title: Genetic association for renal traits among participants of African ancestry reveals new loci for renal function.
abstract: Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.forename: Maija K
authors.initials: MK
authors.lastname: Garnaas
authors.forename: Adrienne
authors.initials: A
authors.lastname: Tin
authors.forename: Anna
authors.initials: A
authors.lastname: Kottgen
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Peralta
authors.forename: Ian H
authors.initials: IH
authors.lastname: de Boer
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Lu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Atkinson
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Ding
authors.forename: Michael
authors.initials: M
authors.lastname: Nalls
authors.forename: Daniel
authors.initials: D
authors.lastname: Shriner
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bibbins-Domingo
authors.forename: David
authors.initials: D
authors.lastname: Siscovick
authors.forename: Ermeg
authors.initials: E
authors.lastname: Akylbekova
authors.forename: Sharon
authors.initials: S
authors.lastname: Wyatt
authors.forename: Brad
authors.initials: B
authors.lastname: Astor
authors.forename: Josef
authors.initials: J
authors.lastname: Mychaleckjy
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Townsend
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.forename: Alan B
authors.initials: AB
authors.lastname: Zonderman
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Mosley
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Charles N
authors.initials: CN
authors.lastname: Rotimi
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
authors.forename: Michele K
authors.initials: MK
authors.lastname: Evans
authors.forename: Michael G
authors.initials: MG
authors.lastname: Shlipak
authors.forename: Holly
authors.initials: H
authors.lastname: Kramer
authors.forename: Michael F
authors.initials: MF
authors.lastname: Flessner
authors.forename: Albert W
authors.initials: AW
authors.lastname: Dreisbach
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: W Linda
authors.initials: WL
authors.lastname: Kao
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D044383:Black People / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate / Q000235:genetics*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D007668:Kidney / Q000502:physiology*; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D001741:Black or African American
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C492987:DOK6 protein, human; C505811:FNDC1 protein, human; D051657:KCNQ1 Potassium Channel; D009363:Neoplasm Proteins