Refining genome-wide associated loci for serum uric acid in individuals with African ancestry.
Hum Mol Genet
; 29(3): 506-514, 2020 02 01.
Article
em En
| MEDLINE
| ID: mdl-31841133
ABSTRACT
OBJECTIVE:
Serum uric acid is the end-product of purine metabolism and at high levels is a risk factor for several human diseases including gout and cardiovascular disease. Heritability estimates range from 0.32 to 0.63. Genome-wide association studies (GWAS) provide an unbiased approach to identify loci influencing serum uric acid. Here, we performed the first GWAS for serum uric acid in continental Africans, with replication in African Americans.METHODS:
Africans (n = 4126) and African Americans (n = 5007) were genotyped on high-density GWAS arrays. Efficient mixed model association, a variance component approach, was used to perform association testing for a total of ~ 18 million autosomal genotyped and imputed variants. CAVIARBF was used to fine map significant regions.RESULTS:
We identified two genome-wide significant loci 4p16.1 (SLC2A9) and 11q13.1 (SLC22A12). At SLC2A9, the most strongly associated SNP was rs7683856 (P = 1.60 × 10-44). Conditional analysis revealed a second signal indexed by rs6838021 (P = 5.75 × 10-17). Gene expression and regulatory motif data prioritized a single-candidate causal variant for each signal. At SLC22A12, the most strongly associated SNP was rs147647315 (P = 6.65 × 10-25). Conditional analysis and functional annotation prioritized the missense variant rs147647315 (R (Arg) > H (His)) as the sole causal variant. Functional annotation of these three signals implicated processes in skeletal muscle, subcutaneous adipose tissue and the kidneys, respectively.CONCLUSIONS:
This first GWAS of serum uric acid in continental Africans identified three associations at two loci, SLC2A9 and SLC22A12. The combination of weak linkage disequilibrium in Africans and functional annotation led to the identification of candidate causal SNPs for all three signals. Each candidate causal variant implicated a different cell type. Collectively, the three associations accounted for 4.3% of the variance of serum uric acid.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácido Úrico
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Negro ou Afro-Americano
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Polimorfismo de Nucleotídeo Único
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Transportadores de Ânions Orgânicos
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Proteínas de Transporte de Cátions Orgânicos
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Hiperuricemia
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Diabetes Mellitus Tipo 2
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Proteínas Facilitadoras de Transporte de Glucose
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Angiotensina Amida
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Hum Mol Genet
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos