TY - JOUR T1 - Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. JF - Nat Commun Y1 - 2018 A1 - Tin, Adrienne A1 - Li, Yong A1 - Brody, Jennifer A A1 - Nutile, Teresa A1 - Chu, Audrey Y A1 - Huffman, Jennifer E A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Robinson-Cohen, Cassianne A1 - Mace, Aurelien A1 - Liu, Jun A1 - Demirkan, Ayse A1 - Sorice, Rossella A1 - Sedaghat, Sanaz A1 - Swen, Melody A1 - Yu, Bing A1 - Ghasemi, Sahar A1 - Teumer, Alexanda A1 - Vollenweider, Peter A1 - Ciullo, Marina A1 - Li, Meng A1 - Uitterlinden, André G A1 - Kraaij, Robert A1 - Amin, Najaf A1 - van Rooij, Jeroen A1 - Kutalik, Zoltán A1 - Dehghan, Abbas A1 - McKnight, Barbara A1 - van Duijn, Cornelia M A1 - Morrison, Alanna A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Fox, Caroline S A1 - Woodward, Owen M A1 - Köttgen, Anna KW - Exome KW - Genetic Predisposition to Disease KW - Glucose Transport Proteins, Facilitative KW - Humans KW - Kidney Function Tests KW - Meta-Analysis as Topic KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Protein Structure, Secondary KW - Uric Acid AB -

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) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). 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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. JF - Nat Commun Y1 - 2021 A1 - Tin, Adrienne A1 - Schlosser, Pascal A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Yu, Zhi A1 - Weihs, Antoine A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Kuhns, Victoria L Halperin A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Bressler, Jan A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - Delgado, Graciela E A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Floyd, James S A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Gelber, Allan C A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Ladd-Acosta, Christine A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Lloyd-Jones, Donald M A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Völker, Uwe A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Waldenberger, Melanie A1 - Levy, Daniel A1 - Akilesh, Shreeram A1 - Woodward, Owen M A1 - Susztak, Katalin A1 - Teumer, Alexander A1 - Köttgen, Anna KW - Amino Acid Transport System y+ KW - Cohort Studies KW - CpG Islands KW - DNA Methylation KW - Epigenome KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Transport Proteins, Facilitative KW - Gout KW - Humans KW - Male KW - Uric Acid AB -

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

VL - 12 IS - 1 ER -