Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels

Adrienne Tin, Yong Li, Jennifer A. Brody, Teresa Nutile, Audrey Y. Chu, Jennifer E. Huffman, Qiong Yang, Ming Huei Chen, Cassianne Robinson-Cohen, Aurélien Macé, Jun Liu, Ayşe Demirkan, Rossella Sorice, Sanaz Sedaghat, Melody Swen, Bing Yu, Sahar Ghasemi, Alexanda Teumer, Peter Vollenweider, Marina CiulloMeng Li, André G. Uitterlinden, Robert Kraaij, Najaf Amin, Jeroen van Rooij, Zoltán Kutalik, Abbas Dehghan, Barbara McKnight, Cornelia M. van Duijn, Alanna Morrison, Bruce M. Psaty, Eric Boerwinkle, Caroline S. Fox, Owen M. Woodward, Anna Köttgen

Research output: Contribution to journalArticlepeer-review


Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10−56) and SLC2A9 (p = 4.5 × 10−7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10−3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

Original languageEnglish
Article number4228
JournalNature Communications
Issue number1
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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