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Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects

Journal of Human Genetics volume 66, pages 161–169 (2021)Cite this article

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A Correction to this article was published on 08 September 2020

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Abstract

Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.

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Acknowledgements

This research has been conducted using the UK Biobank Resource under Application Number 12611. RT is funded by the University of Otago Research Grant awarded to TRM and WHW. Health Research Council NZ funded LKS, ND, TRM and WHW’s time in part (HRC 19/206). WHW is funded by Cure Kids NZ and the University of Otago and Health Research Council NZ (HRC 17/288). WHW is very grateful for the important support provided by Professor Stephen Robertson and the Clinical Genetics Group in the University of Otago, Dunedin, New Zealand.

Eurogout consortium

A. Abhishek, M. Andres, T. Crisan, N. Dalbeth, M. Doherty, L. Jacobsson, M. Janssen, T.L. Jansen, L.A. Joosten, M. Kapetanovic, F. Lioté, H. Matsuo, G. McCarthy, T. Merriman, F. Perez-Ruiz, P.L. Riches, P. Richette, P.C. Robinson, E. Roddy, B. Stiburkova, A. So, L.K. Stamp, A.K. Tausche, R. Torres-Jiminez, T. Uhlig.

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Authors and Affiliations

  1. Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Riku Takei & Wen-Hua Wei

  2. Department of Biochemistry, University of Otago, Dunedin, New Zealand

    Riku Takei, Murray Cadzow, Matt Bixley, Amanda Phipps-Green, Tanya J. Major & Tony R. Merriman

  3. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    David Markie

  4. Shandong Gout Clinical Medical Center, Qingdao, 266003, China

    Changgui Li & Yongyong Shi

  5. Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China

    Changgui Li & Yongyong Shi

  6. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Hyon K. Choi

  7. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China

    Zhiqiang Li & Yongyong Shi

  8. Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China

    Zhiqiang Li & Yongyong Shi

  9. Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, Hubei, China

    Hua Hu & Meian He

  10. Center for Biostatistics, School of Health Sciences, The University of Manchester, Manchester, UK

    Hui Guo

  11. Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand

    Lisa K. Stamp

  12. Department of Medicine, University of Auckland, Auckland, New Zealand

    Nicola Dalbeth

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  1. Riku Takei
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ND disclosures: ND has received consulting fees, speaker fees or grants from AstraZeneca, Horizon, Amgen, Selecta, Arthrosi, Dyve BioSciences, Hengrui. Abbvie, and Janssen, outside the submitted work. The other authors declare no conflict of interest.

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Takei, R., Cadzow, M., Markie, D. et al. Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects. J Hum Genet 66, 161–169 (2021). https://doi.org/10.1038/s10038-020-0821-z

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