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 Ciullo, Meng 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 () and Anna Köttgen ()
Additional contact information
Adrienne Tin: Johns Hopkins Bloomberg School of Public Health
Yong Li: University of Freiburg
Jennifer A. Brody: University of Washington
Teresa Nutile: Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” - CNR
Audrey Y. Chu: National Heart, Lung, and Blood Institute
Jennifer E. Huffman: National Heart, Lung, and Blood Institute
Qiong Yang: National Heart, Lung, and Blood Institute
Ming-Huei Chen: National Heart, Lung, and Blood Institute
Cassianne Robinson-Cohen: Vanderbilt University Medical Center
Aurélien Macé: University of Lausanne
Jun Liu: Erasmus Medical Center
Ayşe Demirkan: Erasmus Medical Center
Rossella Sorice: Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” - CNR
Sanaz Sedaghat: Erasmus Medical Center
Melody Swen: Johns Hopkins Bloomberg School of Public Health
Bing Yu: UTHealth School of Public Health
Sahar Ghasemi: University Medicine Greifswald
Alexanda Teumer: University Medicine Greifswald
Peter Vollenweider: Centre Hospitalier Universitaire Vaudois (CHUV)
Marina Ciullo: Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” - CNR
Meng Li: University of Maryland School of Medicine
André G. Uitterlinden: Erasmus Medical Center
Robert Kraaij: Erasmus Medical Center
Najaf Amin: Erasmus Medical Center
Jeroen van Rooij: Erasmus Medical Center
Zoltán Kutalik: Centre Hospitalier Universitaire Vaudois (CHUV)
Abbas Dehghan: Erasmus Medical Center
Barbara McKnight: University of Washington
Cornelia M. van Duijn: Erasmus Medical Center
Alanna Morrison: UTHealth School of Public Health
Bruce M. Psaty: University of Washington
Eric Boerwinkle: UTHealth School of Public Health
Caroline S. Fox: National Heart, Lung, and Blood Institute
Owen M. Woodward: University of Maryland School of Medicine
Anna Köttgen: Johns Hopkins Bloomberg School of Public Health

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06620-4

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