Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects
| Autor: | Hyon K. Choi, Murray Cadzow, Zhiqiang Li, Hua Hu, David Markie, Tony R. Merriman, Lisa K. Stamp, Hui Guo, Tanya J Major, Amanda Phipps-Green, Yongyong Shi, Changgui Li, Matt Bixley, Wenhua Wei, Meian He, Nicola Dalbeth, Riku Takei |
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| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Male Primates congenital hereditary and neonatal diseases and abnormalities Linkage disequilibrium Abcg2 Gout Quantitative Trait Loci Glucose Transport Proteins Facilitative Genome-wide association study Hyperuricemia 030105 genetics & heredity Regulatory Sequences Nucleic Acid Polymorphism Single Nucleotide Evolution Molecular 03 medical and health sciences Quantitative Trait Heritable Species Specificity Genetics medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Genetic Predisposition to Disease Genetics (clinical) Epigenomics biology nutritional and metabolic diseases medicine.disease Neoplasm Proteins Uric Acid 030104 developmental biology biology.protein Epistasis SLC2A9 Genome-Wide Association Study |
| Zdroj: | Journal of human genetics. 66(2) |
| ISSN: | 1435-232X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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