title: Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.
abstract: Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Tin
authors.forename: Owen M
authors.initials: OM
authors.lastname: Woodward
authors.forename: Wen Hong Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Lu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Daniel
authors.initials: D
authors.lastname: Shriner
authors.forename: Mariam
authors.initials: M
authors.lastname: Semmo
authors.forename: Ermeg L
authors.initials: EL
authors.lastname: Akylbekova
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Wyatt
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Alan B
authors.initials: AB
authors.lastname: Zonderman
authors.forename: Adebowale A
authors.initials: AA
authors.lastname: Adeyemo
authors.forename: Cameron
authors.initials: C
authors.lastname: Palmer
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.forename: Muredach
authors.initials: M
authors.lastname: Reilly
authors.forename: Michael G
authors.initials: MG
authors.lastname: Shlipak
authors.forename: David
authors.initials: D
authors.lastname: Siscovick
authors.forename: Michele K
authors.initials: MK
authors.lastname: Evans
authors.forename: Charles N
authors.initials: CN
authors.lastname: Rotimi
authors.forename: Michael F
authors.initials: MF
authors.lastname: Flessner
authors.forename: Michael
authors.initials: M
authors.lastname: Köttgen
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006073:Gout / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014527:Uric Acid / Q000097:blood*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D014527:Uric Acid