 2020 Apr 9;15(4):e0231336. doi: 10.1371/journal.pone.0231336. eCollection 2020.


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 (r2 = 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 (r2 = 0.06-0.32). The strength of association of SNPs with SUA concentration (negative logarithm of P-values) and the genetic distance (r2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
  • Alleles
  • Asian People / genetics*
  • Chromosomes, Human, Pair 11 / genetics
  • Cytoskeletal Proteins / genetics
  • Female
  • Gene Frequency
  • Genetic Loci
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Hyperuricemia / genetics
  • Hyperuricemia / pathology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Linkage Disequilibrium
  • Male
  • Neoplasm Proteins / genetics
  • Organic Anion Transporters / genetics*
  • Organic Cation Transport Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Republic of Korea
  • Uric Acid / blood*


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Cytoskeletal Proteins
  • FRMD8 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Organic Anion Transporters
  • Organic Cation Transport Proteins
  • SLC22A12 protein, human
  • Uric Acid

Grant support

This work was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF, https://www.nrf.re.kr/eng/index) funded by the Ministry of Education [NRF-2017R1A6A3A11031988 to S.I.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.